Mutation theory of carcinogenesis. Existing theories of carcinogenesis (theories of the origin of cancer)

One of the main questions of carcinogenesis is the question of whether single cells undergo oncotransformation or whether the initial carcinogenic factor(s) affect a large number of similar cells?

The monoclonal origin of neoplasms from the clone (offspring) of one degenerated cell has been shown in the example of tumors originating from B-lymphocytes (B-cell lymphomas and plasma cell myelomas), the cells of which synthesize certain immunoglobulins, as well as in some other types of tumors. However, as the tumor progresses, subclones can develop from the initial clone of tumor cells as a result of additional ongoing genetic changes, the so-called “multiple shocks.”

According to the "tumor field" theory, a field of potentially neoplastic cells is first formed, and then, as a result of the proliferation of one or more such cells, a tumor can develop. In this case, several isolated neoplasms can arise from individual clonal precursors. This theory explains the origin of some neoplasms in the skin, epithelium of the urinary tract, liver, mammary gland and intestines. Recognition of the existence of a tumor field has practical significance, since the presence of one neoplasm in any of these organs should alert the clinician to the possibility of the presence of other similar neoplasms. For example, developing cancer in one breast increases the risk of developing cancer in the other by approximately 10 times.

To explain the mechanisms of occurrence of both the tumor monoclone and the “tumor field,” a number of interrelated concepts have currently been proposed:

Mutation theory of cancer;

Epigenetic theory of cancer;

Chromosome theory of cancer;

Cancer Stem Cell Theory;

Viral theory of cancer;

Immune theory of cancer;

Theory of chemical carcinogenesis;

Evolutionary theory of cancer.

Mutation theory of cancer

According to the mutation theory, the occurrence of malignant tumors is associated with a change (mutation) in the cell genome, and in most cases, a malignant neoplasm is of monoclonal origin, i.e. develops from one mutated germ or, more often, somatic cell. Evidence of the mutational nature of cancer is the detection of mutations in proto-oncogenes and tumor suppressor genes that cause malignant transformation of cells. The main classes of genes and their protein products that can act as oncogenes or tumor suppressor genes are presented in Table 2.

What it is? Using molecular biological methods, it was established that the DNA of normal eukaryotic cells contains sequences homologous to viral oncogenes, which are called proto-oncogenes. Proto-oncogenes are normal cellular genes. Moreover, they are involved in the regulation of the most important cellular processes - cell division, cell death, DNA repair, and their damage as a result of mutation leads to uncontrolled cell division and their increased resistance to apoptosis. They are highly evolutionarily conserved, which also confirms their important role in cell life.

Table 2. Main classes of oncogenes and tumor suppressor genes

Nature of the gene/protein	Gene/protein (examples)	Tumor localization (examples)
Growth factors		Gliomas, sarcomas
	Many tumors
Receptors		Glioblastomas, breast cancer
	Breast, ovarian, salivary gland cancer
Signal transmission		Lung, ovarian, colon and other leukemias
Activation factors		Leukemia, breast, stomach, lung cancer
Transcription factors		Neuroblastomas, glioblastomas
Block factors		Bowel cancer
Transmitters and transmission blockers		Pancreas cancer
	Leukemia, cancer of the peripheral nervous system
Cell cycle control		Breast cancer
	Various tumors
	Melanoma
	Retinoblastoma, osteosarcoma (hereditary)
		Many tumors (1/2 of all) (hereditary)
	Various tumors
Immortality	Telomerase	Various tumors
Other tumor suppressor genes		Bowel cancer (hereditary)
	Breast cancer (hereditary)
DNA repair	Repair genes	Colon cancer, xeroderma (hereditary)
	Breast cancer (hereditary)

There are several main types of mutations that lead to the transformation of a proto-oncogene into an oncogene.

· Mutation of a proto-oncogene with a change in the structure of a specific gene expression product leads to the formation of an altered protein.

Consider, for example, mutations in the tumor suppressor gene TP53, which encodes the p53 protein. p53 protein molecules can be in different conformational states (Fig. 3), performing different physiological functions.

Figure 3. Schematic representation of the different p53 conformational states (epitopes) recognized by specific antibodies. Oncogenic mutations cause an irreversible transition of the molecule into a denatured state, in which a previously inaccessible epitope opens and, conversely, some previously accessible epitopes disappear (according to: B.P. Kopnin Tumor suppressors and mutator genes (avpivnik.ru/works/new/newinf05_doc).

Under normal conditions, the p53 protein is in a latent form with weak transcriptional activity. At the same time, it binds proteins involved in DNA repair, has 3"-5" exonuclease activity and stimulates recombination and DNA repair. Under various stresses and intracellular damage, post-translational modifications of p53 can occur, in particular, phosphorylation and acetylation of certain amino acids, which determines its transition to the so-called stress conformation. Such a protein is much more stable, its amount in the cell increases sharply, and as a transcription factor, it effectively activates and/or suppresses the expression of specific target genes, resulting in cell cycle arrest and apoptosis. In addition, activation of the p53 protein leads to changes in the expression of genes of some secreted factors, as a result of which the reproduction and migration of not only damaged cells, but also surrounding cells can change. At the same time, in a stress conformation, the ability of p53 to stimulate recombination and/or DNA repair is significantly reduced. The main functions of the active p53 protein are presented in Figure 4.

In the p53 protein, the central domain (amino acids 120-290) directly recognizes and binds specific DNA sequences of regulated genes, the so-called p53-reactive elements, consisting of sequences located one after another with a general structure of the type PuPuC(A/T)(A/T) GPyPyPy (Pu - purine, Py - pyrimidine). It is in this DNA-binding domain that the majority of point mutations found in various human tumors are localized.

Nonsense mutations characteristic of tumor cells lead to a sharp change in the conformation of the p53 protein molecule, resulting in a loss or weakening of the ability to bind and activate genes with p53-reactive elements, repress other specific target genes, inhibit DNA replication and stimulate DNA repair. Moreover, since p53 forms tetrameric complexes, mutations in one allele of the TP53 gene cause inactivation of the product of the second, intact allele.

Mutations in the TP53 gene, leading to inactivation of the p53 protein, are the most universal molecular changes in various human neoplasms.

In more than half of all human tumors (50-60% of neoplasms over 50 various types) mutations of the TP53 gene are detected. Unlike other tumor suppressors, which are characterized by mutations that stop protein synthesis (deletions, formation of stop codons, reading frame shifts, mRNA splicing disorders), the vast majority (more than 90%) of TP53 mutations are nonsense mutations leading to the replacement of one from amino acids in a protein molecule to another.

Figure 4. Security functions of p53. Factors causing transcriptional activation of p53 and biological effects caused by changes in their expression.

· Another type of mutations leading to oncotransformation of cells are point mutations in the regulatory sequence of proto-oncogenes, causing an increase in their expression level.

A striking example of such mutations is the activation of proto-ocogenes of the ras and raf families. These genes are involved in cell cycle control and are central regulators of cell proliferation and survival. Point mutations of these genes in cancer-transformed cells lead to constant stimulation of cell proliferation, which promotes tumor growth and invasion and the development of metastases. Mutations in one of the ras family genes: H-ras, K-ras or N-ras are found in approximately 15% of human cancers. 30% of lung adenocarcinoma cells and 80% of pancreatic tumor cells have a mutation in the ras oncogene, which is associated with a poor prognosis of the disease. Mutations of the ras and raf genes, for example, are observed in more than 90% clinical cases human melanoma. There are 3 main forms of mutations in the raf gene: A-raf, B-raf, C-raf. The formation of B-raf mutation plays a key role in the pathogenesis of melanoma. Mutant BRAF protein constitutively activates ERK mitogen-activated protein kinases, which regulate the cell cycle. This stimulates cell proliferation. Such mutations are observed in approximately 60-70% of primary melanomas and in 40-70% of metastatic melanomas. Moreover, B-raf mutations are involved in the initiation, but not the progression, of melanomas. The V600E mutation, in which glutamate at position 600 replaces valine, is found in 80-90% of all B-raf mutations in melanoma; whereas mutations in A-raf and C-raf are rarely observed in melanoma. Mutations in the N-ras and B-raf genes also regulate the expression of integrin subunits, which leads to increased melanoma cell invasion and tumor vascularization, i.e. development of a capillary network in it.

· Transfer of a gene to an actively transcribed region of the chromosome (chromosomal aberrations).

The loss of a chromosome region containing suppressor genes leads to the development of diseases such as retinoblastoma, Wilms tumor, etc.

The functions of suppressor genes are opposite to the functions of proto-oncogenes. Suppressor genes inhibit the processes of cell division and exit from differentiation, and also regulate apoptosis. Unlike oncogenes, mutant alleles of suppressor genes are recessive. The absence of one of them, provided that the second is normal, does not lead to the removal of inhibition of tumor formation, and in some cases, inactivation of suppressor genes leads to the development of cancer.

Thus, the system of proto-oncogenes and suppressor genes forms a complex mechanism for controlling the rate of cell division, growth, differentiation and programmed death.

Currently, numerous confirmations of the mutation (genetic) theory of cancer have been obtained. However, it is known that the frequency of spontaneous mutations of individual human genes per gene is extremely low and is about 10-5, i.e. one mutation per 100 thousand genes. Total frequency dominant mutations in human populations it is 1%, recessive - 0.25% and chromosome mutations - 0.34%. The proportion of people with birth defects, which can appear at different ages, is about 11%. Moreover, for the emergence and further development of a tumor, one mutation is not enough; several different mutations are required.

In most cases, for a normal cell to completely transform into a tumor cell, about 5-10 mutations must accumulate in it. Recent studies show that tumor progression is determined not only by genetic, but also by epigenetic changes, which occur much more often than true mutations.

It turned out that it is a number of epigenetic changes that largely contribute to the destabilization of the genome and a greater likelihood of mutations in genes.

It has now been established that cancer, or malignant neoplasm, is a disease of the genetic apparatus of the cell, which is characterized by long-term chronic pathological processes, or, more simply, carcinogenesis, which develop in the body for decades. Outdated ideas about the transience of the tumor process have given way to more modern theories.

The process of transforming a normal cell into a tumor cell is caused by the accumulation of mutations caused by damage in the genome. The occurrence of these damages occurs both as a result of endogenous causes, such as replication errors, chemical instability of DNA bases and their modification under the influence of free radicals, and under the influence of external causal factors of a chemical and physical nature.

Theories of carcinogenesis

The study of the mechanisms of tumor cell transformation has a long history. Until now, many concepts have been proposed that try to explain carcinogenesis and the mechanisms of transformation of a normal cell into a cancer cell. Most of these theories are of only historical interest or are included as an integral part of the universal theory of carcinogenesis currently accepted by most pathologists - the theory of oncogenes. The oncogenic theory of carcinogenesis has made it possible to get closer to understanding why various etiological factors cause essentially one disease. It was the first unified theory of the origin of tumors, which included advances in the field of chemical, radiation and viral carcinogenesis.

The main provisions of the oncogene theory were formulated in the early 1970s. R. Huebner and G. Todaro, who suggested that the genetic apparatus of every normal cell contains genes, which, if untimely activated or impaired in function, can turn a normal cell into a cancerous one.

Over the past ten years, the oncogenic theory of carcinogenesis and cancer has acquired a modern form and can be reduced to several fundamental postulates:

• oncogenes - genes that are activated in tumors, causing increased proliferation and reproduction and suppression of cell death; oncogenes exhibit transforming properties in transfection experiments;
• non-mutated oncogenes act at key stages of the processes of proliferation, differentiation and programmed cell death, being under control signaling systems body;
• genetic damage (mutations) in oncogenes lead to the release of the cell from external regulatory influences, which underlies its uncontrolled division;
• a mutation in one oncogene is almost always compensated, so the process of malignant transformation requires combined disorders in several oncogenes.

Carcinogenesis also has another side to the problem, which concerns the mechanisms of restraining malignant transformation and is associated with the function of the so-called antioncogenes (suppressor genes), which normally have an inactivating effect on proliferation and favor the induction of apoptosis. Antioncogenes are capable of causing reversion of the malignant phenotype in transfection experiments. Almost every tumor contains mutations in antioncogenes, both in the form of deletions and micromutations, and inactivating damage to suppressor genes is much more common than activating mutations in oncogenes.

Carcinogenesis has molecular genetic changes that make up the following three main components: activating mutations in oncogenes, inactivating mutations in antioncogenes, and genetic instability.

IN in general terms Carcinogenesis is considered at the modern level as a consequence of a violation of normal cellular homeostasis, expressed in the loss of control over reproduction and in the strengthening of cell protection mechanisms from the action of apoptosis signals, that is, programmed cell death. As a result of activation of oncogenes and switching off the function of suppressor genes, a cancer cell acquires unusual properties, manifested in immortalization (immortality) and the ability to overcome the so-called replicative aging. Mutational disorders in a cancer cell concern groups of genes responsible for the control of proliferation, apoptosis, angiogenesis, adhesion, transmembrane signals, DNA repair and genome stability.

What are the stages of carcinogenesis?

Carcinogenesis, that is, the development of cancer, occurs in several stages.

Carcinogenesis of the first stage - the stage of transformation (initiation) - the process of transforming a normal cell into a tumor (cancerous) one. Transformation is the result of the interaction of a normal cell with a transforming agent (carcinogen). During stage I of carcinogenesis, irreversible damage to the genotype of a normal cell occurs, as a result of which it passes into a state predisposed to transformation (latent cell). During the initiation stage, the carcinogen or its active metabolite interacts with nucleic acids (DNA and RNA) and proteins. Damage to a cell can be genetic or epigenetic in nature. Genetic changes refer to any modifications in DNA sequences or chromosome numbers. These include damage or rearrangement of the primary DNA structure (for example, gene mutations or chromosomal aberrations), or changes in the number of gene copies or chromosome integrity.

Carcinogenesis of the second stage is the stage of activation, or promotion, the essence of which is the multiplication of the transformed cell, the formation of a clone of cancer cells and a tumor. This phase of carcinogenesis, unlike the initiation stage, is reversible, at least at the early stage of the neoplastic process. During promotion, the initiated cell acquires the phenotypic properties of a transformed cell as a result of altered gene expression (epigenetic mechanism). The appearance of a cancer cell in the body does not inevitably lead to the development of a tumor disease and death of the body. Tumor induction requires long-term and relatively continuous exposure to the promoter.

Promoters have a variety of effects on cells. They affect the state of cell membranes that have specific receptors for promoters, in particular, they activate membrane protein kinase, affect cell differentiation and block intercellular communications.

A growing tumor is not a frozen, stationary formation with unchanged properties. During the process of growth, its properties constantly change: some characteristics are lost, others appear. This evolution of tumor properties is called “tumor progression.” Progression is the third stage of tumor growth. Finally, the fourth stage is the outcome of the tumor process.

Carcinogenesis not only causes persistent changes in the cell genotype, but also has a diverse impact at the tissue, organ and organismal levels, creating in some cases conditions that promote the survival of the transformed cell, as well as the subsequent growth and progression of tumors. According to some scientists, these conditions result from profound dysfunctions in the neuroendocrine and immune systems. Some of these shifts may vary depending on the characteristics of the carcinogenic agents, which may be due, in particular, to differences in their pharmacological properties. The most common reactions to carcinogenesis, essential for the occurrence and development of a tumor, are changes in the level and ratio of biogenic amines in the central nervous system, in particular in the hypothalamus, affecting, among other things, a hormonally mediated increase in cell proliferation, as well as disturbances in carbohydrate and fat metabolism. exchange, changes in the function of various parts of the immune system.

Malignant neoplasms are not uncommon in nature: tumor-like growths of tissues (crown galls) are described in plants, animals - from invertebrates (arthropods, mollusks) and fish to birds and mammals - are affected by leukemia and various tumors.

Neoplasia is thought to be more common in domestic and captive animals than in the wild, but this is disputed as it may be a consequence of more careful veterinary supervision of captive animals.

There are interesting species-specific differences in the prevalence of malignant tumors: in humans, who have lost such protective derivatives of the body's integument as wool, and switched to eating cooked food, epithelial tumors are more common, while in animals hemoblastosis and sarcomas dominate.

Direct contagiousness has not been proven for any human neoplasm, while some animal neoplasias (Marek's disease in chickens, infectious sarcoma of the external genitalia in dogs, mammary gland cancer in mice) are contagious.

A presentation of the fundamentals of the etiology and pathogenesis of tumor growth is a necessary and important section of general oncology. Currently, thanks to advances in molecular biology, the mechanisms of carcinogenesis have been largely studied. Familiarity with its basics is an important part of the professional erudition of a doctor of any specialty.

The history of ideas concerning the causes and nature of neoplasms goes back to ancient times. A tumor is almost always “plus tissue,” which could not escape the attention of the first physicians. Even the ancient Egyptian embalmers, when making mummies, noted that in some of the dead tumors were easily removed from the body, while in others the tumors grew into the surrounding tissue and were removed only en bloc.

This is probably how macroscopic differences between benign and malignant tumors were first discovered. The latter began to be designated in ancient medicine as “cancer” - in connection with the claw-like growth into the surrounding tissue. The gradual accumulation of factual material about the causes of cancer entailed the emergence of new and modification of existing concepts of carcinogenesis.

It is interesting to note that almost all of the foundations of various previously proposed theories outlined below organically fit into the framework of the modern synthetic theory of the etiology and pathogenesis of cancer and, in principle, do not contradict each other.

Theory of embryonic dystopia

The theory of embryonic dystopia [Conheim, 1882] became the first scientific theory of tumor growth. According to her version, a malignant tumor is the result of a peculiar form of dysembryogenesis.

The body retains dystopic dormant cells of embryonic primordia, which can, under the influence of various exogenous and endogenous stimuli, transform into an active proliferating state leading to the development of a tumor.

This theory has many obvious confirmations. This is the embryo-like appearance of many neoplastic cells with a pronounced degree of their anaplasia, and the embryo-like type of biochemical anomalies (energy metabolism), and the frequent localization of cancer (for example, basal carcinoma) at the places of contact of derivatives of various embryonic rudiments and leaves.

From the standpoint of this theory it is recognized great importance not only prenatal, but also postnatal dystopias of germ cells, that is, the decisive role of the release of a group of germ cells from physiological growth-inhibiting influences, which is illustrated, for example, by the occurrence of nevi and melanomas.

An important point in the theory is that there is a need for the expression (activation) of proto-oncogenes, both in embryogenesis and during the development of cancer, which fits well into the modern theory of tumor growth.

A valuable legacy of Conheim's theory is the idea that a tumor grows only “from itself,” which subsequently served as the basis for the formation of the concept of the clonal nature of malignant tumors [Bernet, 1958].

Theory of chronic nonspecific irritation

The theory of chronic nonspecific irritation [Virchow, 1885] postulates: where cells are repeatedly damaged and regenerate, increased risk cancer. According to this theory, damaging factors can be mechanical irritation (Virchow) and currently recognized chemical and other non-mechanical agents (carcinogens).

It is fundamentally important that Virchow’s theory introduces the idea of ​​the polyetiological nature of cancer. As Virchow predicted, the role of chronic proliferative inflammatory processes as a risk factor for cancer is quite large. During inflammation, when the nucleus and cell are damaged, the expression of proto-oncogenes is stimulated.

Damage can have different consequences (cancer or hyperplasia and regeneration), depending on the genetic state of the target cells and/or the genetic changes induced in them.

Numerous evidence of Virchow's theory includes data on the epidemiology of occupational forms of cancer (cancer of the skin of the scrotum in chimney sweeps, skin of the hands in radiologists, etc.). The theory of irritation formed the basis of ideas that put the action of certain specific carcinogenic factors in first place in the etiology of neoplasia.

Currently, according to WHO estimates, 90% of cancer cases are caused by one or another external damaging factor. This fact itself testifies to the value of the ancestor of modern concepts - the theory of nonspecific irritation.

Theory of transplacental carcinogenesis

The theory of transplacental carcinogenesis, i.e. the induction of tumors in offspring as a result of the action of carcinogenic substances on their mothers during pregnancy is a generally accepted fact.

Indeed, almost all medications used in obstetric practice pass through the placenta. More than 60 compounds are known to cause a transplacental carcinogenic effect in animal experiments.

There are works based on large statistical material indicating the transnational effects of tobacco and alcohol on offspring. Thus, the children of women who smoked got sick twice as often as those of non-smokers.

Some pesticides used in agriculture act transplacentally. There is evidence of transplacental induction of tumors in children under the influence of the antiepileptic drug diphenine.

A tragic experiment was staged by life. In the United States in the 70s, more than 500 cases of vaginal cancer were registered in girls and young women (15-20 years old), whose mothers took synthetic estrogens (stilbestrop, diethyls-tilbestrop) during pregnancy. In this regard, there is an obvious need to thoroughly check all substances and drugs that a pregnant woman comes into contact with.

Field theory of tumor growth

The field theory of tumor growth [Willis, 1951] developed on the basic ideas of Virchow's theory and formally opposes the theory of monoclonal tumor growth, which has now become dominant.

The field theory is based on the position that chronic proliferative inflammatory processes, as risk factors, form a field (zone) in the organ where tumor development occurs. In this case, tumor primordia that are simultaneously located on the tumor field can coexist. different stages oncogenesis and giving rise to the multicentric development of cancer.

An explanation is now being proposed based on the fact that in tissue experiencing carcinogenic influences, “parallel (and not always simultaneous) emergence of several transformed cells is possible - sources of the emergence of several tumor clones.

Thus, each center of neoplasia within the tumor field can be represented by a separate clone with different biological potential and developmental asynchrony. The concept of the tumor field provided a theoretical explanation for the development of cancer relapses with its economical removal and leaving foci of tumor growth in the organ and justification for the expression “small cancer - large operation.”

Theory of chemical carcinogenesis

The theory of chemical carcinogenesis was also formed, as industrial society developed, in line with Virchow's concept.

The theory began to develop in 1775, when the English physician P. Pott described scrotal tumors in chimney sweeps. Development professional hygiene and industry has provided much new alarming evidence in favor of the theory of chemical carcinogenesis. But the creation of a chemical experimental model of a malignant tumor played a decisive role in recognizing the contribution of this theory to oncology.

In 1918, Japanese researchers Yamagiwa and Ishikawa developed skin cancer in mice and rabbits that had coal tar applied to their skin for several months. From this moment on, systematic research in the field of chemical carcinogenesis begins.

The grain of truth introduced by the theory of chemical carcinogenesis into the modern concept of tumor growth is that many substances, interacting with DNA, can cause somatic mutations, some of which are not lethal to cells, but provoke the activation of proto-oncogenes or the inactivation of anti-oncogenes, which causes carcinogenic effect.

Theory of physical carcinogenesis

It is based on provisions that assign an etiological role in the development of cancer to various physical influences on fabric. Historically, the earliest observations are on the role of mechanical damage in carcinogenesis (for example, skin cancer of the thumb in cutters, etc.).

The works of the outstanding Russian virologist G.Sh. were of great importance in the development of the viral oncogene theory. Zilber, who turned its infectious variant into a viral-genetic one, focusing on the integrative interaction of the tumor virus with certain parts of the genome of target cells.

Modern theory carcinogenesis can be called synthetic, since all factors put forward by various early theories as the exclusive cause of cancer can claim the role of etiological factors causing genetic damage (mutations), as a single basis for carcinogenesis.

Thus, chemical, radiation, viral, and other theories of the etiology of cancer have the right to exist as special cases of the modern concept, i.e. Malignant neoplasms are now considered as truly polyetiological diseases.

Despite the wide variety of macro- and microscopic features, ultrastructural, biochemical, immunological and genetic parameters that characterize neoplasms, the latter develop according to certain general laws of origin and growth.

Before turning to the analysis of the causes and mechanism of development of malignant neoplasms, it seems appropriate to outline the main conceptual principles of the modern oncogenic-antiocogenic theory of carcinogenesis.

Conceptual principles of the modern oncogenic-antiocogenic theory of carcinogenesis

1. At the core modern model Carcinogenesis lies in the concept of oncogenes (proto-oncogenes) and antioncogenes (suppressor genes), which became a turning point in understanding the mechanisms of cancer development.

It has been established that two classes of normal regulatory genes play a leading role in tumor formation: proto-oncogenes - activators of cell proliferation and differentiation and suppressor genes (antioncogenes) - inhibitors of these processes. Recently, a third class of cancer-associated genes has been identified, which include mutator genes.

2. The triggering and obligatory event in carcinogenesis is non-lethal damage to proto-oncogenes and suppressor genes in the form of their structural changes. The consequences of such genetic damage (mutations) are activation of oncogenes and inactivation of suppressor genes and mutator genes.

As a result of mutations, imbalances between them occur, and there is a loss of control over normal cell growth, differentiation and proliferation, which ultimately leads to malignant transformation of the cell and the development of a neoplasm.

3. A malignant clone, as such, does not arise through a single mutational event. Activation of one oncogene or, conversely, loss of function of one antioncogene is not enough to transform a normal cell into a tumor cell.

Based on mathematical modeling, it is assumed that to transform a normal cell into a tumor cell, 5 to 7 independent random mutations in at least 4-5 genes (proto-oncogenes, suppressor genes) are required, while benign tumors can develop as a result of mutation of 1-2 genes.

The condition is that both events coincide in the same cell. Only in this case does a normal cell become cancerous. In fact, when a specific tumor clone arises, a much larger number of mutational steps are required to realize the final result. Each tumor, therefore, has its own genetic portrait, which determines its properties.

4. The origin of mutant genes involved in carcinogenesis may be different. Damage to oncogenes and suppressor genes in the somatic cells of the body can be a consequence of exposure to various exogenous and endogenous factors.

In this case, they are not inherited, but determine the transformation of the very cell that acquires them. Most known cancers belong to this type. Damage affecting potential oncogenes (antioncogenes) may occur in germ cells.

In this case, they are inherited through half the set of chromosomes of one of the parents, creating the prerequisites for the development of hereditary familial forms of cancer (hereditary predisposition to cancer).

5. A cancer cell inherits its abnormality to its daughter cells through the mechanisms of genetic classical inheritance. Therefore, from the standpoint of molecular genetics, cancer is genetic disease(a disease of the cell genome!), caused by changes in proto-oncogenes (or suppressor genes).

In this regard, the often discussed issue of carcinogenesis is epidemiological. Obviously, since the tumor is a genetic disease, it is not contagious.

6. Proliferation is a necessary component of the process of carcinogenesis. It may be the result of genetic changes in the cell, or associated with other physiological or pathological processes and precede a change in the genome.

DNA replication in proliferating cells makes them more susceptible to mutations. In actively dividing cells, the probability of spontaneous mutations also increases, so proliferation can be characterized as an early stage of carcinogenesis. A non-dividing, differentiated cell does not become malignant.

7. The genetic concept of carcinogenesis implies that a population of tumor cells is the result of reproduction, starting from one cell - the ancestor of the clone, which has undergone tumor transformation. This is the meaning of the concept of monoclonal development of malignant tumors.

8. Currently, cancer carcinogenesis is understood as a staged, stepwise process, which is based on the concept of initiation, promotion and progression. According to this concept, as a result of initiation, the cell undergoes irreversible changes in its genotype, which, however, are not enough to transform it into a tumor cell.

At the promotion stage, processes occur in the cell that lead to the formation of a tumor phenotype, i.e. transformation of an initiated cell into a malignant one. Tumor progression (Foulds theory) is based on the process of increasing the malignant properties of tumor cells through the selection of appropriate clones.

The transition from one stage of carcinogenesis to another (subsequent or previous) occurs as a result of the influence of exogenous and endogenous factors, which can both promote and counteract this process.

9. Risk and anti-risk factors also play an important role in the implementation of mutations and carcinogenesis. This refers to the role of age, butt, nutrition, bad habits, heredity, socio-geographical and natural-ethnic factors.

Why does a person get cancer? What is the mechanism of its appearance, and why is it so difficult to cure? Without resolving these issues...

Why does a person get cancer? What is the mechanism of its appearance, and why is it so difficult to cure? Without resolving these issues, we will not be able to defeat this deadly disease, despite all the successes of modern medicine. The incidence of cancer is growing inexorably every year in all countries of the world. The inexorable increase in incidence is associated with factors such as the aging population, pollution environment etc. The environmental pollution section includes the so-called electromagnetic pollution, as well as an increase in the level of medical exposure of the population, including due to the increasingly widespread use of computed tomography with contrast enhancement, which I already wrote about on Snob.

Carcinogenesis (lat. Сancerogenesis; Сancer - cancer, gr. Genesis - origin, development) is a complex process of the origin and development of cancer. The tumor process belongs to the group of polyetiological diseases, that is, there is no one main reason that would contribute to the appearance and development of the tumor. The disease occurs when multiple conditions and factors are combined, and hereditary predisposition and the body’s natural resistance also play a role. In the later stages of the disease, cancer is an incurable disease.

There have been many speculations about the causes of cancer. However, there are relatively few truly scientific hypotheses built on a strict analysis of reliable facts.

In the work of the English doctor P. Pott “On cancer of the skin of the scrotum in chimney sweeps,” published back in 1775, cancer was considered as an occupational disease. While cleaning chimneys, soot rubbed into the chimney sweeps' skin and after 10-15 years they developed skin cancer. Two main factors have been identified that cause cancer development: 1) constant irritation and damage; 2) the effect of certain substances that are called carcinogens. Explaining the mechanisms of development of this form of cancer was the beginning new era in the study of the tumor process. The German scientist R. Virchow in 1853 put forward the “irritation theory”, explaining the cause of cancer in the repetition of mechanical or chemical injuries to tissues. Thus, the following factors contribute to the development of lung cancer in smokers: high temperature that occurs during smoking, chronic bronchitis, which causes active proliferation of the lung epithelium, and the presence of carcinogens in tobacco.

It is generally accepted today that smoking, alcoholism, chemicals (carcinogens), the effects of toxic products at work, chronic diseases, viruses, protozoa, fungi, deterioration ecological situation, radiation, hereditary factors contribute to the development of malignant tumors. In total, more than 1000 carcinogenic substances of exogenous (external) and endogenous (internal) nature have been described in the world. But soon after its inception, difficulties arose in Virchow's theory: irritation and carcinogenic effects did not always correlate with each other. In addition, simple irritation did not always lead to the development of cancer. For example, 3,4-benzpyrene and 1,2-benzpyrene have almost the same irritant effect, but only the first compound is carcinogenic.

The end of the 19th century was the heyday of microbiology and the emergence of virology. Many laboratories around the world were looking for the “causative agent of cancer,” and in 1911, the American doctor P. Routh managed to prove the viral nature of some chicken tumors. He obtained an extract from chicken sarcoma that did not contain any cells. Administration of the extract to healthy chickens resulted in the development of a tumor at the injection site. For these experiments P. Routh received the Nobel Prize in 1966. The virus integrates into the cellular genome, introducing additional information into the cell, causing genome disruption and disruption of cell activity. Viruses can also persist in cells for a long time, being in a latent state, and under the influence of carcinogens, physical factors, they are activated. However, using the viral theory, we cannot explain why cancer does not have signs of an infectious disease, and why close people have malignant tumors of different morphological types, for example, the wife had lip cancer, and the husband had stomach cancer.

In 1946, Soviet microbiologist L.A. Zilber formulated a viral-genetic theory of carcinogenesis, which eliminated a number of difficulties of the viral theory, in particular the phenomenon of non-contagiousness of cancer. This theory, supplemented by later ideas, became the basis of the modern concept of carcinogenesis. This concept is based on the theory of oncogene expression. Oncogenes are genes that contribute to the development of the tumor process. Oncogenes have been discovered in viruses (viral oncogenes) and in cells (cellular oncogenes). Oncogenes are structural genes that encode proteins. Normally, they are inactive and repressed, which is why they are called protoncogenes. Under certain conditions, oncogenes are activated or expressed, and oncoproteins are synthesized, which carry out the process of transforming a normal cell into a malignant one. The transformation of proto-oncogene into oncogene is one of the mechanisms of the emergence of malignant cells. However, in this case, no explanation has been found for the phenomenon of the disappearance of the tumor virus from the cancer cell.

In the thirties of the 20th century, research by the German biochemist Otto Warburg showed that the intensity of fermentation in cancer cells was 10-30 times increased. O. Warburg showed that tumor cells receive the energy they need as a result of glycolysis and consume less oxygen than normal tissues. Therefore, O. Warburg suggested that the process of degeneration of a cell into a cancerous one is caused by damage to mitochondria - the respiratory apparatus of cells. The transition to an oxygen-free method of energy, according to the theory of O. Warburg, leads to autonomous uncontrolled division of the cell: it begins to behave like an independent organism that strives to reproduce. O. Warburg's ideas were confirmed in 1953, when other researchers were able to turn normal cells into cancer cells by periodically depriving them of oxygen over a long period. Later it was found that in cancer cells, respiration occurs along with intense fermentation, that is, these cells draw energy from two, usually mutually exclusive, sources. This undermined the foundations of Warburg's cancer theory.

The theory of embryonic germs of tumor growth was proposed by the German pathologist Yu.F. Conheim, according to which in the early embryonic period a large number of cells are formed, which spread throughout the body and under unfavorable conditions (trauma, immunosuppression, prolonged mechanical irritation) can give rise to tumor growth. This theory in different periods Over time, it either aroused interest or experienced periods of oblivion. The understanding of oncogenesis as a special form of embryogenesis was facilitated by the discovery of a tumor marker - alpha-fetoprotein - a protein characteristic of embryonic and tumor cells. Conheim's theory explains well the development of dysontogenetic embryonic tumors (teratomas, dermoid tumors). However, the induction of experimental tumors by implantation of embryonic tissue has not yielded convincing results.

The work of the German scientist Hanselmann, who gave his characteristics to the tumor cell, was of great importance for the development of the doctrine of the causes of tumor growth. He believed that this body cell differs in a special way from the mother cell. Such special properties are morphologically manifested in reduced differentiation, and physiologically - in greater independence of these cells. Hanselmann designated different degrees of differentiation, along with the ability to exist independently, with the term “anaplasia.” This term has retained its meaning to this day.

Thus, all these theories have their shortcomings. We begin our presentation of involutionary theory by listing known facts.

Tumor transformation of a cell is called malignancy. General signs of malignancy:

1. The cell is capable of uncontrolled uncontrolled division and reproduction.

2. There is a violation of cell differentiation; it remains immature and young.

3. It is characterized by autonomy, independence from the controlling and regulating influences of the body. The faster the tumor grows, the less differentiated the cells are.

4. Ability to metastasize. Metastases are cells that can spread throughout the body by hematogenous, lymphogenous or other means and form foci of the tumor process.

5. A malignant cell is characterized by morphological and biochemical atypia. This means that in tumor cells the contact surface area decreases, the number of nexuses - contacts that ensure the adhesiveness of cell membranes - decreases, the composition of membrane glycoproteins changes - carbohydrate chains are shortened. The cell begins to synthesize embryonic proteins that are unusual for mature cells, and the amount of phosphotyrosine increases. All this leads to a violation of the properties of contact inhibition, and the lability of the membrane increases. Normally, cells that come into contact with each other stop dividing. In tumor cells, the lack of contact inhibition leads to uncontrolled proliferation.

Atypia of energy metabolism is manifested in the predominance of glycolysis, an ancient type of metabolism. In tumor cells, a negative Pasteur effect is observed, that is, intense anaerobic glycolysis when changing from anaerobic to aerobic conditions does not decrease, but remains (increased glycolysis in tumor cells determines their high survival under hypoxic conditions). The tumor actively absorbs nutrients. The phenomenon of substrate traps is observed, which consists in increasing the affinity of the enzyme for the substrate (glucose), in tumor cells the activity of hexokinase increases 1000 times. Tumor cells are also a protein trap, which leads to cachexia in the patient. The predominance of glycolysis causes an increase in the concentration of lactic acid in tumor cells. Characteristic acidosis, which leads to disruption of the vital activity of the cell itself (the necrosis zone is usually located in the center of the tumor). Thus, the tumor has a negative effect on the body as a whole, intoxication occurs caused by the products of metabolism and tumor decay. In addition, the tumor deprives the body of necessary nutrients and energy substrates.

Involutional changes in the human body with age occur at all levels: molecular, cellular, organ and at the level of the whole organism. An example of molecular involutionary changes is the presence of so-called telomeric counters - small sequences of nucleotides at the ends of chromosomes, which are shortened by a certain amount with each division. Therefore, the cells of a multicellular organism can divide only a limited number of times, about 50. It is short telomeres that are found in malignant cells. At the organ level, with age there is an increase in the number of stromal elements, usually there is a decrease in the size of the organ and a deterioration in its function. At the organismal level, there is a decrease in growth, visual acuity, muscle strength, reaction speed, etc., which we observe in older people.

Involution at the cellular level, especially under unfavorable conditions, for example, during hypoxia and deterioration of blood supply, can be accompanied by the appearance in cells of some signs of the simplest unicellular organisms, primarily anaerobic type of respiration. In some cases, it is possible to acquire the ability for unlimited division - then cancer occurs.

Hypoxia is considered today as a key factor in the pathogenesis of malignant neoplasms. There is experimental and clinical evidence that hypoxia of tumor cells affects their growth, enhances malignant progression, in particular metastatic potential, and also reduces sensitivity to chemotherapeutic drugs and ionizing radiation.

Unfavorable conditions for the body's cells in the form of a decrease in metabolic rate, changes in the ionic balance of the body, and a shift in the pH of the environment to the acidic side increase in older people. These factors and general involutional changes at other levels of the human body contribute to involution at the cellular level. Thus, the involutional theory of carcinogenesis answers the question of why the incidence of cancer increases with age.

Of course, there are cases of certain types of cancer in at a young age, for example, Ewing's sarcoma, lymphogranulomatosis. However, this is rather an exception to the rule, and does not exclude the general trend of increasing cancer incidence with age. Childhood cancer incidence can be explained by the fact that cases of involution in early age They also occur at other levels of the body. For example, the involution of the thymus begins already with adolescence. In addition, anemia, which causes tissue hypoxia, is also common in children.

The fact that the mechanism of malignant transformation is genetic, and the changes affect the hereditary apparatus of the cell, is beyond doubt, despite the fact that the next generations of cancer cells retain all the basic properties of the previous generation. Probably the genetic mechanism for the transition of a cell to a more primitive existence is preserved in a multicellular organism for the possibility of survival of each individual cell during the onset of unfavorable conditions for it. The main one among these unfavorable factors is hypoxia. In this case, the cell temporarily switches to an anaerobic type of nutrition. For such a transition to a more or less autonomous existence under unfavorable conditions, so-called proto-oncogenes are retained in the cell genome. After the environment improves, the cell undergoes a reverse transformation and returns to its normal state. This occurs normally with the vast majority of such transformations. However, if there is no reverse development of the cell after improvement external conditions its existence, this may be the cause of the formation of benign and malignant tumors. Oncogenes, according to this theory, should be part of the genome of protozoa and cells as normal genes encoding proteins that provide the cell with the ability of anaerobic respiration, accelerated division, and autonomous life in an unfavorable environment.

The total number of genes in the human genome is about 100,000. Among them there are about 100 true proto-oncogenes, that is, cellular genes, disruption of the normal function of which can lead to their transformation into oncogenes and tumor transformation of the cell. Conversion of a proto-oncogene into an oncogene leads to the synthesis of an oncoprotein. Under the influence of the oncoprotein, the regulation of cell growth, proliferation and differentiation is disrupted, conditions are created for accelerated DNA replication and continuous cell division.

Thus, the genetic transformation of individual cells of the body into a single-celled protozoan organism helps the individual survival of the cell, but leads to the gradual death of the macroorganism. Probably, such a mechanism for the survival of cells of multicellular organisms under conditions of hypoxia and deteriorating environmental conditions is universal in the animal and plant world and is genetically determined. In the vast majority of cases, it helps overcome long-term deterioration in living conditions. After these conditions improve, the normal structure of the cell is restored. However, the line beyond which uncontrolled division of a transformed cell occurs, which the own immune system cannot cope with, is very thin. In exceptional cases, when this line is crossed, the death of the individual occurs. However, the existence of such a mechanism provides advantages in the survival of most organisms of a certain biological species. The death of a relatively small number of organisms in which breakdowns of this mechanism occur does not affect the survival of the entire species of these organisms as a whole.

After involutive malignant transformation, the cell can usually perform its functions inherent in it before the restructuring, although not in full. For example, melanoma cells produce melanin pigment, osteogenic sarcoma cells produce bone tissue, cancer cells thyroid gland- thyroid hormones, etc. This function of malignant cells is usually pathologically altered (bone tissue is produced randomly by osteosarcoma cells), but its presence often helps in diagnosis (detection of overproduction of specific proteins and hormones) and treatment, for example, with a selective method radiation therapy radioactive iodine for thyroid cancer).

2. Autonomous, unlimited growth in the number of tumor cells, as a result of which tumors arise. The colonial mode of existence is a feature of some protozoa. For example, Volvox forms a colony as a result of incomplete reproduction. A colony is more resilient than single cells.

3. Reducing the need of malignant cells for external proliferative signals is the so-called substrate independence (anchorage-independence). While most types of normal cells are able to reproduce only if they are attached to a certain non-cellular matrix. Protozoa are able to reproduce without a substrate, in liquid nutrient media.

4. Proliferation of most tumor cells occurs in the form of asymmetric mitotic division, while normal cells are characterized by mitosis. Protozoa reproduce sexually and asexually. The most common non-sexual method is halving (amitosis).

5. In structure, tumor cells differ from normal ones in size, in the ratio of the volume of the nucleus and cytoplasm, the peripheral position of the nucleus is possible, the presence of one or more nuclei, the absence of a nucleus and nucleolus, a different set of chromosomes is possible within the same tumor. Protozoan polymorphism explained asexual reproduction. Different amounts of chromatin are the result of proliferation and detachment from the mother of several daughter cells, in which an arbitrary amount of chromatin appears. The core can be of various shapes, often displaced to the periphery.

6. The ability of tumor cells to metastasize includes the ability to break away from the general tumor mass, the ability to move and secrete proteolytic enzymes. The eviction of individual cells from colonies and the beginning of new colonies by them is a property of colonial protozoa.

8. Enhanced anaerobic glycolysis by tumor cells, even in the presence of oxygen, is their main difference from normal cells. Anaerobic glycolysis is an echo of that ancient era when there was no oxygen in the Earth's atmosphere and single-celled organisms existed due to glycolysis. Modern protozoa have still retained this property of their ancestors.

Based on the proposed involutional theory of carcinogenesis, the increase in the likelihood of tumor metastasis after its biopsy, non-radical surgery, non-radical chemotherapy or radiation therapy can be explained by the attempt of autonomous tumor cells, which have signs of protozoa, to find a safe place in the human body - in the bones, lungs, liver, brain. And the fact that after a course of radiation therapy in radiology malignant cells develop radioresistance and an increase in proliferative activity can be explained by the appearance after irradiation of new generations of tumor cells that have acquired greater resistance to ionizing radiation and increased their proliferative activity.

The main methods of treating malignant cells existing today are not effective enough, since they are aimed only at destroying tumor elements and do not take into account the conditions in which the tumor and the body exist during treatment. Chemotherapy, radiological and surgical methods of treating cancer worsen the general condition of the patient - anemia, leukopenia, intoxication with chemicals and radioactive substances (chemoradiation treatment) appear, and the patient becomes traumatized ( surgery). These are the main methods of cancer treatment that are used in clinics in all countries. Just a couple of days ago, the American Food and Drug Administration (FDA) approved the use of a completely new direction in oncology - gene therapy for patients aged 3 to 25 years suffering from acute lymphoblastic leukemia.

New directions in the improvement and treatment of oncological diseases must be sought in new methods of treatment, in the so-called adjuvant therapy, in means of physical and chemical influence that improve the general condition of the patient and worsen the conditions for the existence of the tumor.

In radiation therapy, agents that increase the sensitivity of malignant cells to ionizing radiation are called radiomodifying agents. Moreover, a number of methods for enhancing the radiosensitivity of tumors are based on the use of the oxygen effect (Medical Radiology, page 326). Due to the fact that hypoxia is considered as a key factor in the involutive development of malignant cells, it is necessary to improve various methods oxygenation of the tumor and the body as a whole. Restoring the normal state of peripheral blood and preventing anemia (as one of the factors that prevents the supply of oxygen to tissues) is another mandatory element therapy for cancer patients.

New medical treatments for cancer will no doubt continue to emerge, given new theories and experimental discoveries in this direction. But it is already clear that in the prevention and treatment of cancer it is advisable to use drugs that eliminate anemia and improve oxygenation and blood supply to the tissues of the human body. It turns out that well-known recommendations that promote health are also useful for preventing cancer. For example, physical exercise and walks in the fresh air improve oxygenation and blood supply to tissues. All kinds of ancient breathing practices are also useful, for example pranayama, hatha yoga, qigong. For people who do not know such practices, it is necessary to at least regularly perform simple breathing exercises, for example, take 10 deep breaths 3 times a day (this is the only way fresh air reaches the alveoli, which can be equated to a short walk in the fresh air). The resulting slight dizziness, the so-called “oxygen intoxication,” means that you have achieved the result - saturation of the body with oxygen.

The photo shows a cancer cell dividing.

GENERAL THEORY OF CANCER (A.E. Cherezov) - 1997

PREFACE

The fight against malignant neoplasms is not only one of the most pressing problems in medicine and biology, but also affects many aspects social life general stva. Among the causes of death in most industrialized countries, malignant neoplasms occupy 2nd - 3rd place. Every year in the world people get sick with malignant neoplasms. 6 million people have developed diseases, and in 2000 they will require treatment

10 million suffer from these diseases (Parkin et al., 1984; Muir, 1986). The dynamics of mortality from malignant tumors over two decades is also disappointing: the results of the analysis showed that the number of men dying from cancer in industrialized countries had actually increased by 40% (WHO. Cancer incidences..., 1985).

Answering the question of critics: is it worth fighting for life? which, at the cost of great effort, a doctor can bestow on a patient,“Can life be so gloomy?” the famous French oncologist J. Mathe (Mathe, 1977) answered that cancer patients ask themselves not how they will live, but whether the doctor can give them hope for life.

People need information that will be able to meet their needs, on the basis of which you can find a more effective way to treat cancer. New approach to tumor formation - this is a real opportunity to take a step forward in the treatment of cancer, to achieve the cherished goal, especially since we are talking about a new theory of cancer that changes traditional views.

What is the current understanding of the nature and mechanism of cancer in the oncogene theory? According to the authors of the monograph on the molecular basis of carcinogenesis (Kiselev et al., 1990, p. 268), “the A clear and consistent picture of the genetic processes leading a cell to tumor transformation is still missing...

The nature of these changes, the factors stimulating these changes... still remain (in most cases) a mystery... what are the specific molecular mechanisms of the transformation of a normal cell into a tumor one? The authors are forced to admit that, naturally, they cannot give a direct answer.” As we can see, the picture is not so optimistic. But, despite the uncertainty on a number of issues, most scientists believe that the formation of any tumor is based on irreversible changes in DNA oncogenes in a certain population of cells.

The essence of the concept of oncogenes (Seitz, 1990) comes down to the statement that the source of malignant growth lies in a normal cell, in its genome, but the initiating impulse comes from outside. The cause of transformation is considered to be activation under the influence of chemical, physical, biological factors of one’s own genes (proto-oncogenes), which normally control proliferation, differentiation, and maturation.

Activation of proto-oncogenes consists of a quantitative or qualitative change in them and the proteins they encode. Molecular genetic events are associated with this: gene amplification (multiplying the number of gene copies), translocation (substitution of a powerful promoter) of proto-oncogenes, point mutations, rearrangement, insertions in the nucleotide sequences of these genes.

However, sometimes experimenters and theorists do their own thing, and clinicians do their own, and there is no connection between theory and experimental data. According to a number of authors, in clinical terms, the oncogene theory does not work well or is insufficient to comprehend all the accumulated material.

This contradictory situation, when, on the one hand, the almost complete victory of the molecular genetic theory is proclaimed, and on the other hand, its weakness in practical terms, the inability to explain the clinical picture of tumor formation, is recognized, forced the author of this monograph to look for the secret of the mechanism transformation in a completely different direction, which resulted in the construction of the tissue theory of cancer (Cherezov, 1987, 1990, 1993).

To build a general theory of carcinogenesis, it was necessary to identify the “common denominator” mechanism that unifies the action of various carcinogens, eliminates the diversity of factors and leads to a single final result. As it turned out, this common denominator mechanism is not located in the cell, as previously assumed, but is associated with tissue homeostasis, its nonspecific reaction in the form of compensatory proliferation.

The established view that the mechanism of cancer is caused by an irreversible pathology of the cell genome, mutation of oncogenes, has been destroyed, and along with it the theoretical foundation of the cell has been destroyed.

basic ideas of oncology, its main dominant direction.

How can one justify the idea of ​​a new approach, tissue theory? The cornerstone of tissue theory is to address the question of the mechanism of control, proliferation and the level at which it is controlled. It is generally accepted that the cause of tumor formation is a violation of the control of proliferation. In the traditional molecular genetic approach, it is assumed that disruption of proliferation control is caused by damage to the cell genome, for example, mutations in 3-4 oncogenes or other irreversible changes in the genome. However, from the fact of violation of proliferation control, it does not necessarily and unambiguously follow that it is caused by a violation of genetic control. The fact is that proliferation in tissue is controlled by two different mechanisms: at the genetic level and at the level of tissue homeostasis. However, synchronizing and correlating mitotic activity different groups cells relative to each other at the level of genetic control of an individual cell is impossible, since regulation of the supracellular tissue system is necessary; This regulation is carried out by tissue homeostasis.

An alternative approach arises: either the mechanism of cancer is associated with a violation of genetic control, or it is caused by a violation of tissue regulation. How to prove which of the two principles of violation underlies tumor transformation? Obviously, a theory built on the basis of different principles will give different consequences, which will be confirmed or refuted by experimental data.

It is easy to see that from the theory based on disruption of tissue regulation, it follows that cell transformation should be reversible, i.e. Tumor cells, upon induction of differentiation, should normalize, losing their malignant characteristics. From the theory based on the violation of genetic control as a result of irreversible changes in oncogenes, it follows that the normalization of tumor cells is nonsense, a paradox that contradicts the theory and should not take place. From this point of view, the oncogene theory contradicts data on the normalization of cancer cells during differentiation. It is symptomatic that even obvious facts regarding the normalization of tumor cells within the framework of the oncogene theory are interpreted as phenotypic normalization, without allowing for the possibility of complete (genetic) normalization, since in this case the oncogene theory is refuted.

However, the tissue theory does not discard the oncogene theory, but includes its basic idea of ​​pathological activation

oncogenes as a cause of malignancy of a cancer cell. At the same time, this idea is modified, dissected in a tissue model, and receives a different interpretation on a different basis. The analysis revealed that the properties of tumor cells that were identified as malignant are found in normal clonogenic stem cells, therefore, when tissue control is disrupted, they determine tumor growth. It follows that these properties of stem cells are necessary, but not sufficient for the development of a tumor; the second condition for transformation is a violation of the tissue control mechanism. It becomes clear that stem cells are potentially malignant; when tissue control is disrupted, they proceed to malignant growth. To substantiate the idea of ​​a new transformation mechanism, the stages in the history of the development of concepts, cancer hypotheses, basic clinical and experimental data were analyzed, and a correlation between them and the main patterns of tumor formation was identified.

During the study of the problem, it became clear that the tissue theory meets the requirements that the general theory of carcinogenesis must satisfy.

The analysis showed that there are implicitly two directions in theoretical oncology. One of them is traditional, linking the cause of cancer with genetic damage, the other is non-traditional, remaining in the shadow of dominant concepts, based on facts that do not fit into the mainstream. This concerns facts related to tissue changes in precancer, increased proliferation, impaired differentiation, embryonicization, etc. The tissue theory of tumor formation has adopted everything rational that has been created in each of these two directions. The new model of carcinogenesis combines on a new basis modern concepts of carcinogenesis and concepts that have become classic in the history of oncology.

Checking the basic principles of the tissue model on a large clinical and experimental material showed that the new theory well explains, based on one principle, the main patterns of tumor formation, some of which have not yet had a rational interpretation. A new approach to cancer made it possible to clarify the mystery of the nature and mechanism of hormonal cancer, which had no explanation in the molecular genetic theory.

The concept of “carcinogenic profile” and the concept of “common denominator mechanism”, which are directly oriented towards clinical problems of tumor formation, logically follow from the tissue theory and are its constituent parts. Within the framework of these concepts, it was possible to concretize

to tease out the concept of a carcinogenic factor, carcinogenicity, i.e. identify a common feature, a common transforming property in various carcinogens.

The content of the concept of carcinogenicity turned out to be completely different than it was previously imagined, including not only the factor that is the carrier of carcinogenicity, but also its “intangible” temporary structure (intensity, mode of exposure), which changes the initial properties, which are often not carcinogenic in themselves. As it turned out, carcinogenicity is associated not with genotoxicity, but with the promoter effect of carcinogens. In other words, a potential carcinogenic factor becomes such only as a result of a certain structure of influence corresponding to the carcinogenic profile, which is associated with the restorative properties of tissue homeostasis. The reader will discover this and much more for the first time.

Based on the tissue theory, a new concept of the AIDS mechanism has been proposed, which solves the main problems of multiple lesions (immunodeficiency) of cells of the immune system that had no previous explanation. The new concept of AIDS allows us to identify new directions for treating this disease.

All readers of this book will be interested in following the developments of the general theory of carcinogenesis, based on the new principle of transformation.

The new theory includes other methods of fighting tumors, this is an approach to the ideal remedy, called the principle

“golden bullet”, but on a different theoretical basis, therefore the principle of the “golden bullet” is modified.

As for the form of presentation of the material, the monograph is not a review; the facts presented are more illustrative, schematic in nature, and do not pretend to cover the issues completely. The emphasis is on the logic of the relationship of data, on a systematic, more in-depth analysis of facts, concepts and the rigor of the conclusions that follow from them. It was these theoretical issues that turned out to be a weak point, one might say, an Achilles heel, on the path to further advancement of oncology and cancer treatment methods.

The integrity and completeness of the theoretical structure make it possible to identify systemic determination, absorb everything rational, and establish a correlation between the main groups of data. The logical relationship between facts creates the necessary framework, where the meaning (semantics) of an individual fact (group of facts) is determined in the context of interdependent data. Proof of certain provisions, based on systemic determination, has a number of advantages, since it allows one to evaluate which results are true and which are false, since semantics

of a specific fact can enter the semantic field of the theory only in a certain way, based on the determination of the whole.

Within the framework of tissue theory, it was possible to clarify the nature and mechanism of development of benign tumors and their difference from malignant ones, to rethink the problem of precancer, to identify the mechanism of hormonal cancer, the mechanism of viral carcinogenesis, leukemia, and to take a new approach to the problem of the tumor field , polyclonality. A rational explanation of the main problems, as well as problems that previously had no interpretation, suggests that the new theory works well in explaining clinical and experimental facts, which compares favorably with the oncogene theory.

In conclusion, I would like to express my gratitude to those people who determined the possibility of my scientific activity in the leading scientific institutions of the country: at Moscow State University, at the All-Union Biological Center of the Russian Academy of Sciences in Pushchino-on-Oka, at the Institute of Higher Nervous Activity and Neurophysiology of the Russian Academy of Sciences, at the Institute of Philosophy of the Russian Academy of Sciences and a number of other institutions.

My first scientific work was devoted to the study of changes in nuclear proteins of the liver of rats under the influence of ß-naphthol and the protective function of vitamin A. The work was carried out under the guidance of a prominent specialist in the field of vitaminology, prof. K.M. Leutsky. Part of this work was done on the basis of the Interfaculty Laboratory of Bioorganic Chemistry named after. A.I. Belozersky (building “A”) of Moscow State University under the leadership of Ph.D. chem. Sciences, Head, Department of Isotopes E.P. Senchenkova. I am grateful to everyone who helped me in this work and my further scientific growth. I was provided with great assistance in preparing the manuscript by Associate Professor, Ph.D. biol. Sciences, Faculty of Biology, Moscow State University K.L. Tarasov. The valuable advice and comments of Professor G.Kh. were also taken into account. Shingarov and senior researcher at the Laboratory of Tumor Biochemistry of the Voronezh Scientific Research Center of the Academy of Medical Sciences of the Russian Academy of Sciences, Dr. medical sciences M.A. Shlyankevich, as well as Dr. medical sciences, professor, laureate of the USSR State Prize A.B. Chakli-na. I express my deep gratitude and appreciation to them for their assistance, recommendations and reviews.

Moscow, 1997

A.E. H slices

MAIN STAGES IN THE DEVELOPMENT OF THE THEORY OF CARCINOGENESIS

The early stage of oncological views: the theory of Virchow, Conheim, Fischer-Wasels




In 1773, the Lyon Academy in France announced a competition for the most accurate definition of cancer as a disease. First place was awarded to the author of the formulation: “This disease is as difficult to define as it is to treat.” We find one of the first mentions of cancer in the famous Edwin Smith Papyrus, dating back to 2500 BC. and named after the scientist who deciphered it. The Egyptian priest-physician Imgotep, deified during his lifetime, gives the following description and instruction: “If you examine a woman and find a dense swollen tumor in her chest, and the breast is cool and there is no fever, if there is no granularity in the chest and fluid does not flow from the nipple, but when pressed, it does not change its size and the woman does not cry out in pain, then the disease with which you are called to fight has no cure” (see: Chaklin, 1990).

In the 12th century. BC e. In China, during the Yin Dynasty, ai disease was already known - this term is still used to describe cancer in China today. During the Song Dynasty (960 - 1279), the books “The Book of Treasures of Weiji” and “The Medical Directory of the House of Ren” appeared, which contain the following description: “Ai arises under the skin and goes deep into the tissues. Upon autopsy, the tumor resembles inner part karst cave, small tubercles with pointed tips, sometimes blue color, protruding like eyeballs protruding from their orbits, Their poisonous roots grow deep into the body.” Details

Cancerous tumors are described in the Ebers Papyrus, dating back to 3730-3710. BC e.

Among the ancient Hindus we first encounter the division of tumor-

differentiate between malignant and benign. In the Indian sacred books - the Vedas - we find a description of tumors, as well as an indication that they are subject to excision. The greatest contribution to the development of ancient oncology was made by Hippocrates and Abu Ibn Sina (Avicenna). In Avicenna’s classic work “The Canon of Medicine” (11th century), which was a reference book for all physicians for 600 years, the teacher of the East pointed out that it is necessary not to miss the initial stage of this disease, and if a tumor is removed, then within healthy limits fabrics. Avicenna mainly wrote about external tumors and, like Hippocrates, proposed cauterizing them with a hot iron.

We find a description of this disease in ancient sources on the territory of Rus'. Thus, among the unique manuscripts of the Ipatiev Monastery near Kostroma, a chronicle from 1287 was found, which tells about the illness of Prince Galitsky. The chronicler gives a detailed description of cancer of the lower lip.

We will return to questions about the history of the development of ideas about the nature of cancer in the pre-experimental period. Let's now move on to the current state of the problem and outline the problem. Despite significant progress associated with the development of molecular oncology, a complete and consistent picture of genetic processes in cancer is still missing. The general idea is that the formation of any tumor is based on irreversible changes in certain DNA genes in a certain population of cells. At the same time, the nature of these changes, the factors stimulating the changes, and the specificity of their action still remain a mystery (Kiselev et al., 1990).

However, there are alternative approaches - not all concepts of carcinogenesis associate the cause of transformation with genetic disorders. It should be taken into account that in the molecular genetic theory of oncogenesis, a common denominator mechanism has not yet been identified, which should explain how various carcinogenic factors are unified and ultimately lead to a common result. Existing concepts of oncogenesis do not cover all known facts, which is necessary to build a general theory. The construction of a general theory of cancer is possible along the path of integration, on a new theoretical basis of all leading concepts in which there is a rational element. The task is to select cancer concepts and highlight the grains of truth in each of them, which involves identifying logically related,

“joining” provisions that can be combined into a holistic, consistent theory.

As a result of integration on a new basis, it will be possible to establish a relationship between the level of tissue changes in precancer and the activation of oncogenes in the cell as the end result of transformation. To solve a number of issues, it is necessary to reach another level of organization, since the molecular genetic theory does not take into account tissue changes, in particular the role of tissue control of proliferation. It is based on the idea that the transformation mechanism is completely knowable at the level of the cell genome. Apparently, there is a need to criticize this postulate and move away from traditional ideas that hinder further progress in research into the mechanism of tumor formation.

The need to move to the tissue level in order to identify the mechanism of carcinogenesis can be justified as follows. Currently, the role of proliferation during carcinogenic exposure is reduced to an increase in the pool of young cells, as a result of which the probability of the necessary mutations that determine transformation increases. This does not take into account the role of cell rejuvenation from the point of view of destruction of the structure and function of tissue homeostasis, which controls cell proliferation and differentiation. However, long-term tissue rejuvenation as a result of carcinogenic exposure leads to a distortion of the tissue system for regulating proliferation; this is an alternative mechanism of transformation. Reproduction and regeneration of tissues is carried out due to the division of stem cells, which have a full set of potentially “malignant” properties, they are minimally differentiated, clonogenic, immortalized, have autonomous division (autocrine stimulation of mitosis), and they have activated oncogenes. The mitotic activity of stem cells and proliferation in general is controlled by tissue homeostasis, so when it is disrupted, these clonogenic cells proceed to uncontrolled tumor growth. This cancer mechanism, based on damage to the tissue control system, well explains the ability of tumor cells to normalize during differentiation, i.e., the phenomenon of transformation reversibility.

There are two possible approaches to constructing a general theory of cancer. Either, based on an analysis of facts, build a theory anew, as if starting from scratch, or, by analyzing the history of the formation and development of the concepts of carcinogenesis, try to identify an integral structure through their integration. It is obvious that existing concepts should not be considered as mutually exclusive, they can be in a complementary relationship. Both the first and second options should lead to the same result.

The coincidence of the results will be evidence confirming the correctness of the new concept.

Let us turn to the initial stages of the formation of theoretical oncology. At the origins of modern concepts of oncogenesis were two theories. These are the theory of irritation of R. Virchow (1867) and the theory of germinal rudiments of Conheim (Cohnheim, 1877). Based on a large clinical material, Virchow suggested the etiological significance of repeated mechanical and chemical damage for the occurrence of cancerous tumors. Virchow admitted the possibility of direct irritation as the cause of tumor growth, accelerating the processes of cell division in these areas. This position of Virchow’s teaching was subject to objections; the possibility of formative growth accelerating the influence of any stimuli was denied. However, when studying the action of sex hormones, it became clear that their influence leads to hyperplastic changes in some normal organs, for example, in the mammary glands, in the uterus, in the vagina and in the pituitary gland during pregnancy. Synthetic chemical androgens cause proliferative changes in the prostate gland, and Lacassagne's experiments (Lacassagne, 1947) showed the development of rapid hyperplasia of the mammary gland epithelium, even in males, after repeated injections of estrogenic hormones, and then the appearance of cancerous tumors of the mammary glands. It is now well known that the use of chemical stimuli, such as polycyclic hydrocarbons, causes diffuse cell proliferation.

The growth-accelerating effect of various stimuli - both exogenous and endogenous - is reliable, and its connection with tumor growth is obvious. Assessing Virchow's theory, many oncologists believe that the weak side of the idea of ​​irritation as an etiological factor in the occurrence of true tumors is the insufficient definition of the concept of irritation; it does little to help understand the tumor-producing effect attributed to it, since not all types of irritation lead to the formation of tumors. Why does this happen, i.e. the reason for the ambiguity is explained in the concept of the carcinogenic profile, which will be discussed further.

Focusing on the irritation factor, as a result of which proliferation increases, Virchow’s concept acts as a model that describes the beginning of the transformation mechanism, therefore it complements Conheim’s theory of germinal rudiments. The latter assumed that all true tumors are formed from embryonic rudiments left unused during the period of emergence and growth of the embryo. The concept of Con-game is in a certain sense close to the modern concept

stem cells. The development of a tumor, as is known, is preceded by a long period of rejuvenation and tissue embryonication due to impaired differentiation of stem cells, which, like germ cells, have enormous proliferative capacity.

From this position, Virchow's theory describes the conditions under which embryonic cells, as a result of rejuvenation, destroy the tissue structure and function of homeostasis and get out of control. Thus, these theories gave rise to two ideas that are part of the arsenal of modern concepts. These are the idea that chronic proliferation is directly related to cancer and the idea that stem cells play a role in tumorigenesis.

It remains unclear why accelerated proliferation promotes tumor formation, causing, according to the new cancer theory, stem cells to escape control. This question will be gradually revealed from different sides during the presentation of the material.

The next aspect of tumor formation is associated with the role of developing tissue anaplasia (decreased cell differentiation), which leads to the relative independence of the tumor focus. Many authors, based on experimental material, show that the possibility of reverse development of differentiated cells is doubtful; this phenomenon is much more rationally explained by underdevelopment and impaired differentiation of young cells resulting from the division of stem cells. This is evidenced by data on the ability of cancer cells to undergo differentiation, losing their malignant properties, as well as data on the loss of the ability of differentiated cells to divide.

To assess the oncological meaning, the significance of tissue rejuvenation, it is necessary to take into account those changes that occur in the system of tissue homeostasis as a result of impaired differentiation. The “sociality” of the cell, the ability to be controlled by the tissue, is, as evidence shows, the result of maturation. Various receptors appear on the cell surface that capture regulatory signals, the cell loses the ability to divide and proceeds to the production of tissue-specific proteins and the performance of tissue functions. The reverse process of rejuvenation of the cellular composition leads to cell autonomy and uncontrolled growth. The idea of ​​the role of rejuvenation (embryonication of cells) as a cause of carcinogenesis was born a long time ago, but it was not substantiated, did not receive a completed form, and therefore did not become a competing model. From the standpoint of the modern view, it appears not as an independent factor, but as additional condition strengthening mutational

process. The emerging alternative associated with this factor must still be developed and justified. So let's clarify these ideas. According to the first idea, the malignant properties of a cancer cell are the result of oncogene mutations; according to the second, transformation is caused by the embryonication of cells that destroy tissue homeostasis, which leads to uncontrolled growth of stem cells. The result in the form of uncontrolled tumor growth when tissue control is violated differs from the results of genetic control violation, which makes it possible to check which mechanism is correct. The reversibility of cell transformation as a result of inducing differentiation refutes the idea of ​​irreversible damage to the genome as a mechanism of transformation.

Let us continue to consider the concepts of cancer that have become stages in the history of oncology. The regeneration-mutation theory of B. Fisher-Wasels (1929) emphasizes the special importance of cell regeneration for oncogenesis. As a result of regeneration, young, multiplying cells appear in places where the carcinogen is exposed. According to Fischer-Wasels, regeneration is

“sensitive period” in the life of cells when transformation can occur. However, regeneration occurs only in the form of reactions to ongoing degeneration under the influence of damaging influences. This circumstance forces us to take into account a variety of factors that cause damage to cells and tissues. The very transformation of normal cells into tumor cells occurs, according to Fischer-Wasels, due to changes in metastructures, i.e. in the smallest particles of cellular and intercellular living matter. Later Fischer-Wasels (1936) put forward the series

“laws” that determine the pathogenesis of malignant tumors: the law of the latent period - the onset of action of any carcinogenic factor before the appearance of signs of a tumor; the law of the primacy of tissue damage followed by long-term regeneration; the law of formation of a tumor germ with subsequent malignancy. Assessing the Fischer-Wasels theory, we can say that it correctly focused on regeneration as a result of cell damage by carcinogens, but could not reveal the role of the proliferative reaction; the mechanism of cancer itself remained unknown.

Conheim's ideas were further developed in the teaching of Ribbert (Ribbert, 1914) about the emergence of tumor germs not only in the embryonic, but also in the independent period of life of people and animals. Ribbert borrowed from Conheim's theory his main idea about the emergence of a tumor from pre-formed tumor rudiments, but abandoned the position on the obligatory emergence of rudiments in the embryonic period

life. The rudiments can arise, according to Ribbert, due to injuries and inflammatory processes. Under the influence of the exclusion of cell groups from their anatomical and physiological connections, that “autonomy” of the rudiments arises, which ensures uncontrolled growth. He emphasized that true tumors, unlike infectious-inflammatory proliferations, grow “from themselves.” Another important point is that a group of cells must be in some isolation, in other words, must escape the influence of tissue control.

In the 60s, the polyetiological theory was considered the most widespread and agreed upon. She associated the appearance of tumors with a wide variety of harmful influences on the body - both local and general. The pathogenesis of tumor transformation is considered as a result of regenerations following repeated damage. This theory was based on the fact that various harmful influences can generate the smallest non-lethal damage in tissues, which causes compensatory repeated regenerations. However, they lead to tumor formation only in cases where the nervous or hormonal systems, which maintain normal relationships between all tissue components in the body, are simultaneously damaged, ensuring normal growth and reproduction of cells. Many oncologists assumed that tumor cell proliferation was based on changes in metabolism, protein and carbohydrate. It was already well known that when tumors are induced by various factors, dystrophic proliferations appear that are capable of inorganic growth. The next significant point is that there is a certain correspondence between the dose of carcinogenic exposure and the strength of the tumor-producing effect. According to a number of authors, this refutes the position of the virusogenetic theory that the carcinogenic effect is carried out by tumor-producing viruses alone, since in this case there would be no correlation with the dose of the carcinogen. From our point of view, the presence of a dependence of the carcinogenic effect on the dose and intervals of application of the carcinogen raises the problem of the structure or regime of carcinogenic effects as a necessary condition for transformation. The fact of the presence of such a structure, the parameters of which can be established empirically in each specific case (it is different for different tissues and carcinogens), indicates the presence of some mechanism in the tissue, i.e. the required structure of influence is a reflection of the homeostasis structure of the tissue. In other words, the structure of the carcinogenic effect necessary to induce a tumor will reflect the para-

meters of tissue homeostasis, its ability to recover after damage.

Let us note that raising the question of the presence at the tissue level of a structure that determines the regime of carcinogenic effects necessary for the development of tumor formation is a new approach to the mechanism of tumor formation. This means that the transformation mechanism is determined not by mutations in the cell, but by the tissue proliferation control system. A certain symmetry arises between the required carcinogenic profile and the properties of tissue homeostasis.

In 1923, O. Warburg (1926) discovered a high rate of formation of lactic acid by cancer cells and came to the conclusion that the ability to obtain energy due to

"lactic acid fermentation" of glucose and growth due to the energy of this process is the main biochemical characteristic of cancer cells. The primary cause of cancer, in his opinion, is the replacement of breathing with oxygen in normal cells te-la fermentation of sugar. Warburg, unfortunately, did not address the central problem - the mechanism that controls the division of normal cells and is lost in cancer. Let us cite the point of view of I.F. Seits and P.G. Knyazev (1986, p. 15), they write: “Undoubtedly, the differences in energy metabolism discovered by Warburg are important, however, being such, they are at level of the biochemical organization of the cell and are not deep enough to touch the core of the problem of cancer, uncontrolled growth... The primary cause should be sought at the level of control of gene expression, the details of which are still unknown.” This remark of the authors is of fundamental importance, however, from our point of view, based on the position about the violation of the control of proliferation, it is impossible to make an unambiguous conclusion that it is caused by a violation of genetic control.

To understand this issue and semantic ambiguity, consider the following example. Let us imagine as a diagram a system consisting of relatively autonomous subsystems, where each subsystem has its own regulatory system. We will denote regulation at the subsystem level as the first level of regulation, and at the level of the entire system as the second level of control. It is possible to synchronize the functioning of the system as a whole using a second-level control mechanism, since regulation at the subsystem level does not extend to the entire system. If this were not so, then the sub-systems would enter into a competitive relationship with each other for control over the system. If, instead of abstract systems, we consider tissue homeostasis, which controls proliferation, and instead of a subsystem, the regulation of the cell on

level of the genome, it becomes clear why the violation of the control of proliferation during tumor formation is associated in the new theory with tissue control, and not with genetic control.

One can cite as an example considerations of an evolutionary nature. There is a logic to the fact that transformation depends on the stability of tissue homeostasis. If genetic mutations determined transformation, then organisms would constantly suffer from cancer. The system of tissue homeostasis is more reliable, since it does not depend on a single event in the cell, but is based on the dynamics of the reproduction of cell populations, i.e. the integrative result of the functioning of a large collection of cells.

On the other hand, if genetic mutations accelerated the division of single-celled organisms, then genetically abnormal organisms would receive an evolutionary advantage. This raises the question of the ambiguity of the concept of cancer development due to mutation in a single cell.

Although these arguments are of a general nature, they emphasize the non-obviousness and problematic nature of the traditional approach to transformation as a result of genetic disorders due to the nonspecific influence of various carcinogenic factors, which does not fit into the idea of ​​the specificity of molecular genetic relationships. The question may arise: why are we talking about a nonspecific effect, where does this come from? It is obvious that such a large number of carcinogens, different in nature, do not have a common specific property.

From the works of Warburg it is known that glycolysis of body cells is maximum at the earliest stages of embryonic development, but gradually decreases as the embryo differentiates. A number of characteristics of a differentiated cell disappear completely during the process of dedifferentiation. Therefore, a change in breathing, from our point of view, is not the cause of cancer, but a consequence of cell rejuvenation, namely the result of a change in the composition of enzymes; this can be justified by the fact that similar changes are observed during regenerative processes.

We have touched on some aspects of the basic theory of carcinogenesis, and it is in this issue that fundamental changes need to be made. Expressing a general position on this issue, I.F. Seits and P.G. Knyazev (1986, p. 35) write: “Since the main function of neoplastic cells is their reproduction, and the material substrate of this process is nucleic acid acids, it is in this category of cell substances that one would primarily expect changes during cancer and leukemic degeneration in relation to both chemistry and metabolic transformations... One can therefore expect that the decisive changes

Discoveries in the field of elucidating the nature of neoplasms will come precisely from the study of the composition, structure and transformation of nucleic acids. This would be the logical conclusion of a long journey and the triumph of that school of thought that recognizes changes in genetic material as the primary impulse of cancerous or leukemic degeneration.”

What's wrong with these seemingly perfect conclusions? Despite the fact that the material substrate for cell reproduction is nucleic acids, this does not mean that the mechanism of control of proliferation in tissue is carried out at the level of the cell genome. The mechanism of tissue control is taken out of brackets. This question represents the alternative approach that was not visible due to the apparent unambiguity and obviousness of the traditional approach. What facts can confirm or refute the concept of impaired proliferation control? Obviously, if the violation of control is due to the breakdown of tissue homeostasis, then cancer cells should be able to normalize as a result of stimulation of differentiation. If a disturbance occurs at the genome level in the form of mutations or other irreversible changes in the genome, then the transformation must be irreversible. Data on the normalization of tumor cells during differentiation (Schwemberger, 1987) confirm the first concept, i.e. upon differentiation, cancer cells lose their malignancy and normalize, which would be impossible if the transformation was caused by irreversible changes in the genome. The second argument is that irreversible changes in the genome would lead to an irreversible block (impairment) of differentiation, since the data do not confirm this, the mechanism of transformation due to mutations is refuted.




The concept of “convergence” and “divergence” of tumor progression




The concept of “convergence” by J. Greenstein (1951) is important in understanding the mechanism of carcinogenesis (see: Seitz, Knyazev, 1986). This prominent scientist developed the idea that tumors acquire certain common biochemical properties. This refers to enzymes and other qualities of tumor cells. This direction is based on the fact that in the process of tumor formation, progressive dedifferentiation takes place

Each normal cell has a number of morphological and biochemical features that allow it to perform physiological functions in the tissue. Along with the fundamental processes of energy and growth, it is characterized by specific processes characteristic of a given tissue. Progressive dedifferentiation leads to the loss of specific enzymes; in neoplasms only enzymatic systems are preserved, providing the functions of energy supply and reproduction necessary for survival. As a result of progression, tumors become similar to each other. The author came to the conclusion that neoplasms of various origins are more similar morphologically and biochemically than each of them with its normal tissue. Data show that there is a correlation between the decrease in the activity of specific enzymes and the rate of tumor growth.

Assessing the “convergence” hypothesis, V.S. Shapot (1975) noted that the hypothesis about the unification of metabolism of tumors of different histogenesis is correct, but not completely. Vast experimental material indicates the existence of a reverse trend - the phenotype of an individual cell of a malignant tumor turns out to be unique, and the spectrum of biochemical characteristics is unique, each time including different combinations of deviations from the norm. A contradiction arises between the trends of development, assimilation and increasing diversity of properties. How can these discordant trends be reconciled? From our point of view, these contradictory directions of change can be reconciled by correlating one or another trend with the degree of progression, i.e. tumor formation phase. It is obvious that the “convergence” hypothesis is true not only for the entire transitional state of tumor formation, but for tumors that are far advanced in the direction of dedifferentiation. The same hypothesis is incorrect for the initial and intermediate phases of development, since in these states the spectrum of diversity of properties increases due to the appearance of cells that are in different phases of differentiation. The scatter of properties will be minimal when all cells are differentiated or undifferentiated. Another aspect of the increase in diversity in tumor progression is related to the fact that intermediate states of cell differentiation, in terms of the implementation of the genetic program, may correspond to other tissues, as happens during embryogenesis, when the organism “passes through” the programs of other species. This analogy explains why cells characteristic of other tissues can be found in a tumor. Thus, V.S. Shapot’s argument is valid, but relates to a different stage of tumor formation, so it does not contradict the concept of “convergence”.

Deletion hypothesis




When analyzing carcinogenesis caused by azo dyes, it was found that dimethylaminoazobenzene binds to cytoplasmic proteins of the liver. During carcinogenesis, the content of cellular protein that reacts with the dye constantly decreases until it completely disappears in the formed hepatoma. It has been suggested that growth-controlling proteins bind to the carcinogen. -The “loss” of these regulatory proteins leads to unlimited growth. Further research did not clarify the understanding of the significance of this group of proteins in chemical carcinogenesis. Thus, it was shown that during carcinogenesis of the skin of mice by polycyclic hydrocarbons, a similar process of binding and disappearance of proteins occurs. From these facts it was concluded that the combination of a carcinogen with a certain cytoplasmic protein causes an irreversible change or loss of this protein, which plays a decisive role in carcinogenesis. It was assumed that the loss of the protein relieved the inhibition of nuclear division and promoted tumor formation.

Assessing this model of carcinogenesis, I.F. Seits and P.G. Knyazev (1986) noted that it has not yet been possible to provide sufficiently convincing evidence for the “loss” hypothesis; they write:

“Carcinogens bind not only to proteins, but also to other cell components, and above all to nucleic acids, this is what you should pay attention to” (p. 39).

Unfortunately, the oncogene theory did not clarify this hypothesis, and there are reasons to disagree with the interpretation and assessment given by I.F. Seits and P.G. Knyazev.

What is the essence of the problem of protein loss, what is the mechanism of this phenomenon? Obviously, is there another way to explain the phenomenon of “falling out”? The solution to this problem is contained in the above concept of “convergence”, more precisely, in one of its aspects. The bottom line is that progressive rejuvenation, which is observed during carcinogenesis, and, accordingly, cell dedifferentiation is associated with a gradual decrease in the amount of synthesized tissue-specific proteins. As a result of dedifferentiation, the enzymatic spectrum changes towards a decrease in the number of synthesized proteins, until some of them completely disappear. This means that the decrease in the amount of protein occurs not due to binding to an exogenous factor, but due to embryonication of the tissue. Carcinogens cause increased proliferation, and this determines the progressive embryonalization of tissue, as a result of which the spectrum of synthesized proteins is distorted. Next, we will look at how this affects the mechanism of proliferation control, namely the structure of tissue homeostasis.

Epigenetic concepts

Hypotheses substantiating the leading role of epigenetic factors in neoplasia are based on the fact that inherited quasi-reversible changes can occur during differentiation without changing genetic information. For example, the epigenetic consequences of reactions of p-hydroxy-esters of amines and amides with amino acids (methionine, cysteine, tyrosine, tryptophan) in proteins and with guanine and other bases in various RNAs are considered as mechanisms of carcinogenesis. The idea that such reactions underlie the reversibility of transformation was expressed by Nobel Prize laureates F. Jacob and J. Monod (Jacob, Monod, 1961). She soon received confirmation in the form of a demonstration of the rapid epigenetic effect of methylcholanthrene in the liver of rats. Based on these reactions, it was suggested that tumors may arise as a result of potentially reversible aberrations during differentiation, which are the result of modification of transport RNAs induced by carcinogens. What caused the emergence of epigenetic concepts, what facts do they explain? The emergence of concepts that do not connect the mechanism of transformation with mutations is based on data on the normalization of tumor cells when stimulating differentiation. From this point of view, epigenetic concepts of historical

skies precede the tissue theory and are related.

In connection with the phenomenon of normalization of cancer cells, the problem of changing the foundations, the principle of the oncogene theory, arises. On the one hand, it is necessary to preserve the rational grain of the oncogene theory, on the other hand, it is necessary to change the principle of the transformation mechanism. The tissue model of carcinogenesis retains the idea of ​​activation of oncogenes, but in a different form, not due to damage to the genome or proteins, but as a result of disruption of tissue homeostasis and clonogenic cells with activated oncogenes going out of control. Thus, it is possible to separate the idea of ​​activation of oncogenes in stem cells and their escape from the control of the tissue system from the idea of ​​genomic disruption as the presumed cause of transformation.

There are a number of hypotheses that highlight such aspects as abnormal gene expression and a shift in the isozyme spectrum in tumors. S. Weinhouse (1972) (see: Seits, Knyazev, 1986) studied deviations in genetic expression manifested in isoenzyme changes using experimental hepatomas. He concluded that faulty programming of genetic information is a common phenotypic feature of cancer. This should also include the appearance of fetal proteins. He believed that genes that were active

in the embryonic state and repressed during differentiation, they are reactivated in cancer. S. Wemhouse note significant changes in experimental hepatomas of varying degrees of differentiation. With a decrease in the degree of differentiation of hepatomas, glucokinase activity practically disappears. In this group of tumors, there is an almost complete disappearance of the highly active isozyme, which plays a key physiological function in the normal liver, and significant derepression of isozymes that are weakly active in the mature liver. These data correspond to those of the embryonic liver (Khodosova, 1988).

Characteristic changes in experimental hepatomas are aldolase isoenzymes. Aldolase A is the dominant form of the enzyme in the fetal liver. Aldolase B is the only form of this enzyme in mature liver. With a decrease in the degree of differentiation, aldolase A begins to appear, and, like hexokinase isoenzymes, poorly differentiated hepatomas completely lose aldolase B, which is replaced by the highly active aldolase A isozyme.

Similar transformations occur in hepatomas with the enzyme pyruvate kinase. In slowly growing, highly differentiated hepatomas (9618 A), pyruvate kinase activity is high, but low in moderately differentiated tumors and practically absent in fast-growing, poorly differentiated ones.

How to interpret the given data? Analyzing the problem of changes in the enzymatic, protein spectrum of tumors in the process of progression, I.F. Seits and P.G. Knyazev write: “Cancer is characterized by a loss of host control over cell proliferation. “The other side of the coin” is impaired differentiation and accompanying changes in the expression of certain functionally important genes... Many attempts have been made to find a connection between the proliferative processes of tumors and their enzymatic activities, but without success. This is understandable, since a simple determination of gross enzymatic activities often does not reveal subtle and deep shifts determined by the altered molecular structure of individual isoenzyme components” (p. 43). We presented this point of view in order to compare it with the interpretation of these processes from the position of the tissue model. One may not agree that impaired differentiation is the “other side of the coin” of impaired proliferation control. From our point of view, cause and effect in the sequence of events are confused here. Does dedifferentiation precede transformation or vice versa? From our point of view, disruption of differentiation precedes transformation, since rejuvenation

tissue is also a characteristic sign of regenerative processes, which do not necessarily turn into tumor formation. When exposed to carcinogenic effects, the rejuvenation of the cellular composition at the initial stages is reversible - when the carcinogenic effect ceases, the tissue is normalized. This proves the nonspecificity of the carcinogenic effect and the nonspecificity of the initial phase of tumor formation. Regarding the connection between proliferation under carcinogenic exposure and enzymatic activities, the following model can be proposed. It is known that accelerated long-term proliferation necessarily causes rejuvenation of the cellular composition due to competition between proliferation and differentiation - cells do not have time to undergo differentiation. Since the composition of enzymes synthesized by stem and differentiated cells is different, an increase in the proportion of low-differentiated stem and committed cells in the tissue will change the enzymatic spectrum, as evidenced by the data discussed above. For example, embryonic α-fetoglobulin antigens are detected in normal tissues and can increase quantitatively not only in cancer, but also in the regenerating liver, hepatitis and cirrhosis, as well as in the “preneoplastic” liver soon after the start of feeding carcinogens (Abelev, 1971).

What is common in various carcinogenic factors? Specialists in chemical carcinogenesis believe that special

The exact carcinogenic components of various tars, soot, oils, cigarette smoke and betel nuts have not yet been revealed. From the position of molecular genetic theory, carcinogenicity is identified with genotoxicity. At present, this issue has not been completely resolved.

The difficulty in determining the carcinogenic components in the listed carcinogens is due to the fact that they can be carcinogenic mechanical damage or a factor such as implantation of a solid plate into the tissue. The mechanism of hormonal cancer also has no explanation in the oncogene theory, since hormones, according to the generally accepted point of view, are not classified as carcinogens, since they are not genotoxic factors (Dilman et al., 1989). Note that hormones cause cancer only when they are in excess and their effect is long-lasting. Obviously, the point is not in a separate component that is carcinogenic, but in the very nature of the intense, long-term functioning of the tissue, since the increased functional load on the tissue initiates accelerated proliferation, which causes cell rejuvenation. The accumulation of such cells destroys the well-functioning reproducible system of tissue homeostasis. Thus,

It can be concluded that a common carcinogenic factor is a long-term regime of increased proliferation, which destroys the tissue control system.

5. The problem of chronic proliferation as a factor of carcinogenesis in the history of oncology

In methodological terms, the idea of ​​accelerated proliferation as a factor in carcinogenesis has a number of advantages, since it allows us to explain how carcinogenic factors of different nature lead to a single result.

Compensatory proliferation is nonspecific and acts as defensive reaction from various damaging factors, this function fits well into the idea of ​​the mechanism

"common denominator". The general point of view was that the common denominator mechanism that carries out the leveling and unification of carcinogens is located in the cell and is associated with damage to oncogenes, i.e. that activation of oncogenes acts as such a mechanism. However, pathological activation of oncogenes is the end result of transformation (the mechanism of transformation itself remains unknown), and it does not reveal the mechanism of action and unification of carcinogens. This argument is strengthened if we take into account the specificity of molecular genetic processes, which does not correspond to the wide variety of carcinogenic factors. Thus, a common denominator at the individual cell level cannot be detected, which refutes the oncogene theory. This gives grounds for searching for a common denominator mechanism at the level of tissue homeostasis that controls cell proliferation. But this means that the mechanism of cancer cannot be understood at the single cell level. Since accelerated proliferation can be caused by an excess of hormones due to hormonal imbalance (mitogenic effects) or it is initiated by damage or cell death, it follows that chronic proliferation is a “bottleneck” of carcinogenesis, i.e. various carcinogens have an oncological, transforming effect by initiating compensatory proliferation. Virchow systematically developed the idea of ​​accelerated proliferation in carcinogenesis, but he was not the first to draw attention to accelerated proliferation as a causative factor in the mechanism of cancer. Similar statements dominate the pre-experimental oncology literature. This is stated in Wenzel’s monograph (Wenzel, 1815), and in many medical manuals published both at the beginning of the 19th century and in the 18th century. (see: Salyamon, 1974).

Van Swieten (1700-1772) associated the cause of stomach cancer with chronic inflammation. This was also the opinion of his teacher Burgaw (1668-1738) (Bamberger, 1855) (see: Wolff, 1907). Later, doctors argued that nonspecific tissue damage could lead to tumor formation. Analyzing this issue, L.S. Salyamon (1974, p. 10) writes: “The position about the connection between inflammation and cancer arose not as a theoretical guess, but as an empirical generalization. Dozens of generations of doctors have observed with their own eyes and felt with their own hands tumors localized in previously inflamed tissue.” But what is the mechanism of the connection between chronic proliferation and transformation, neither then nor now could it be discovered: the problem of precancer and the role of chronic proliferation remained undisclosed in the molecular genetic theory.

What prevented the development of the idea of ​​nonspecific irritation? Contrary to the findings, tumors sometimes did not arise in animals exposed to “stimulants.” Tumors did not appear either in the experiments of Ganau (1889), who applied coal tar to the scrotum of rats, or in the subsequent experiments of Kazen (1894) (see: Shabad, 1947).

What is the reason for a number of failures in the induction of experimental cancer?

From the perspective of the tissue model, the structure, or profile, of the carcinogenic effect on the tissue is of fundamental importance: strength, duration of exposure, intervals between exposures. This is precisely the reason for the first failures in inducing tumors. The same carcinogen under different modes of exposure has different effects, including non-tumor effects. The apparent triviality of nonspecific irritation hides the secret of the true mechanism of cancer. Many scientists, however, based on unsuccessful experiments, abandoned this idea for many years, which essentially destroys mutation and molecular genetic theory. On the other hand, on the basis of clinical data, the greatest physicians in the history of medicine came to the idea of ​​nonspecific irritation.

Refuting Virchow’s theory, L.S. Salyamon (1974, p. 15) writes: “In the 40s, experimental oncology already had facts that contradicted this theory. If Virchow's concept were true, then any chronic tissue damage should cause tumors. However, this does not happen... it was not possible to obtain tumors by lubricating the skin of mice with acetone, benzene, xylene, toluene, turpentine, mustard oil, etc. or by introducing silk thread, infusor soil, crushed glass, shar-lahrot and dozens of other irritants under the skin of animals... The need arose

the ability to find a specific mechanism of action of carcinogens, different from the nonspecific action of banal irritants.”

With this approach, a contradiction arises with other types of facts indicating the nonspecific nature of many carcinogenic factors. For example, with the help of chronic trauma to the skin, tumor formation can be caused: friction of harness in pack and draft animals causes cancer in the areas of friction. Mohammedans who shave their heads with poorly sharpened razors and this constantly injure the scalp develop cancer in these places (Labard, 1979). In India, in the state of Kashmir, during the winter cold, local residents tie a wicker cloth called kangri to their stomachs for warmth, and place pots of hot coals in it. This type of exposure causes kangri cancer. The same cancer is known among the Japanese, who wore capro stoves filled with hot coals. Chronic burns to the abdomen led to the development of skin cancer. “Sari” cancer (India) occurs from wearing coarse woolen fabric, as a result of prolonged skin irritation. It is important to highlight a general feature of carcinogenesis - the nature of the irritating factor does not matter; the determining qualities of carcinogens are the level of tissue injury and duration of action, which correlates with the nature of proliferation. The fact that cancer can be caused by various carcinogenic factors proves its non-specific nature. From this point of view, the solution to the mystery of cancer lies in the mechanism of the common denominator. What is carcinogenicity as a property in various factors of carcinogenesis? In the oncogene theory, the concept of carcinogenicity remained unexplored, since not all carcinogenic factors are genotoxic. If this Chemical substance, then the role of mechanical friction, trauma or, for example, implantation of a solid plate into tissue, etc., is not clear. These carcinogenic factors cannot be combined on the basis of any common feature. The nonspecificity of the cancer mechanism follows from the fact that a huge number of carcinogens of different nature can cause cancer.

In theoretical terms, if we turn to the beginning of experimental oncology, a contradiction arose between the conclusion made by the classics of medicine, based on clinical experience, and the conclusion made by representatives of the young developing experimental oncology, based on negative results on the induction of tumors by various carcinogenic agents. factors. Unfortunately, the conclusion of the experimenters, obtained on the basis of negative results, turned out to be more convincing.

Let us turn to the origins of modern concepts of cancer.

With the advent of genetics, the search for clues to the mechanism of cancer is moving in a new direction. Isn't tumor transformation a consequence of mutations? The effect of ionizing rays began to be associated not with an “irritating” effect, but with mutagenic activity. From this period, the history of oncology is divided into two stages - the pregenetic period and the genetic period. The pinnacle of the genetic trend was the molecular genetic theory of the oncogene.

However, not all oncologists followed this leading trend linking cancer to mutations. Thus, biologist L. Heilbrun (1957, p. 212) notes that “... in modern books devoted to cancer, the question of the connection between cancer and damage and irritation is pushed into the background by many new facts, perhaps more minor.” And oncologist I. Berenblum (1961, p. 79) exclaims: “I have always been surprised that the idea of ​​​​the carcinogenic effect of simple “irritation” is considered to have long been rejected.” Even the facts obtained by the most experienced scientists were accepted with great distrust. However, many years of experience of H.H. Petrova and H.A. Krotkina (1928, 1944) showed that malignant tumors of the gallbladder can be caused in guinea pigs by prolonged irritation with a foreign body.

Stereotypes of perception associated with the refusal to consider nonspecific irritations as carcinogenic factors prevented the identification of the true mechanism of cancer.

How can one move from a “trivial” irritation to a tumor effect? Please note that in the given example of experiments with guinea pigs, the authors indicate the need for long-term exposure. We have approached a new, unexplored problem - the “structure” of carcinogenic effects, on which the proliferation regime depends. We are talking about the structure of the impact, i.e. carcinogenic profile. Obviously, the concept of a carcinogenic factor includes, in addition to physical embodiment, for example in the form of a substance, radiation, mechanical impact, virus, etc., another component that seems intangible, but is easy to detect experimentally: this is time , frequency and strength of impact. This component of the characteristics of carcinogenic effects determines the dynamics of the impact and, accordingly, the proliferation regime, therefore the degree of tissue embryonication depends on it.

In a paradoxical form, the reality of the phenomenon of a carcinogenic profile can be expressed in the statement that a carcinogen without a carcinogenic profile (or with an insufficiently high profile) is not a carcinogen. Conversely, a non-carcinogenic hormone turns into a true carcinogen if it creates or induces a carcinogenic profile. Thus, we put forward

We consider the concept of a carcinogenic profile, which takes into account the dynamics of exposure and the ability to restore tissue homeostasis, i.e. takes into account the relationship between the properties of tissue homeostasis, its ability to restore itself and the dynamic parameters of carcinogenic effects. Having abandoned nonspecific factors, the search for the causes of cancer falls into a logical trap - the problem arises of how such a large number of factors of different nature cause the same effect. This contradiction can be resolved under one condition, if we assume that there is a mechanism of a common denominator, which at the input levels the diversity of carcinogens. Revealing such a mechanism will mean revealing the mystery of cancer.

Activation of oncogenes as a result of transformation is not suitable for this role, since the common denominator mechanism is at the input of the tumor formation process, and activation of oncogenes, as the oncogene theory suggests, is the final result. Assessing the oncogene theory, F.L. Kiselev et al. (1990, p. 315) write: “What are the specific molecular mechanisms of transformation of a normal cell into a tumor cell? The authors are forced to admit that, naturally, they cannot give a direct answer... molecular oncology arose as a science after 1980. It follows that for such a short time of its existence, it could not resolve the main question... what is the mechanism for controlling the regulation of cell division... However, it can probably be argued that cancer is a disease of the genetic apparatus of the cell, i.e. consolidation of gene changes in a certain population of cells.”

Already from the first steps in the development of ideas about the nature of tumor formation, it became clear that this problem affects the fundamental principles of living systems and therefore it is impossible to hope to obtain a quick answer purely empirically, without analyzing the essence of transformation. According to N.N. Petrov (1959), true tumors are closely related to the very essence of life in multicellular organisms. Another prominent Soviet scientist, I.V. Davydovsky (1959, 1961), expressed the idea that “the predominantly practical direction of medical science contributed to the identification of many etiological factors causing malignant growth, but greatly inhibited knowledge of the biological essence of the latter.” The biological essence, as I.V. Davydovsky pointed out, with the extreme diversity of causal factors must be uniform, which implies the need for a general biological approach to the study of cancer problems.

It seemed that it would be possible to proceed in theoretical constructions directly from the factual material that provides clinical experience. In this case, tissue changes would

whether in the spotlight. But, unfortunately, this did not happen, and the rich clinical material concerning precancerous conditions remained away from the genetic approach. To a certain extent, this is due to the stages of development of theoretical oncology. The search for the mechanism of cancer at the cellular, then at the molecular genetic level is determined by the stages of development of biology itself. Theoretical oncology seemed to repeat these stages, refracting them through the prism of its problems. The birth of molecular biology naturally gave rise to molecular oncology. The basic postulate that the mechanism of cancer is realized at the cellular level received additional reinforcement when oncogenes were discovered. However, despite the widespread recognition of the molecular genetic theory, the transformation mechanism itself is taken from the previous mutation concept; from this point of view, it is not a fundamentally new theory. The old, criticized mutational concept of cancer in the form of the oncogene theory has received a modern molecular genetic form. Obviously, a differentiated assessment of the oncogene theory is necessary: ​​destroying the idea of ​​a transformation mechanism based on genetic irreversible changes, it is necessary to preserve the idea of ​​activation of oncogenes in its alternative version associated with a violation of tissue homeostasis, which controls the division of stem cells, having activated oncogenes and a cancerous phenotype. In other words, cells with activated oncogenes, which are not repressed due to the blocking of differentiation, go out of control. To repress the activation of oncogenes, it is necessary to induce differentiation. Consequently, the activation of oncogenes directly depends on the degree of differentiation and disruption of tissue control.

6. N.N. Petrov’s views on the nature and mechanism of tumor formation

Turning to the works of the leading oncologist Nikolai Nikolaevich Petrov (1876 - 1964), it should be noted that they are a stage in the development of oncological thought, therefore it is necessary to comprehend them from the perspective of today. Let us analyze the main provisions of this teaching. Regarding the definition of the concept of a tumor, N.N. Petrov (1947, p. 2) wrote: “At present, we firmly stand in the position of recognizing as true tumors only those processes that are based on cell reproduction... a tumor is this is a local increase in volume that occurs

occurring as a result of cell multiplication... this concept includes only such cases of an increase in volume depending on cell multiplication, when the multiplying cells turn out to be atypical, i.e. differ from the corresponding normal ones by their incomplete differentiation and polymorphism.”

The question of the mechanism of cell embryonication during tumor and regeneration processes is of fundamental importance. According to N.N. Petrov, the disruption of differentiation is explained not by the fact that a mature cell begins to develop in the opposite direction, but by the fact that young cells do not go through the differentiation stage. The same point of view is defended by D.S. Sarkisov (1977).

However, N.N. Petrov was a supporter of the mutation theory, explaining his position, he wrote: “We find no reason to

seem to be based on the mutation theory of malignant growth, since it explains to us more clearly than other theories the appearance in the body of new cell breeds with special properties, morphology and function, which are then transmitted to the direct descendants of these cells in an unlimited number of generations” (p. 425).

However, the main question arises: did N.N. Petrov, in his research, come across facts that did not fit into the mutation hypothesis? This question is of fundamental importance. Analyzing the nature of tumor formation, he wrote: “But true mutations always arise suddenly, and malignant growth often occurs gradually, passing through the stage of transitional “precancerous changes”; Is it possible to talk about malignant mutations under such conditions? Doesn't this mean admitting the possibility of a whole series of successive mutations directed in a certain direction, which would contradict the very essence of the doctrine of mutations? No, that doesn't mean it. Mutations are irreversible changes that are inherited, and “precancerous changes” are not mutations, but reversible changes that completely fit within the framework of adaptive processes that can still disappear or be replaced by others when environmental conditions change. Precancerous changes are not forms of sequential transition of normal cells into cancerous ones, but only the necessary preparation for the occurrence of a single malignant mutation” (1959, p. 425).

It is noteworthy that N.N. Petrov reveals a really existing contradiction in the first part of his reasoning, which he then tries to criticize and discard. The facts presented by the author contradict the mutation concept, but since no other explanation existed at that time, they are discarded. From our point of view, the observed contradiction can be interpreted differently. Let us present several arguments. The established fact of normalization of transformed cells destroys the idea of ​​irreversible changes in the genome due to mutations as the cause of cancer. The transfer of malignant properties during the division of cancer cells is also not hereditary, since daughter cells are able to normalize. This is proven by the fact that cancer cells in the tumor are able to differentiate. Below this pattern will be analyzed in more detail. As for the contradiction that the author discovered, it objectively exists and confirms the above objections. The gradual development of tumor formation through a precancerous condition contradicts the nature of the mutational change, which indicates a different mechanism for the development of events in cancer. However, such a development of the process, as N.N. Petrov notes, does not fit into the idea of ​​mutation

tions. It is clear that the discovered contradictions are objective, but these are only part of those problems that are inexplicable in the oncogene theory and the mutation concept.

Chemical carcinogenesis concepts




During the development of oncology, the old concepts were replaced by theories of chemical carcinogenesis. The idea has been formed that malignancy is a stepwise process consisting of at least two stages - the induction stage and the activation stage (Berenblum, 1956, 1961, 1950; Boyland, 1969). The fact that when the dose of a carcinogen is increased, the latent period of malignancy is reduced to a certain value, and after that the increase in dose has no effect, led to the conclusion that the emergence of a malignant tumor occurs due to a violation of some system common to all somatic cells (Dunning, 1961).

However, work on chemical carcinogenesis did not give the expected results for understanding the mechanism of transformation.

As an example, let us cite the hypothesis of J. Miller and E. Miller (1955). The authors put forward the idea that the introduced dye is converted in the body into a derivative capable of combining with certain liver proteins, which play an important role in the cell’s reactions to the action of intracellular and external factors that regulate growth. The binding of these proteins to the dye can inhibit or stop further synthesis of these proteins. As a result, the next generation of cells will contain fewer proteins that were affected by the dye. Eventually, cells may be formed that do not contain these proteins at all. Thus, the authors explained the gradual decrease in the amount of protein during carcinogenesis due to its binding by an external dye.

From the standpoint of tissue theory, the decrease in the amount of proteins can be explained by the progressive rejuvenation of cells, since poorly differentiated cells synthesize a different composition of proteins, more depleted.

One of the prominent places among chemical theories of carcinogenesis is occupied by Warburg's concept (Warburg, 1926). In 1923, Warburg discovered a high rate of formation of lactic acid by cancer cells and came to the conclusion that the ability to obtain energy from the “lactic fermentation” of glucose and to grow due to the energy of this process is the main biochemical characteristic of cancer cells .

The primary cause of cancer is, according to Warburg, the replacement of oxygen respiration in normal cells by sugar fermentation in cancer cells (Warburg, 1926).

Warburg showed that the ability of cancer cells to transplant is closely related to their ability to undergo glycolysis. Their loss of glycolytic activity leads to loss of the ability to move. Cancer cell metabolism is a combination of oxidative and glycolytic metabolism (respiration/aerobic glycolysis).

Benign tumors according to this ratio, they occupy an intermediate position. It was further shown that the metabolism of the embryo is practically glycolytic, which fits well into this pattern. The formation of cancer cells from normal ones, according to Warburg, occurs in two stages. In the first phase, due to various reasons, irreversible damage to breathing occurs, after which a long period of struggle for existence begins. Those cells that survive are those that are able to compensate for the resulting energy deficit through the mechanism of glycolysis.

From Warburg's works it is known that body glycolysis is maximum in the earliest stages of embryonic development, but gradually, as the embryo differentiates, it decreases. Warburg considered the glycolytic activity of embryonic tissues as a legacy of undifferentiated ancestors, in the light of the pattern according to which ontogeny repeats phylogeny.

Let us try to explain the discovered patterns from the position of the tissue model. The transition from one type of energy metabolism (respiration) to another - glycolysis, which is more primitive - can be explained on the basis of data obtained by Warburg himself. The fact is that the enzymes that ensure respiration in a differentiated cell are synthesized as the cell differentiates. Stem and committed cells, i.e. poorly differentiated cells in the early stages have a different composition of enzymes and, accordingly, a different type of energy - glycolysis. Therefore, during the differentiation of embryonic cells, glycolysis gradually decreases. The process of carcinogenesis, as is known, is associated with the progressive rejuvenation of cells - this leads to the appearance of cells with a different enzyme composition, which changes the type of respiration. This issue is discussed in more detail and consistently in Chapter VII, where modern concepts that explain changes in energy in cancer cells are analyzed.