General stages of carcinogenesis. Carcinogenesis: theories and stages The effect of a tumor on the body

Moscow State Medical and Dental University named after. A.I. Evdokimova

Department of Oncology and Radiation Therapy

Head of the department: Doctor of Medical Sciences, Professor Welsher Leonid Zinovievich

Teacher: Candidate of Medical Sciences, Associate Professor Gens Gelena Petrovna

Abstract on the topic:

Carcinogenesis.

Completed by: 5th year student,

Faculty of Medicine (Dept.),

Menshchikova E.V.

Moscow 2013

According to Virchow's theory, cell pathology underlies any disease. Carcinogenesis is a consistent, multi-stage process of accumulation by a cell of changes in key functions and characteristics, leading to its malignancy. Cellular changes include dysregulation of proliferation, differentiation, apoptosis and morphogenetic reactions. As a result, the cell acquires new qualities: immortalization (“immortality”, i.e. the ability for unlimited division), absence of contact inhibition and the ability for invasive growth. In addition, tumor cells gain the ability to avoid the action of specific and nonspecific antitumor immunity factors of the host organism. Currently, the leading role in the induction and promotion of carcinogenesis belongs to genetic disorders. About 1% of human genes are associated with carcinogenesis.

4 stages of carcinogenesis:

Initiation stage (changes in cellular oncogenes, switching off suppressor genes)

Metabolic activation phase (conversion of procarcinogens into carcinogens)

DNA interaction phase (direct and indirect genotoxic effect)

Phase of fixation of induced changes (DNA damage should appear in the progeny of target cells capable of producing a proliferative pool.)

Promotion stage

I (early) phase is a restructuring of the phenotype that occurs as a result of epigenetic changes (i.e., gene expression) induced by the tumor promoter.

A change in gene expression, which allows the cell to function under conditions of reduced synthesis of gene products.

II (late) phase - represents qualitative and quantitative changes covering the period of cell functioning under conditions of switching gene activity, ending with the formation of neoplastically transformed cells (neoplastic transformation - the manifestation of signs characterizing the ability of cells to unlimited proliferation and further profession, i.e. accumulation malignant potential

Progression stage: developed by L. Foulds in 1969. There is a constant staged progressive growth of the tumor with its passage through a number of qualitatively different stages in the direction of increasing its malignancy. During tumor progression, its clonal evolution can occur; new clones of tumor cells appear as a result of secondary mutations. The tumor is constantly changing: progression occurs, usually towards increasing its malignancy, which is manifested by invasive growth and the development of metastases. Stage invasive tumor characterized by the occurrence of infiltrating growth. A developed vascular network and stroma appear in the tumor, expressed to varying degrees. There are no boundaries with adjacent non-tumor tissue due to the growth of tumor cells into it. Tumor invasion occurs in three phases and is ensured by certain genetic rearrangements. First phase of tumor invasion characterized by a weakening of contacts between cells, as evidenced by a decrease in the number of intercellular contacts, a decrease in the concentration of some adhesion molecules from the CD44 family and others, and, conversely, an increase in the expression of others that ensure the mobility of tumor cells and their contact with the extracellular matrix. The concentration of calcium ions on the cell surface decreases, which leads to an increase in the negative charge of tumor cells. The expression of integrin receptors increases, ensuring cell attachment to the components of the extracellular matrix - laminin, fibronectin, collagens. In the second phase the tumor cell secretes proteolytic enzymes and their activators, which ensure the degradation of the extracellular matrix, thereby clearing the way for invasion. At the same time, the degradation products of fibronectin and laminin are chemoattractants for tumor cells that migrate to the degradation zone during third phase invasion, and then the process repeats again.

The metastasis stage is the final stage of tumor morphogenesis, accompanied by certain geno- and phenotypic rearrangements of the tumor. The process of metastasis is associated with the spread of tumor cells from the primary tumor to other organs through lymphatic and blood vessels, perineurally, and implantation, which became the basis for distinguishing types of metastasis. The process of metastasis is explained by the theory of the metastatic cascade, according to which a tumor cell undergoes a chain (cascade) of rearrangements that ensure spread to distant organs. During the process of metastasis, a tumor cell must have the following qualities:

penetrate into adjacent tissues and lumens of blood vessels (small veins and lymphatic vessels);

separate from the tumor layer into the blood (lymph) stream in the form of individual cells or small groups of them;

maintain viability after contact in the blood (lymph) flow with specific and nonspecific immune defense factors;

migrate to venules (lymphatic vessels) and attach to their endothelium in certain organs;

invade microvessels and grow in a new place in a new environment.

The metastatic cascade can be roughly divided into four stages:

formation of a metastatic tumor subclone;

invasion into the lumen of the vessel;

circulation of the tumor embolus in the bloodstream (lymph flow);

settling in a new place with the formation of a secondary tumor.

Currently, there are several concepts of oncogenesis, each of which predominantly affects stage 1 and (or) stage 2 of carcinogenesis

Mutation theory of carcinogenesis A normal cell turns into a tumor cell as a result of structural changes in the genetic material, i.e. mutations. The concept of a multi-stage process of carcinogenesis, the decisive prerequisite for which is the unregulated expression of a transforming gene - an oncogene, pre-existing in the genome, has become an axiom.

The transformation of a proto-oncogene into an actively acting oncogene is ensured by the following mechanisms. 1. Attachment of a promoter to the proto-onocgene– a section of DNA to which RNA polymerase binds, initiating transcription of a gene, including an oncogene located directly behind it. These types of regions (promoters) are contained in large terminal repeats (LTR) DNA copies of RNA viruses. The role of a promoter can be performed by transposing genome elements– mobile genetic elements capable of moving throughout the genome and being integrated into its various parts

2. Insertion of an enhancer into the cell genome(enchancer - amplifier) ​​- a section of DNA capable of activating the work of a structural gene located not only in the immediate vicinity of it, but also at a distance of many thousands of nucleotide pairs or even built into the chromosome after it. Motile genes have amplifier properties, LTR DNA copies.

3. Chromosomal aberrations with translocation phenomena, the role of which in the mechanisms of tumor transformation of cells can be illustrated by the following example. In Burkitt's lymphoma, the end of the q-arm of chromosome 8, having separated from it, moves to chromosome 14: a homologous fragment of the latter moves to chromosome 8; and an inactive gene here(proto-oncogene), located in the segment that falls on chromosome 14, is inserted after the active genes encoding the heavy chains of immunoglobulin molecules and is activated. The phenomena of reciprocal translocation between the 9th and 22nd chromosomes occur in 95% of cases of myelocytic leukemia. Chromosome 22, with one arm shortened as a result of such a translocation, was called Philadelphia.

4. Point mutations of the proto-oncogene, For example, C-H-raS, reportedly different from the normal gene (C-H-raS) with just one amino acid, but nevertheless causes a decrease in guanosine triphosphatase activity in the cell, which can cause bladder cancer in humans.

5. Amplification (multiplication) of proto-oncogenes, which normally have a small trace activity, causes an increase in their total activity to a level sufficient to initiate tumor transformation. It is known that there are about 5 million copies of the gene in the clawed frog egg tus. After fertilization and further division of the egg, their number progressively decreases. Each cell of the future tadpole during the embryonic period of development contains no more than 20-50 copies of the myc gene, which ensure rapid cell division and embryo growth. In the cells of an adult frog, only a few genes are detected tus, while in cancer cells of the same frog their number again reaches 20-50. 6. Transduction of inactive cellular genes (proto-oncogenes) into the genome of a retrovirus and their subsequent return to the cell: it is believed that the oncogene of a tumor virus is of cellular origin; When animals or humans are infected with such a virus, the gene “stolen” by it ends up in another part of the genome, which ensures the activation of the once “silent” gene.

Oncoproteins can:

imitate the action of pathway growth factors (self-tightening loop syndrome)

can modify growth factor receptors

act on key intracellular processes

Tissue theory of carcinogenesis

The cell becomes autonomous, because the tissue system for controlling the proliferation of clonogenic cells with activated oncogenes is disrupted. The main fact confirming the mechanism based on disruption of tissue homeostasis is the ability of tumor cells to normalize during differentiation. The study of continuous keratinizing rat carcinoma using autographic analysis showed (Pierce, Wallace, 1971) that cancer cells, when dividing, can produce normal offspring, that is, malignancy is not genetically fixed and is not inherited by daughter cells, as assumed by the mutation hypothesis and molecular genetic theory. Experiments on transplanting tumor cell nuclei into previously enucleated germ cells are well known: in this case, a healthy mosaic organism develops. Thus, contrary to the idea that transformed oncogenes are allegedly preserved in normal tumor cells during differentiation, there is reason to question the connection of genetic disorders with the transformation mechanism as a direct cause.

Viral theory of carcinogenesis

To become malignant, a cell must acquire at least 6 properties as a result of mutation of genes responsible for cell division, apoptosis, DNA repair, intracellular contacts, etc. In particular, on the way to acquiring malignancy, a cell, as a rule, is: 1) self-sufficient in terms of proliferation signals (which can be achieved by activation of certain oncogenes, for example, H-Ras); 2) insensitive to signals that suppress its growth (which occurs when the Rb tumor suppressor gene is inactivated); 3) is able to weaken or avoid apoptosis (which occurs as a result of activation of genes encoding growth factors); 4) tumor formation is accompanied by enhanced angiogenesis (which can be achieved by activation of the VEGF gene, encoding vascular endothelial growth factors; 5) genetically unstable; 6) does not undergo cell differentiation; 7) does not age; 8) is characterized by a change in morphology and locomotion, which is accompanied by the acquisition of properties for invasion and metastasis. Since gene mutations are random and quite rare events, their accumulation to initiate cellular transformation can last for decades. Cell transformation can occur much faster in the case of a high mutagenic load and/or defective (weak) genome protection mechanisms (p53, Rb, DNA repair genes and some others). If a cell is infected with oncogenic viruses, proteins encoded by the viral genome that have transforming potential disrupt normal cellular signaling connections, providing conditions for active cell proliferation.

It is well known that approximately 15-20% of human neoplasms are of viral origin. Among the most common such virus-induced tumors are liver cancer, cervical cancer, nasopharyngeal cancer, Burkitt's lymphoma, Hodgkin's lymphoma and many others. Currently, experts from the International Agency for Research on Cancer (IARC) consider the following viruses to be oncogenic for humans:

Hepatitis B virus and Hepatitis C virus, HBV/HCV, causing liver cancer; As a result of genetic rearrangements, gene deletion occurs X and some of the genes PreS2 , in which case the liver cells become HBsAg-negative and finally escape immunological control. Next, there is a selection of cells in which HBV DNA is integrated and which contain 3 main trans-activators, namely: HBx, LHBs and/or MHBs(t). Trans-activators activate cellular genes responsible for cell proliferation, cytokine synthesis (IL-6), etc. Cytokines secreted by cells containing trans-activators create a microenvironment of adjacent fibroblasts, endothelial cells, etc., which in turn secrete other growth factors that stimulate paracrine proliferation of hepatocytes. Increased proliferation of hepatocytes can lead to genetic damage, which will contribute to the selection of cells with accelerated proliferation and their acquisition of signs of malignant transformation. In liver tumor cells, inactivation of the tumor suppressors p53, Rb, BRCA2 and E-cadherin often occurs. Activation of telomerase in liver cells at the stage of their transformation into malignant cells and disruption of the functioning of a number of important signaling systems were also noted.

Certain types (16 and 18) of human papillomavirus (HPV)- being the etiological agent of cervical cancer and some tumors of the anogenital area; It has been established that transforming genes are mainly genes E6 and E7, less E5. Mechanism of gene functioning E6 and E7 comes down to the interaction of the products of these genes with the products of 2 suppressor genes p53 and Rb and the subsequent inactivation of the latter, which leads to uncontrolled growth of infected cells. Studies have shown that each of the above-mentioned 3 genes of latent HPV infection, which has transforming potencies, contributes to the disruption of cell signaling pathways, an increase in its proliferative activity and the accumulation of additional genetic changes. It is worth noting that therapeutic and preventive vaccines against HPV have been created. Which stimulate the immune system against E6 and/or E7 early viral proteins (tumor antigens), which prevent infected cells from entering apoptosis and the senescence phase, and also generate virus-neutralizing antibodies specific for the HPV capsid.

Epstein-Barr virus (EBV)), taking part in the occurrence of a number of malignant neoplasms; The mechanism of carcinogenesis is complex and little studied. In particular, the LMP1 protein, localized in the membrane, imitates the function of the constitutively activated CD40 receptor and partially replaces this function. By recruiting adapter molecules TRAF through the activation domains CTAR1 and CTAR2 activates the transcription factors AP-1 and NFkB and thus induces the expression of genes regulated by these factors (epidermal growth factor receptor, EGFR, CD40, surface activation markers, adhesion molecules, etc.) . In addition, LMP1 interacts with Jak3 kinase and thus activates STAT signaling pathways that stimulate cell proliferation and movement. LMP2A activates the Akt/PBK kinase, causing a number of effects, the most striking of which is the suppression of apoptosis. EBNA2 mimics the transcriptional function of the processed form of Notch (a transmembrane protein that converts contacts with surrounding cells into genetic programs that regulate cell fate), the constitutive activity of which leads to the development of lymphoid and epithelial tumors. The main function of EBNA1 is to ensure the replication and maintenance of the episomal state of the EBV genome.

Human herpesvirus type 8 (HHV-8), which plays an important role in the occurrence of Kaposi's sarcoma, primary effusion lymphoma, Castleman's disease and some other pathological conditions;

Human T-cell leukemia virus (HTLV-1), which is the etiological agent of T-cell leukemia in adults, as well as tropical spastic paraparesis and a number of other non-oncological diseases. The mechanism of trans-activation of the transcription of a number of viral and cellular genes (cytokines, their receptors, cyclins, etc.) associated with cell proliferation and promoting the growth of infected HTLV-1 cells. The Tax protein can also trans-repress the transcription of certain genes, acting through the transcriptional co-activator p300. Tach also inactivates cell cycle checkpoints and DNA polymerase (DNApol), reducing the activity of all 3 DNA repair systems and thereby causing genetic instability, which ultimately leads to the emergence of a tumor cell.

Human immunodeficiency virus (HIV)- does not have transforming genes, but creates the necessary conditions (immunodeficiency) for the occurrence of cancer.

Despite the different organization of human oncogenic viruses and the unequal spectrum of their target cells, they have a number of common biological properties, namely: 1) viruses only initiate the pathological process, increasing the proliferation and genetic instability of the cells they infect; 2) in individuals infected with oncogenic viruses, the occurrence of a tumor is, as a rule, an infrequent event: one case of a tumor occurs among hundreds, sometimes thousands of infected people; 3) after infection, before the tumor appears, there is a long latent period, lasting years, sometimes decades; 4) in the majority of infected individuals, the occurrence of a tumor is not necessary, but they may constitute a risk group with a higher possibility of its occurrence; 5) for malignant transformation of infected cells, additional factors and conditions are required that lead to the selection of the most aggressive tumor clone.

Theory of chemical carcinogenesis.

Most “strong” carcinogens have both initiating and promoter properties, and all promoters, with rare exceptions, exhibit carcinogenic activity if used in high doses and for a sufficiently long time. The division into initiators and promoters corresponds to a certain extent to the division of carcinogens 1. Genotoxic

Carcinogens direct action dissolves when dissolved

the formation of highly active derivatives containing an excess positive charge, which interacts with negatively charged (nucleophilic) groups of the DNA molecule, forming a stable covalent bond. During replication, a nucleotide bound to a carcinogen residue may be misread by DNA polymerase, resulting in mutation. (Ex: N-nitrosoalkyl urea, nitrogen mustard, diepoxybutane, beta-propiolactone, ethyleneimine)

Carcinogens indirect action are low-reactive compounds activated by the action of enzymes.

DETOXIFICATION OF CHEMICAL CARCINOGENS (oxidation of procarcinogen by cytochrome P-450 isoforms)

METABOLIC ACTIVATION (Some procarcinogens are activated, turning into direct carcinogens - highly reactive derivatives that are covalently bound by cellular proteins and nucleic acids.

2. Non-genotoxic

These include compounds of various chemical

structure and different mechanism of action: promoters of two-stage carcinogenesis, pesticides, hormones, fibrous materials, other compounds (it should be noted that both pesticides and hormones can be promoters of carcinogenesis). Non-genotoxic carcinogens are often called promoter-type carcinogens. Promoters, as already mentioned, must act in high doses, for a long time, and, very importantly, continuously. A more or less long break in their use is accompanied by

stopping carcinogenesis (new tumors no longer appear) or even regression of existing tumors. They cause cell proliferation, inhibit apoptosis, and disrupt the interaction between cells. The following mechanisms of action of non-genotoxic carcinogens are known:

a) promotion of spontaneous initiation;

b) cytotoxicity with persistent cell proliferation (mitogenic effect);

c) oxidative stress;

d) formation of a carcinogen-receptor complex;

e) inhibition of apoptosis;

g) disruption of intercellular gap junctions.

CARCINOGENIC CLASSES OF CHEMICAL COMPOUNDS:

Polycyclic aromatic hydrocarbons.

Aromatic amines.

Aminoazo compounds.

Nitroarenes.

Nitroso compounds.

Aflatoxins.

Metals (nickel, chromium, beryllium, cadmium, cobalt, arsenic, lead, mercury.)

Fibrous and non-fibrous silicates.

Hormonal theory of carcinogenesis The independent existence of hormonal carcinogenesis in humans was denied for a long time. It was believed that hormones play the role of risk factors predisposing to the development of leading non-communicable diseases, including malignant neoplasms.

With the study of so-called adducts - complexes of DNA with the corresponding compound, including those of a hormonal nature in experiments in vivo The nature of the results obtained, and accordingly the conclusions, began to change. A significant role in recognizing the ability of some hormones (such as diethylstilbestrol and natural estrogens) to cause DNA damage was played by the research of I. Liir’s group together with J. Weiss, one of the leading experts in the field of studying the metabolites of classical estrogens - catechol estrogens, in particular 2- and 4-hydroxyestrone and 2- and 4-hydroxyestradiol. The result of this long-term work was an original concept, the essence of which is as follows: classical estrogens can, to one degree or another, be converted into catechol estrogens, which are involved in the reactions of the metabolic-reduction cycle with the formation of quinones, semiquinones and other free radical metabolites that can damage DNA, form its adducts, lead to mutations, and therefore initiate neoplastic transformation. The main objections to this concept are that catechol estrogens are very unstable, their concentration in the blood and tissues is relatively low, and that the mentioned model does not take into account hormone-induced increased proliferation. Nevertheless, direct experiments have shown that of all the estrogen derivatives studied, the most carcinogenic are the 4-hydroxy derivatives, which are also the most genotoxic. 2-hydroxy metabolites have almost no blastomogenic effect, but they can suppress the activity of catechol-O-methyltransferase (COMT) and, accordingly, prevent the inactivation of 4-hydroxy derivatives, which is also of great practical importance. According to data from the group of H. Adlerkreutz, obtained by gas chromatography and mass spectrometry, the level of catechol estrogens in the blood and especially their excretion in the urine is far from being so low. Interestingly, based on these results, significant differences were established between Asian and Caucasian populations, which also differ in the frequency of detection of cancer of the reproductive system.

There is every reason to believe that two main types of hormonal carcinogenesis are possible: promoter or physiological, when the effect of hormones is reduced to the role of peculiar cofactors that enhance cell division (promotion stage); and genotoxic, when hormones or their derivatives have a direct effect on DNA, promoting the induction of mutations and initiation of tumor growth. The reality of the first is evidenced by classical observations, the idea of ​​risk factors and hormonal-metabolic predisposition to the development of tumors, and numerous epidemiological and laboratory data. The second is supported by an increasing number of studies that demonstrate the ability of hormones (for now - mainly estrogens) to damage DNA: form adducts, enhance the unweaving of its chains, form breaks, etc., which can lead to other, more specific (problastomogenic) changes at the cellular genome level.

Antiblastoma resistance Anti-blastoma resistance is the body's resistance to tumor growth. There are three groups of antiblastoma resistance mechanisms.

Anticarcinogenic mechanisms acting at the stage of interaction of a carcinogenic agent with cells: inactivation of chemical carcinogens in the microsomal system; their elimination from the body in the composition of bile, urine, feces; production of antibodies to relevant carcinogens; inhibition of free radical processes and lipid peroxidation (antiradical and antiperoxide reactions), provided by vitamin E, selenium, superoxide dismutase, etc.; interaction with oncogenic viruses, interferon, antibodies, etc. Anti-transformation mechanisms: maintaining gene homeostasis through DNA repair processes; synthesis of tumor growth inhibitors, providing suppression of cell proliferation and stimulation of their differentiation (function of antioncogenes).

Anticellular mechanisms aimed at inhibiting and destroying individual tumor cells, preventing the formation of their colony, i.e. tumors. These include immunogenic mechanisms - nonspecific (EC reaction) and specific (reaction of immune T-killers; immune macrophages), - non-immunogenic factors and mechanisms (tumor necrosis factor, interleukin-1, allogeneic inhibition, contact, ke-lon - regulatory neurotrophic and hormonal influence – etc.).

Thus, studying the processes of carcinogenesis is a key point both for understanding the nature of tumors and for finding new and effective methods for treating cancer.

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 the control of the body’s signaling systems;
• 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 general, 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.

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The concept that malignant tumors arise as a result of staged changes is based on epidemiological, experimental and molecular biological studies.

Many years ago, before the discovery of oncogenes and anti-oncogenes, oncoepidemiology suggested that the incidence of cancer, which increases as a person ages, is explained by the fact that carcinogenesis passes through a number of independent stages, and since mutation is an accident, the process usually lasts many years.

There is no longer any doubt that the latent period of cancer (from initial changes in the cell to the first clinical manifestations) can last up to 10-20 years.

The later developed doctrine of oncogenes and antioncogenes confirmed this and laid a solid foundation for the concept of staged, or staged, or multi-step carcinogenesis.

According to this concept, the formation of a malignant tumor is not a one-time event, but a chain of successive interconnected events, each of which is caused by the influence of certain factors, both external and internal. During these events, there is a consistent accumulation of damage to the cell genome, which leads to qualitative changes in their structure and function, etc. ultimately, to impaired differentiation and acquisition of tumor-specific properties.

Currently, carcinogenesis is divided into three stages, often overlapping each other. The first, irreversible stage is called initiation, and the carcinogens that cause it are called initiators. The second, reversible stage was called promotion, and the corresponding agents were called promoters. The third stage is the formation of a malignant tumor with all its inherent properties - progression (Fig. 3.22).

Rice. 3.22. Stages of carcinogenesis.

During each stage, certain etiological factors operate, each of them has specific morphological manifestations and is characterized by special changes in the genome.

Initiation (or tumor transformation) is the first step, the essence of which is a rapid (minutes, hours), irreversible and non-lethal change in the genome of somatic cells in the form of mutations.

In this case, activation of oncogenes or suppression of antioncogenes occurs and, accordingly, increased reproduction of oncogene proteins and loss of regulatory gene proteins (antioncogenes). However, cells transformed in this way remain inactive without an additional stimulus to proliferation. It is believed that the further process of carcinogenesis may be interrupted at this stage.

Promotion is the next step, which consists of interaction between the transformed cell and a number of promoter factors. As a result, cells with high reproductive activity are selected and a fairly extensive clone of altered cells is formed, endowed with the basic properties of malignancy, that is, the main phenotypic characteristics of the tumor appear.

In other words, a primary tumor node is formed. However, it is generally accepted that the tumor formed at this stage is not capable of infiltrating growth and metastasis.

Progression consists in the occurrence of additional changes in the structure of the genome, when mutations and selective selection of cell clones (subclones), most adapted to changing conditions of existence and most aggressive towards the host organism, lead to the emergence of a morphologically detectable tumor, already endowed with truly malignant properties - infiltrating ( invasive) growth and the ability to metastasize. Below is a more detailed description of the individual stages of carcinogenesis.

Initiation stage

The carcinogen is not a specific mutagen, i.e. interacts with the DNA of various genes, but only activation of oncogenes and/or inactivation of suppressor genes can initiate the subsequent transformation of a normal cell into a tumor cell.

However, as mentioned above, mutations caused by a carcinogen do not always lead to initiation, since DNA damage can be repaired. And at the same time, even a single exposure to the initiator can lead to carcinogenesis.

Ultimately, under the influence of carcinogens, irreversible damage to the genotype of a normal cell occurs and a pre-tumor (transformed) cell appears with hereditarily fixed properties that distinguish it from normal in a number of ways.

Thus, transformed cells differ from normal ones in their social behavior and biochemical properties. The social behavior of cells is their relationship with the matrix on which they grow and with each other. Features of the social behavior of transformed cells are associated primarily with a violation of their morphology and movement. Transformed cells are able to produce growth factors that stimulate their own (autocrine) reproduction.

In transformed cells, active sugar transport and anaerobic glycolysis are enhanced, and the composition of surface glycoproteins and lipids changes. The most important property of transformed cells is their immortality; without this property they could not form a tumor.

Finally, the offspring of the transformed cell is capable of promotion, during which it undergoes appropriate selection for the ability to overcome antitumor defense and acquire new properties (for example, metastasis), which may not depend on the carcinogen that caused the appearance of the original tumor cell,

Thus, the concepts of “transformed” and “tumor” cells are not strictly identical. Transformed cells do not show signs of malignancy such as invasive growth and metastasis.

At the same time, for the emergence of a “real” malignant cell, initiation alone is not enough; additional stimuli (promoters) are required, which is what happens at the next stage of carcinogenesis.

Promotion stage

Therefore, to secure initiation, a cell modified by a carcinogen must complete at least one proliferation cycle. It is the stimulation of the proliferation of initiated cells and the consolidation of existing and sharply increasing new mutations in the process of division in subsequent generations that constitutes the essence of the promotion stage.

It is clear that with rapid cell division, the probability of gene damage increases sharply, which means that the population of such cells is able to quickly accumulate an increasing number of new mutations, from which their malignant variants can arise.

Factors and substances that determine the transition to the promotion stage and stimulate the proliferation of initiated cells are called promoters. Since the function of promoters is to stimulate the division of initiated cells, they are also called mitogens.

Most promoters have weak carcinogenic properties or even do not exhibit them at all. Chemical compounds of an exo- and endogenous nature (some medications, certified salt, hormones, bile acids, growth factors, etc.) can act as promoters.

Promoters can also be initiators if they are used in high doses and for a long enough time, and most “strong” carcinogens have both initiating and promoter properties. However, the result from the “initiator-promoter” combination is tens and hundreds of times greater than the carcinogenic effects of each of the factors taken separately.

The effect of carcinogens-mutagens is sometimes called initiating, and promoters - activating. The initiating effect is irreversible and is associated with DNA mutation. The promoter effect is reversible. In contrast to initiation, when the action of the promoter is terminated, carcinogenesis may develop further, at least at its early stage, and tumor regression may occur.

A certain organotropy of promoters has been noted, for example, the specific promoter of breast and uterine cancer is estrogens, etc. In the late period of promotion, in addition to promoters, there may be other mechanisms for regulating cell proliferation, such as immune surveillance, agents that stimulate progression, etc.

So, if exposure to an initiator causes mutational activation of an oncogene and/or inactivation of an antioncogene, then the subsequent effect of promoters leads to increased proliferation and clonal propagation of such mutant cells. This leads to the formation of a critical mass of initiated cells, their release from tissue control, and clonal selection of viable cells, which creates great opportunities for initiated cells to realize the potential of malignant ones.

But this requires long-term and relatively continuous exposure to promoters and only in a strictly sequential combination - first initiating and then promoting factors (Fig. 3.23).

Rice. 3.23. Scheme of the sequence of exposure to carcinogenic factors in carcinogenesis. I - initiating and P - promoting factors

If the promoter is used before initiation or when the pause between the influence of the initiator and the promoter is too long, the tumor does not occur.

The end result of the promotion stage is the completion of the process of malignant transformation (malignization), the acquisition by the cell of the main features of a malignant phenotype and the formation of a recognizable tumor.

It should be noted that the terms “initiation” and “promotion” refer only to events in these phases, and not to the mechanisms of carcinogenesis. Each of these stages includes many links leading to the activation of proto-oncogenes and/or inactivation of suppressor genes and the synthesis of oncoproteins. In this case, a whole panorama of events unfolds, in which cascades of a wide variety of molecular processes participate.

Progression stage

Based on the principle of monoclonal cancer, which postulates the origin of all tumor cells from one single transformed stem cell, it is logical to assume that the tumor should be homogeneous in its structure, i.e. must consist of cells with the same morphological and functional characteristics. However, in reality this is far from the case.

The initial monoclonality of a tumor does not mean that its cells are standard. Typically, tumor cells differ from each other much more than differentiated cells of the corresponding normal tissue, which gives grounds to talk about polymorphism in most neoplasms. It is well known that during the course of their development, many tumors become more aggressive and increase their potential for malignancy.

In other words, during the evolution of neoplasms, a complex of abrupt qualitative changes is observed, which are usually characterized as their progression. The doctrine of tumor progression, formulated by I. Foulds (1976), turned out to be one of the most profound concepts developed by modern oncology.

It was shown that during growth, non-oppastic cells, on the one hand, become autonomous from the body, but on the other, are under constant pressure from various selection factors, i.e. evolve as a single-celled organism. It is the evolution of clones, leading to their diversity and increase in adaptive viability, and not just growth and dispersal, that constitutes the essence of the concept of “tumor progression.”

Tumor progression is not just an increase in tumor size, it is a qualitative change with the appearance of an essentially new tumor with varied properties, despite its monoclonal origin.

Currently, progression is understood as a change in the totality of tumor characteristics (karyo-, geno-, and phenotype, cell differentiation) in the direction of an increasingly consistent increase in malignancy.

Progression implies that, as a result of various influences, the primary clone of tumor cells gives rise to many subclones that differ significantly from it in morphofunctional terms. The general direction of these differences is expressed in amazing adaptability to changing living conditions and giving the tumor advantages in the competition with the body for survival.

In addition, a growing tumor tends to be enriched with such subclones that “knock out the extra ones” in competitive intercellular relationships. In this sense, intratumoral selection has a directed, adaptive character, because manifests itself in the selection of cells most adapted to further survival, growth, invasion and metastasis.

Progression is believed to be a consequence of multiple accumulating mutations in tumor cells. Moreover, some of them can be lethal and lead to the “loss out” of the subclone, others can provide it with a dominant role, but the tumor always has sufficient material for selection, especially if we take into account the mutagenic nature of the therapeutic effects on it.

The process of the emergence and development of structural and functional differences when the original clone is divided into subclones is called divergence of tumor cells (Latin divergens - diverging in different directions). Moreover, the rate of formation of mutant subclones for different tumors is very different.

Thus, as a result of many years of profession, the neoplastic process from the initially monoclonal stage passes into the late, polyclonal stage, and tumor cells by the time of their clinical detection are distinguished by pronounced heterogeneity, i.e. geno- and phenotypic heterogeneity. Heterogeneity underlies the progression, directed towards increasing the malignant properties of the tumor “from bad to worse”.

The selection of the most malignant cells that are better able to survive is not the path of progress, but the path of anti-evolution and destruction of the organism, in which a highly complex cell can degrade to a primitively simple one, providing only for itself, but not for the organism.

So. by selecting cell populations and their continuous development towards increasing autonomy, subclones are formed that are able to evade the immune response, better adapted to unfavorable conditions (oxygen deficiency, etc.), capable of infiltrating growth and metastasis, resistant to radiation and drug therapy, and etc. (Fig. 3.24).

Rice. 3.24. Scheme of the tumor profession [Moiseenko V.I. et al. 2004].

An example of drug resistance is the generation of tumor cells with the MDR1 gene, which represents one of the most difficult problems in drug treatment.

In addition, there may be variability in the tumor's response to factors that inhibit (or stimulate) its growth.

For example, during the process of progression, the ability of tumor cells to respond to hormonal influences changes and often hormone-sensitive tumors become hormone-resistant due to the loss of specific hormone receptors.

Tumor progression is characterized by qualitative changes in tumor tissue, usually leading to increasing differences between it and the original normal tissue.

The main morphological signs of progression are the loss of the tumor's organo- and histotypic structure, decreased differentiation (anaplasia), cytogenetic changes, simplification of its enzyme spectrum. At the molecular level, progression is manifested by multiple independent mutations in cells.

As a result, by the time a tumor is clinically detected, its cells are characterized by pronounced heterogeneity, which creates serious difficulties for clinical and pathomorphological diagnosis. It is well known how difficult it can be to detect an unremarkable primary tumor in the presence of unquestionable distant metastases, especially undifferentiated ones.

Factors of selective mutational selection of tumor cells are: pronounced genetic instability; immunological mechanisms; hormonal factors; infection (usually viral); exposure to carcinogenic or toxic substances; therapeutic (radiation and drug therapy) measures, etc. Most often, mutations of malignant cells are predisposed by their genetic instability, i.e. high degree of susceptibility to secondary (random, spontaneous) mutations during the growth of subclones.

An important factor in progression is immune control, since cells with a particularly high concentration of tumor antigens are destroyed by immune mechanisms, while the growth of aggressive (anaplastic) clones is accompanied by antigenic simplification and they are successfully selected.

Under any influence, the frequency of mutations increases significantly if tumor cells lose the mechanisms of their elimination or correction, which are provided mainly by the p53 suppressor gene, which controls the constancy of the genome through apoptosis. Therefore, inactivation of p53 and blocking of apoptosis at different stages of carcinogenesis largely determines further tumor progression.

Thus, cancer develops from a single cell, but by the time of clinical manifestation the tumor is a population of heterogeneous cells, which creates an individual “genetic” portrait for it.

It is the ability of malignant cells to mutate and form cellular variants that is one of the most insidious properties of a tumor. The primary or “inherent” feature of a tumor is unregulated growth, and the rest are “secondary” properties or features that change during progression.

Therefore, malignant cells of even the same tumor differ in metastatic potential, radioresistance, sensitivity to antitumor drugs, etc., which makes them relatively invulnerable to the effects of special treatment methods. Consequently, the progression of tumors determines not only the course, but also the prognosis of the disease.

It is clear that genetic instability, heterogeneity and selection occur long before the clinical detection of a tumor. The development of the tumor as a monoclone and the principle of tumor progression are consistent with clinical evidence that a long latent period is required for the neoplasm to reach a clinically recognizable stage.

The ability of a tumor to regress, and tumor cells to normalize the phenotype, opens up new possibilities for therapy aimed not at destroying a tumor cell, but at reducing malignant properties and increasing its differentiation).

It should also be pointed out that the monoclonal nature of cancer and the concept of tumor progression do not negate the certain significance of the idea of ​​the field theory of oncogenesis.

In a tissue, under the influence of carcinogens, several transformed cells can appear, which can give rise to the development of several tumor clones. Subsequently, they compete with each other and with the immune system, which can lead to the death of some of them.

Or it may happen that in an equal fight several clones will survive and multicentric development of cancer will arise, as is repeatedly observed in experimental and clinical conditions. In this case, each tumor center can be represented by a monoclone.

In conclusion of this chapter, it can be stated that. Despite significant progress achieved in recent years in understanding the basic mechanisms of carcinogenesis, many questions remain unclear. The initial euphoria, when with the discovery of oncogenes and suppressor genes it seemed that the problem of cancer had been completely solved, has now passed. The scale of the problem turned out to be disproportionately greater than expected.

The multiplicity of molecular events and the ambiguity of the interaction of genetic mechanisms during tumor growth are amazing. And at the same time, the successes achieved by molecular biology allow us to draw a number of conceptual conclusions.

Regardless of the etiological factors, neoplastic transformation is a consistent, multi-stage process of accumulation of mutations and other genetic changes, the result of a complex cascade of molecular transformations and interactions in which a “coherent” ensemble of oncogenes and suppressor genes is involved, as well as the result of ineffective functioning of the mechanisms of innate and acquired antitumor immunity.

The key moments of carcinogenesis are the activation of oncogenes and the inactivation of suppressor genes, which occur under the influence of a variety of carcinogenic factors. Changes in the genetic program of the cell and disruption of intracellular signaling connections are the main features of the tumor cell.

The set of genetic changes, in turn, ensures that, as a result of a rather long evolution, the tumor cell and its descendants acquire a number of specific properties. From these positions, cancer should undoubtedly be considered as a genetic disease that develops as a result of mutations that arise during the life of an individual or are inherited by descendants.

The great variety of oncogenes and antioncogenes and the different frequencies of their mutations obviously allow the possibility of their combination in the etiology of tumors. This creates an extremely complex and confusing picture when it comes to analyzing the mechanism of occurrence of any specific tumor.

It is this diversity and heterogeneity that greatly limits the possibilities of developing tumor therapy based on knowledge of the genetic changes that have occurred in them. It is very important to emphasize that the total number of such genetic damage is at least 5-7 per tumor cell.

Apparently, most often such mutations occur sequentially and independently of each other. However, the simultaneous occurrence of genetic disorders is also possible.

Uglyanitsa K.N., Lud N.G., Uglyanitsa N.K.

The first stage of tumor growth is called (1)

Stages of carcinogenesis (3)

Physical carcinogens include (4)

The creator of the viral-genetic theory of tumor occurrence is (1)

In humans, they are of viral origin (2)

For the first time experimentally proved the role of viruses in the etiology of tumors (1)

It is typical for endogenous carcinogens (3)

Endogenous chemical carcinogens include (3)

The possibility of the formation of endogenous carcinogens was first proven (1)

Nitrosamines (2)

Nitrosamines include (2)

Aminoazo compounds (4)

a) have a local effect

b) have organotropy+

c) cause bladder and liver cancer+

d) are part of aniline dyes+

e) are included in some food colorings+

a) diethylnitrosamine +

b) methylnitrosourea +

c) 3,4-benzpyrene

d) methylcholanthrene

e) aniline dyes

a) have organotropy+

b) can be synthesized in the stomach from nitrates and amines in the presence of hydrochloric acid+

c) have a local effect

d) are part of aniline dyes

b) Yamagiwa

c) Ishikawa

d) L.M.Shabad +

e) L.A. Zilber

a) polycyclic aromatic hydrocarbons

b) metabolites of tryptophan and tyrosine +

c) cholesterol derivatives +

d) nitrosamines

e) simple chemical compounds

f) free radicals and nitric oxide +

a) are formed in the body +

b) have a weak carcinogenic effect +

c) have a long latent period +

d) have a strong carcinogenic effect

e) have a short latent period

b) Yamagiwa

c) Ishikawa

d) L.M.Shabad

e) L.A. Zilber

37. Find a match:

a) Bitner milk viruses, chicken leukemia viruses, mice 1

b) viruses of the Papova group 2

c) Epstein-Barr virus 2

d) Rous sarcoma viruses1

e) HTLV-1 virus 1

f) papillomavirus 2

g) hepatitis B virus 2

a) Burkitt lymphoma+

b) myeloid leukemia

c) retinoblastoma

d) T-cell leukemia+

e) xeroderma pigmentosum

a) L.M.Shabad

b) L.A. Zilber+

c) Yamagiwa

d) Ishikawa

a) alpha, beta radiation+

b) gamma radiation+

c) ultraviolet rays+

d) X-ray+

e) infrared rays

a) initiation+

b) progression+

c) promotion+

d) regression

e) metastasis

a) promotion

b) cocarcinogenesis

c) progression

d) initiation+

e) procarcinogenesis

a) promotion+

b) cocarcinogenesis

c) progression

d) initiation

e) procarcinogenesis

44. Find a match:

1. Initiation

2. Promotion

3. Progression

a) transformation of a normal cell into a tumor cell1

b) proliferation of transformed tumor cells2

c) increase in malignant properties of the tumor3

Cancer- cancer, (here - cancerous tumor), genesis- origin, emergence. Carcinogenesis- a science that represents modern views on the origin of tumors, not only cancer ones. A broader and etymologically correct name for the process in domestic oncology is blastogenesis. In foreign literature, both concepts are often considered identical.

In any multicellular organism, throughout the entire life process, the cellular composition of tissues is renewed, while the volume of a particular tissue or organ is relatively constant. Natural cell death, which occurs through apoptosis, is controlled by the body. Replenishment of lost cells occurs through the proliferation and differentiation of stem cells, which are under strict control. This process is controlled by growth factors. Control is carried out through several mechanisms, some of which have been deciphered, but many processes remain unclear. Stem cells can be in an undifferentiated state up to a certain point or have initially minimal signs of differentiation, and upon receiving a certain signal they undergo transformation into a cell of the corresponding tissue. During the process of reproduction, they can accumulate genetic changes that gradually increase the risk of cell degeneration and its transformation into a tumor cell. There is an increasing functional imbalance between genes that control cell apoptosis.

The etiology and pathogenesis of tumors are studied in the section of experimental oncology. For this purpose, various models of tumor pathology in animals are used: spontaneous and induced by exposure to carcinogens, as well as transplantable tumors and tumor tissue cultures. Experimental data show that any tumor, including dysembryogenetic, can be reproduced in an animal when carcinogenic effects are applied. Modern methods of biochemistry and immunology, cytology, electron microscopy allow

study changes in the genetic apparatus of the cell during the process of malignancy.

Despite the active study of the etiology and pathogenesis of tumors, many unresolved issues remain in modern ideas about these problems. Thus, signs of cellular atypia accompany cell proliferation during physiological processes, but up to a certain point the cells are not tumorous. Thus, the starting point should be considered the mutagenic effect of a certain factor on the chromosomal apparatus of the cell.

Tumors- a special type of pathology that is quite widespread in wildlife. Tumors are known in plants and in all classes of animals. They are characterized by autonomous growth and proliferation of cells at the site of the disease, while the tumor initially grows from the original germ, without involving surrounding unchanged cells in this process.

According to modern concepts, tumors appear as a result of a violation in some place of the regulation of reproduction processes. If this control is violated, an excess of tissue of appropriate differentiation (hyperplasia) may occur. According to clinical observations, this most often happens in middle and old age, and therefore cancer usually manifests itself as a disease of the elderly. Over time, mutations accumulate in the cells of this zone, signs of a benign and then a malignant tumor appear.

Malignant tumor, neoplasm - a special form of tissue growth that has certain specific properties. Signs of malignancy The following are currently recognized.

1. An uncontrolled process of cell reproduction that cannot be controlled by the host organism. Every normal tissue cell has the property of apoptosis. Apoptosis- genetically programmed cell death after a certain period of time. Without external influence, the tumor cell does not die, or only dies together with its carrier.

2. Ability to metastasize.Metastasis- a phenomenon in which tumor cells break away from the main focus and are carried throughout the body by lymph or blood. Some cells that have separated from the primary tumor mass, moved with the flow of lymph or blood to other regions of the body, give rise to growth

secondary tumors - metastases. Tumor cells are weakly adherent to each other, easily separated from the resulting conglomerate and enter the vascular bed, but the fact that a cell enters the vascular bed does not mean that metastasis will develop. It is known that, despite the presence of tumor emboli, metastases in some organs (spleen, myocardium, skeletal muscles) rarely develop. Thus, the appearance of metastasis cannot be reduced only to mechanical blockage of capillaries by tumor emboli. The cell must enter the extracellular space, which happens due to the properties of the tumor cell to destroy the vascular endothelium. Cancer metastases also go through a phase in their development promotions. The tumor process spreads throughout the body.

3. Invasive, infiltrative, locally destructive growth.Infiltrative tumor growth- penetration of tumor cells into surrounding unchanged tissues. The main feature malignant tumor is its expansion beyond the territory intended for a given tissue. If the tumor grows into the underlying tissue, invasion of tumor cells occurs - the first sign of a malignant tumor.

All subsequent generations of malignant tumor cells, just like the original ones, have all of the listed properties: the ability for a non-stop proliferation process, infiltrative growth and metastasis.

The last two signs are not absolutely specific. For example, a kind of screening (metastasis) can be caused by a purulent focus (septicopyemia), endometriosis (endometrial growths in different organs). Invasive growth is characteristic of neural elements and melanoblasts in the embryonic period of development, trophoblasts during pregnancy. The mechanism of these processes is different, but the important fact is that such properties are not characteristic only of tumors.

Tumor, blastoma (from Greek blastos- sprout, embryo), neoplasm- a pathological process accompanied by excessive, unregulated proliferation of tissues, which consist of qualitatively changed cells of the body that have lost their differentiation. Carcinogenesis, blastogenesis, neogenesis, oncogenesis - (neos- new, onkos- tumor, genesis- origin, occurrence) - terms denoting the process of transformation of a normal cell into a tumor cell. Tumor transformation (blast transformation) -

critical stage of oncogenesis, i.e. the moment of final transformation of a normal cell into a tumor cell. It is difficult to detect experimentally, and in clinical conditions it is almost elusive. Another sign of malignancy is the spread of tumor cells into surrounding tissues, where cells of a given tissue should not be. This second sign of a tumor, invasive growth, is characteristic only of malignant tumors.

One of the most important characteristics of tumors is morphological. It tells you what tissue the tumor came from. The number of tumor types known today is about two hundred. Cancer is one of the types of malignant tumors, namely a malignant tumor arising from cells of epithelial tissue (mucous membranes, skin, glandular epithelium). There are several variants of the structure of cancer: squamous cell, basal cell, adenocarcinoma, etc., developing from different layers and types of epithelium. The most common glandular cancer is adenocarcinoma. Mucous membranes are found in most internal organs, so cancer can potentially occur in any of them.

Malignant tumors arising from tissue cells of mesenchymal origin (muscles, cartilage, bones, fatty tissue, etc.) are called sarcomas. Sarcomas develop more often in young people. Cancer occurs 10-15 times more often than sarcoma, and older people are more likely to get sick. In addition to cancer and sarcoma, there are many other malignant tumors: melanomas, various tumors of hematopoietic tissue.

3.1. THEORIES OF TUMORS

An increase in tissue volume in the area of ​​the pathological focus (swelling) accompanies some other non-tumor pathological processes - trauma, inflammation, etc. This is due to swelling and lymphocytic infiltration of the damaged area. Intensive cell proliferation also occurs during various physiological and pathological processes: during wound healing, productive inflammation, regeneration, organization of hematomas and encapsulation of foreign bodies, hyperplasia, etc. In all these cases it is adaptive and protective in nature. True tumors grow due to a quantitative increase in transformed cells.

Theoretical assumptions about the nature of tumors have been expressed for a long time, but hypotheses on the basis of which scientific research could be carried out appeared only in the 18th-19th centuries. with the advent of microscopy and the advent of histology. Ideas about the structure of tissues and the possibility of studying their deep layers using X-rays were also a serious stimulus for the development of oncology.

The early stage of ideas about the nature of oncological diseases is associated with the names of Virchow, Conheim, Fischer-Wasels and others. Based on a large clinical material, R. Virchow (1867) suggested the etiological significance of repeated mechanical and chemical damage for the occurrence of cancerous tumors. Conheim (1877) suggested the dystopia of embryonic primordia as the cause of the development of tumors. According to the Fischer-Wasels theory (1929), special importance was attached to regeneration in the process of oncogenesis, which can provoke the transformation of cells into tumor cells. The theory of chemical carcinogenesis was confirmed by clinical observations. At the end of the 18th century, P. Pott described scrotal cancer in chimney sweeps. In 1916, classic studies by Yamagiwa and Ichikawa were published, showing the possibility of obtaining animal tumors induced by coal tar.

Currently, there are various theories and hypotheses of oncogenesis - hereditary, chemical, viral, chromosomal, etc., none of which can yet be considered a single, generally accepted one. All theories reflect only different aspects of one process - damage to the cell genome.

It has now been proven that any living cell contains proto-oncogenes in its DNA structure. These are sections of the cell's genome, certain polypeptide compounds, which under certain conditions become active forms - oncogenes. The latter, in turn, cause blast transformation of the cell (malignant degeneration, carcinogenesis), which gives rise to tumor growth. There are a great many factors that contribute to the transition of proto-oncogene to its active form - chemicals, radiation, insolation, viruses, etc.

During tumor transformation processes are observed, the following are used to designate them: special terms. To understand the processes occurring in tumor tissue, it is necessary to distinguish between their contents.

Hyperplasia- increase in the number of cells without their qualitative changes. Proliferation- reproduction. Dysplasia- a process in which atypical proliferation is detected, a violation of the form of structuring and organization of cell layers; this phenomenon is mentioned most often to assess the degree of tumor transformation of the tissue as a whole. Depending on the severity of nuclear and cellular atypia, dysplasia of low, moderate and high degrees is distinguished, while the structure and shape of the cells change, they have different sizes and shapes. Dysplasia is usually accompanied by symptoms dystopia(layering, immersion) of cell layers. Whereas for each individual cell the degree of atypia on the way of its transformation into a tumor.

In a tumor cell, as a rule, its ultrastructural properties change dramatically. Studying tumor cells with electron microscopy allows us to trace the presence of a significantly larger number mitochondria, providing the cell with energy and increasing the intensity of metabolic processes. Abnormal mitochondria appear, their shape, size and location change. Additional nuclei appear in the cell. Often tumor cells are multinucleated, and the ratio of cytoplasm to nucleus usually changes in the direction of increasing the nucleus. A sharp atypia in the ultrastructure of all cell organelles can be traced; it is expressed in an increase in their number and shape. A significant amount appears in the tumor cell lysosomes and increasing their functional activity, aimed at ensuring the vital activity of the tumor cell through the hydrolysis of proteins, fats, carbohydrates and the formation of initial products that the cell cannot synthesize.

A significantly pronounced degree of atypia, determined by light and ultrastructural microscopy, is designated by the term "anaplasia". Tissue anaplasia- lack of cell differentiation, loss of cells’ ability to form normal tissue structures and their loss of specialized function, returning it to a more primitive type.

These morphological details bring anaplastic tumor cells and embryonic cells closer together to a certain extent and indicate their greater metabolic activity. When applied to tumors, this term is not accurate, since the cells do not return to previously passed stages of evolution. During tumorigenesis, cells acquire

differentiation other than normal during regeneration or embryogenesis, therefore it is more correct to use the term “cataplasia”. Cataplasia cells (cata- a prefix denoting movement from top to bottom) - an approach to a more primitive structure, immature tissue. In addition, phenomena can be observed in tumors metaplasia, which represents the replacement of one type of mature tissue with another, developing from the same germ layer, is a pathology of cell differentiation. Apoptosis- the process of programmed cell death is the main natural means of protection against excessive proliferation and tumor progression. Autonomy- uncontrolled growth.

The process of oncogenesis has its own patterns and stages. The main stages are as follows: initiation, promotion, division of the modified cell and, finally, the actual growth of the tumor. In phase initiation Irreversible damage to the cell genotype occurs: mutations, chromosomal rearrangements, the cell becomes predisposed to transformation. This latent period has different durations and different outcomes. Such a cell can remain and exist for some time among unchanged cells, and can die without turning into a tumor cell.

Further, at the same preclinical stage, after completion of the initiation phase, the phase begins promotions. There is an enhanced transformation of proto-oncogenes into oncogenes. The second phase is characterized by the fact that the cell acquires a phenotype corresponding to the altered genotype. The phenotype of the transformed cell is realized during its life in the form of atypia, varying degrees of external changes. This stage is also reversible and the cell can return to its normal phenotype. Long-term exposure to carcinogens is required for the transformed phenotype to become stable.

Initiation and promotion are caused by the action of carcinogens in the external or internal environment. The second phase of preclinical cancer ends with the division of such a transformed cell. This is the beginning of the growth of the tumor itself, which almost immediately becomes autonomous. The next stage is the fixation of the disturbed genotype in daughter cells - cloning. Then a colony of transformed cells begins to form. The size of the emerging colony of tumor cells does not yet exceed a formation with a diameter of 1-2 mm. In this form, this colony can exist indefinitely. Its duration

directly depends on the degree of loss of apoptotic mechanisms and the degree of immune response. Angiogenesis plays a significant role at this stage, which ensures the supply of nutrients to the site of tumor development. This process depends on the production of the appropriate vascular endothelial growth factor. The production of enzymes called metalloproteinases destroys the intercellular substance. At this point, vascular growth and increased proliferation of altered cells occur, and the actual phase of tumor growth begins. A colony of tumor cells receives conditions for further growth and spread and exit from the primary focus. The accumulation of tumor mass occurs not only due to intensive cell proliferation, but also due to a longer lifespan, as well as due to the increased supply of plastic agents to the tumor, which occurs due to the processes of neoangiogenesis.

At this stage of oncogenesis, the nature of cell division differs from all physiologically determined types of reproduction. The oncogene encodes messenger RNA, and the synthesis of a hormone or specific protein, for example epidermal growth factor, begins. At the same time, an excess number of receptors for this protein appears on the cell surface. Thus, the cell stimulates its own division, but the mechanisms of switching from the apoptosis program to another program remain unclear.

The receptors receive the signal from the synthesized protein, then this signal is transmitted to the cell nucleus and reaches the same oncogene. The latter disrupts the processes of natural regulation of the amount of protein produced and, instead of limiting its synthesis, a vicious circle of excess production arises, which is commonly called apocrine stimulation of the cell. At a certain stage, the effect of apocrine stimulation of one cell, due to the constant production of stimulating growth factors, is converted into paracrine stimulation of neighboring cells. First, the number of receptors on their surface increases, then the signal is transmitted to the cell nucleus, stimulating there the genes responsible for the production of the same factors. There is a violation of DNA repair, differentiation and apoptosis of cells, which leads to the development of precancer and cancer in the late stages of carcinogenesis.

The biochemical properties of cells that have lost normal differentiation change. Biochemical anaplasia of tumors

characterized by a number of metabolic features that distinguish them from normal tissues. Tumor tissue is rich in cholesterol, glycogen and nucleic acids. In tumor tissue, glycolytic processes predominate over oxidative ones; there are few aerobic catalytic systems, i.e. cytochrome oxidase and catalase. Pronounced glycolytic processes are accompanied by the accumulation of lactic acid in the tissue. This peculiarity of tumor metabolism also enhances its similarity to embryonic tissue, in which the phenomena of anaerobic glycolysis predominate. The set of hormonal and other specific receptors may change on the surface of tumor cells.

Tumor progression - changes in the properties of the tumor as it grows. It is usually associated with an increase in one or more of the listed properties towards greater aggressiveness, for example, there is a loss of sensitivity of the tumor to treatment with hormones and other drugs. These phenomena are associated with the accumulation and deepening of genetic disorders occurring in tumor cells. Tumor progression goes in the direction of increasing signs of malignancy.

3.2. STAGES OF CARCINOGENESIS. EXOGENOUS AND ENDOGENOUS CARCINOGENS

Modern science has unequivocally proven that any living cell on Earth contains proto-oncogenes (special polypeptide substances), which, under certain conditions, transform into an active form - oncogenes. But oncogenes already build the blast, malignant version of the cell, which gives rise to tumor growth. There are a great many factors that contribute to the transition of proto-oncogene to its active form - chemicals, radiation, insolation, viruses, etc. All these factors are inherently carcinogenic.

In accordance with modern ideas carcinogenesis - a multi-stage process of accumulation of genetic mutations and other DNA disorders, leading to disruption of the cell cycle, differentiation, apoptosis, as well as ineffective functioning of cellular immunity. Carcinogenesis undergoes several stages of accumulation of genetic changes of varying duration, and the time required for the final trans-

cell formation into a tumor cell varies not only among different tumors, but also among individual individuals. This is largely due to the duration of exposure to the carcinogen, its dose, and the body’s resistance.

Exposure to a carcinogen can be long-term in small doses or single, but of high intensity (solar radiation, radiation). Factors that promote the transition of proto-oncogene to an active form are called carcinogenic.

According to WHO experts (1979), "carcinogen “is an agent that, due to its physical or chemical properties, can cause irreversible changes and damage in those parts of the genetic apparatus that exercise control over somatic cells.” Among them, endogenous and exogenous carcinogens are distinguished. Exogenous Carcinogenic factors are usually divided into mechanical, physical, chemical, radiation, and viral. Of the many reasons that increase the risk of developing a malignant tumor in the body, their importance as a possible leading factor is unequal. It is estimated that nutritional factors in the development of cancer are leading and range from 30-35%. Smoking determines the development of cancer in 30%, viral agents - in 17%, alcohol - in 4%, environmental pollution - in 2%, family history - in 1-2%.

The most significant in the development of pretumor, and therefore tumor pathology, are the effects of mechanical factors (chronic injury) and various chemicals, entering the body with food, as well as smoking. So, 80-90% of all forms of cancer in humans are the result of environmental factors: chemicals, viruses, physical agents (X-rays, radium and ultraviolet rays). For radiation exposure, a non-threshold concept of carcinogenesis has been adopted. Even minimal doses of radiation can provoke blast transformation. Under the influence of radiation, tumors can develop in various organs. The risk of hemoblastosis occurring in the skin, bones, lungs, mammary and thyroid glands, etc. is considered to be greatest.

Carcinogenic substances include representatives of various classes of chemical compounds: polycyclic hydrocarbons, azo dyes, aromatic amines, nitrosamines, etc. A large number of carcinogenic agents related to polycyclic hydrocarbons (3,4-benzpyrene, 20-methylcholan-

tren, 9,10-dimethyl-1,2-benzanthracene, etc.), which have a local tumor-causing effect, aminonitrogen compounds (orthoamino-azotoluene, etc.), which have a selective organotropic effect, and some other classes of compounds. These are mainly polycyclic aromatic hydrocarbons, which are formed during the combustion of coal, oil, gasoline, and tobacco. Carcinogens enter the human body through inhalation, as well as through food and water. The most common carcinogen, 3,4-benzopyrene, which emerged as a consequence of urbanization and human industrial activity, is used as an indicator of air pollution.

Mutations in genes and changes in their function can occur under the influence of various reasons; in everyday conditions, the leading risk factors for cancer development are poor diet and smoking. The most significant, widespread and potentially removable carcinogenic factor is considered smoking. According to WHO estimates, approximately 80-85% of lung cancers, 80% of lip cancers, 75% of esophageal cancers, 40% of bladder cancers, and 85% of laryngeal cancers are associated with tobacco smoking. A clear indicator of the importance of smoking in the development of various tumors is the fight against tobacco smoking in the United States, as a result of which the number of cancer diseases decreases by approximately 0.5% per year. Russia ranks one of the first in the world in terms of smoking prevalence. Approximately 50-60% of men are active smokers, and the number of women smokers is very high.

An even more powerful carcinogen consumed by humans is ethanol. Each individual factor can cause a 2-3-fold increase in risk, and when combined, they increase the risk by more than 15 times. It has been revealed that drinking more than 100 ml of pure alcohol per day contributes to the development of tumors of the digestive organs, breast and a number of other diseases. The connection between alcohol consumption and an increased risk of developing tumors of the oral cavity, pharynx, esophagus, larynx, liver, mammary gland, lung, and colon has been proven by numerous epidemiological studies. For quite a long time, the statement about the dangers of smoking, even among oncologists, did not meet with understanding. A study with the simplest methodology (interviewing patients undergoing examination for suspected tumors, followed by comparison with final diagnoses) revealed a strong association with smoking of lung cancer, and in

subsequently and organs of the oral cavity, pharynx and larynx, prostate gland, kidneys, etc.

Exogenous factors include various substances that enter the body with food, and in some cases with drinking water. With them, the human body receives both substances that promote carcinogenesis and inhibit it. Increasing the consumption of fiber, pectins and fetates contained in vegetables and fruits helps bind carcinogens.

Normal intake of vitamins and microelements into the body is necessary for the stable operation of the system for neutralizing carcinogens and DNA repair. Epidemiological studies have shown that vitamin A and carotene play a significant preventive role in the development of epithelial neoplasms. In preventive measures, replenishment of carotene deficiency is ensured through appropriate nutritional supplements. The body's resistance to carcinogenic effects is also weakened by insufficient consumption and absorption of other vitamins, especially C, E, B2 and PP, which regulate the processes of keratinization and determine the viability of general immunity. Deficiency of these substances is a serious risk factor for the development of squamous cell carcinoma of the upper respiratory tract, digestive tract and lungs.

Various unfavorable environmental situations, individual and living conditions, habits, and dietary habits should also be considered exogenous. 30-70% of cases of colon cancer are associated with excess consumption of fats, salt, nitrites and nitrates, smoked foods and preservatives, deficiency of fiber and vitamins, and excess energy value of food. The role of fats, especially saturated fats, in the etiology and pathogenesis of cancer of the breast, prostate, colon and rectum, and lung has been proven.

Genotoxic carcinogens, activators and cocarcinogens include products contaminated nitrites, nitrates, salts of heavy metals, arsenic, beryllium, cadmium, lead, nickel etc. The study of such substances is important not only from the standpoint of elucidating the etiology of tumors, but also has other tasks - eliminating them from the human environment in order to prevent the formation of tumors.

Research in virology has led to the discovery of a number of viruses that cause tumors in animals. Currently

It has been proven that some human tumors are viral in nature. This is the Epstein-Barr virus, which causes nasopharyngeal cancer and Burkitt's lymphoma. Hepatitis B and C viruses are currently associated with hepatocellular cancer. These viruses are the second most important carcinogen in the world after smoking. Up to 80% of all primary malignant liver tumors are associated with these agents. In practice, the importance of preventing hepatocellular cancer has been shown. Widespread implementation of specific vaccination significantly reduces the risk of developing hepatocellular cancer among populations with a high level of infection.

Four families viruses identified as etiological agents of human malignant tumors. Cancer of the cervix, larynx, penis, vulva, anus, and skin is associated with human papillomavirus (HPV-16, HPV-18, HPV-33). Moreover, it is known that oncogenic viruses do not have species specificity (Zilber L.A., 1967, Svet-Moldavsky G.Ya., 1967). It has been established that viruses of the herpes group are synergists with human papillomaviruses in the etiology of genital neoplasms. This fact allows us to explain the mechanism of implementation of many risk factors. The importance of factors such as socioeconomic status and sexual promiscuity in the development of genital tumors has been noted. There is a clear dependence of the relative risk on the number of sexual partners and the intensity of the sexual history. This determines and allows for the development of measures for the prevention and early diagnosis of such diseases. For example, infection with the human papillomavirus and associated changes in the epithelium of the cervix are the basis for the formation of risk groups.

Some types of lymphomas are associated with viruses containing DNA, and the development of T-cell leukemia is associated with retroviruses containing RNA. To date, quite strong evidence has been accumulated of the viral origin of some other tumors: meningiomas, glioblastomas, melanomas, LGM, Kaposi's sarcoma. It is believed that the fact of infection with the human papillomavirus is not enough for the development of a tumor. The influence of some exogenous or endogenous cofactors is necessary to activate viral carcinogenesis. It has been proven that such exogenous cofactors can be smoking, as well as additional viral infections, such as herpes simplex (herpes symplex).

In some cases, contact with a certain substance triggers the development of a certain type of cancer. Thus, the most common factor provoking the development pleural mesothelioma- a rare tumor developing in the cavity of the pleura, pericardium or peritoneum - is contact with asbestos. The time elapsed between such contact and the development of the tumor can be 20 years or more. There was no clear connection between the intensity and duration of contact with asbestos and the location of tumor development. Most authors tend to believe that peritoneal tumors develop after longer exposure. These tumors are often diagnosed late, although they develop relatively slowly.

Contact with beryllium(production of cupronickel) provokes the development of chronic inflammatory changes in the lungs, against the background of which professional lung cancer develops, and less often cancer of other organs. Berylliosis is characterized by the formation of granulomas in the distal parts of the lungs with predominant localization in the lower and middle parts. In fact, this is a systemic disease, since the lymph nodes, liver, spleen, kidneys, skin, myocardium, etc. are involved.

Oncogenic effect X-rays and various radioactive sources noticed and actively studied from the very beginning of their use in medicine. Radioactive iodine causes the development of thyroid cancer, etc. The process of progression from low to high atypia can take anywhere from several months to several years. The development of cancer is a multi-stage and often quite lengthy process. More often, the appearance of a tumor is preceded by the appearance of precancerous formations. The progression of precancerous pathology is due to the ongoing effect of carcinogenic factors. Discontinuation of this action can prevent malignancy, even when the precancerous disease is on its way to cancerous transformation.

the birth has only a minor transformation left to undergo. The difference between a healthy and an atypical tumor cell can also be traced at the subcellular level. The standard set of 46 chromosomes can be more or less. The location and length of loci in chromosomes change, proto-oncogenes turn into oncogenes, which leads to the development of a tumor. The DNA content in the cell nucleus (cell ploidy) is currently recognized as a fairly reliable objective criterion for assessing the degree of dysplasia. The diploid set of chromosomes indicates a higher degree of cell differentiation. As tumors, both primary and metastatic, “naturally” develop, there is a tendency to accumulate and worsen signs of malignancy.

In the primary tumor and metastases, the level of malignancy varies. Typically, in metastatic tumors, the degree of disruption of cell differentiation is more significant than in the primary tumor, i.e. cells in metastases are less mature than in the primary tumor and this is manifested by more rapid growth of the metastasis than the primary tumor. The time for the appearance of metastases after recognition of the primary tumor may vary. Sometimes metastases develop very quickly and are diagnosed before the primary tumor is identified, although more often they develop after 1-2 years. In some cases, 7-10 years after removal of the primary tumor, so-called late, latent, dormant metastases develop.

Thus, a tumor is a pathology caused by damage to the genetic apparatus of the cell, which causes disturbances in the processes of division, differentiation, and renewal of cellular composition. Currently, the following stages of carcinogenesis are distinguished. In the early stages, these are changes at the level of the progenitor cell, or stem cell of a given tissue, followed by DNA damage, a mutation in the genome of the somatic cell, leading to the activation of proto-oncogenes, and the inactivation of apoptosis genes and suppressor genes. Particularly important in this process is the mutation of genes encoding the synthesis of proteins of growth factors and proteins that block these factors, as well as proteins that regulate the process of apoptosis, responsible for the suppression and destruction of defective cells. There is a violation of DNA repair, proliferation, differentiation and apoptosis of cells, which leads to the development of precancer and cancer in the late stages of carcinogenesis.

In the cells of most tumors, genetic defects are multiple. Mutations at the early stages of cell differentiation have a greater carcinogenic effect. The process of malignancy is multi-stage and is accompanied by complex gene damage. An interesting two-stage theory of carcinogenesis developed by A.G. Knudson (1971). According to this theory, the first mutation in the genetic apparatus can occur at the stage of the germ cell. Since the resulting mutation is inherited, this leads to the formation of a clone of cells with a high risk of tumor transformation. Subsequent genetic damage occurs much later in the corresponding target tissue. This causes familial, hereditary forms of cancer. In this regard, a distinction is made between sporadic forms of cancer, when both stages of damage occurred during life, and hereditarily determined forms, when the second “blow” fell on the genetic cellular apparatus already prepared from birth.

The process of blast transformation constantly occurs in the body. Over the course of a day, about a million mutated cells can form in the body, which is a volume of about 0.1 cm. With an adequate rise in immune tension, cells dangerous to the body die, and a tumor does not arise. Some of them are transformed into normal ones, and the majority are destroyed by the body, since they are recognized as foreign. Why a malfunction in the immune system occurs and another potential tumor cell is not destroyed remains unclear. The older the organism, the more reason to expect the occurrence of disturbances in immune processes in various organs. Therefore, tumors still remain a disease of older people.

The development of a malignant tumor can continue for several years. The average growth rates of tumors are known. From the formation of the first cancer cell to a tumor with a diameter of 2 cm in breast cancer, it takes about 3 years (Denox, 1970). According to other data, for breast cancer the average cell doubling time is 272 days. This means that it takes about 10 years for a tumor the size of one cubic centimeter to develop. On average, stomach cancer grows slightly faster. It is believed that approximately 2-3 years pass from the onset of stomach cancer to its clinical manifestation. Lung cancer up to a size of 1.0-1.5 cm in diameter develops within 6-8 years, and stomach cancer -

within 5-7 years. Initial and preclinical stages of cervical cancer, according to V.K. Vinnitskaya (1979), last 12-15 years. Sometimes lightning-fast forms of growth occur - within a few months.

Endogenous factors. The occurrence of tumors is also possible against the background of changes in the internal environment of the body, in particular due to hormonal imbalance. Hormonal factors are the most important. The role of estrogens in the development of breast cancer is generally accepted. Estrogen replacement therapy, carried out for a number of pathological conditions, leads to an increased risk of developing endometrial cancer. Long-term chronic diseases that reduce immunity, embryogenesis defects, etc. belong to endogenous risk factors for the development of cancer. Some endogenous metabolic products also have carcinogenic properties: steroid hormones, tryptophan metabolites, etc. when they accumulate excessively or undergo qualitative changes. It is known that tumorigenesis is stimulated by obesity, which is always accompanied by an excess of estrogen.

The appearance of a malignant tumor can be facilitated by endogenous factors such as a hereditary predisposition to cancer, past illnesses and a decrease in immunological status. It has been established that tumor growth is accompanied by damage to T- and B-lymphocytes and a decrease in the overall immunological reactivity of the body. Quite often in clinical practice, long-term inflammatory processes are observed, which are accompanied by pronounced proliferation processes. Often a tumor develops against the background of a benign neoplasm.

3.3. MODERN THEORIES OF CARCINOGENESIS

The most common idea about the causes of tumor diseases is the so-called polyetiological a theory suggesting the possibility of tumor development under the influence of various tumor-causing factors listed above.

In addition to polyetiological, it has independent significance viral theory, since there is an idea that viruses play a role in the occurrence of all tumors, and various carcinogenic agents have only a contributing role. According to some

virologists (Zhdanov V.M.), saprophytic viruses or viruses that cause infectious diseases (herpes viruses, adenoviruses, etc.) can have an oncogenic effect.

According to this theory, there are various viruses in the cell that are in a state of biological equilibrium with the cell and the whole organism. Pathological processes do not arise until this balance is disturbed. The cell and the virus are constantly exposed to various factors of the external and internal environment (physical and chemical), and under certain conditions the virus acquires the ability to penetrate the cell’s genome. This leads to a number of pathological changes in the cell, most often to its death, but an oncogenic effect is also possible. The apoptosis mechanism is disrupted and the cell life cycle is not completed on time. All this indicates great difficulties in the search for antiviral prevention of tumors.

The only specific area of ​​cancer prevention remains the prevention of exposure of the body to those numerous physical and chemical factors of the external and internal environment that provoke the oncogenic effect of viruses on the cell. The main directions of modern prevention of malignant tumors are based on this.

The theory is relatively new tissue mechanism of carcinogenesis. It is based on disruption of tissue homeostasis as a result of long-term chronic proliferation, causing disruption of cell differentiation. The tissue theory of carcinogenesis is an alternative to the currently dominant mutational (clonal-selection) concept of cancer, according to which tumor cells are the result of mutations and subsequent selection and cloning of cells that have fundamental differences not only from the progenitor cell, but also from the stem cell included into the composition of this fabric. There is ample evidence that stem cells and progenitor cells (“committed” cells) have a certain “malignancy” even in the absence of a carcinogenic effect on the tissue.

In summary, the main provisions of the tissue theory of carcinogenesis are as follows. Carcinogenic (damaging) effects on tissue cause, on the one hand, the death of a certain number of cells, and on the other, stimulate compensatory chronic proliferation. In the tissue the con-

concentration of growth factors and the concentration of kelons, which control stem cell division, decreases. The number of stem and committed cells in the tissue increases. The so-called “embryonicization” of tissue occurs, cells lose transmembrane receptors and adhesion molecules, and the “malignancy” of stem and committed cells is fully manifested in the absence of tissue control over the mitotic cycle. A malignant tumor appears and the process of metastasis develops.

The tissue theory of carcinogenesis logically substantiates the origin of tumors against the background of some precancerous conditions, but it is unlikely that it can be fully used to explain viral carcinogenesis and tumor cell transformations as a result of reliable DNA mutations under the influence, for example, of radiation factors. In the tissue theory of cancer, decisive importance is attached to changes in intercellular and intertissue relationships, which is not denied in the polyetiological theory, but in the latter these factors are not given such decisive importance. As is most often the case, the truth obviously lies in the middle: mutational and tissue theories of carcinogenesis complement each other and can be used to create a unified theory of the origin of malignant tumors.

The growth and development of a tumor are undoubtedly dependent on the state of reactivity of the body. Resistance to the effects of carcinogens is individual, generally depends on the immune system and correlates with the general resistance of the body. The body's ability to neutralize carcinogens to certain limits has been proven, which determines the difference in the dose and timing of their exposure, which ultimately causes the development of a tumor. This became quite obvious when specific tumor antigens were discovered in tumor cells, and they were different in different tumors. Tumor cells containing antigens foreign to the body induce the formation of humoral antitumor antibodies, but their role in the development of protective antitumor immunity is insignificant.

Much more important is cellular immunity, which develops according to the type of transplantation immunity. Morphologically, this process is manifested by the accumulation in the tumor stroma and especially in the tissue bordering the tumor of immunocompetent cells: T- and B-lymphocytes, plasma cells, macrophages. Clinico-mor-

Phological observations show that in cases where the tumor stroma is rich in immunocompetent cells, the tumor develops slowly. In the absence of such infiltration, tumors grow rapidly and metastasis occurs early. In addition, it was noted that in the early stages of tumor development, even before the appearance of metastases, there are signs of antigenic stimulation in regional lymph nodes in the form of hyperplasia of lymphatic follicles with an increase in the size of their reproduction centers. It has also been established that blood lymphocytes from patients with a tumor process have a direct cytotoxic effect on tumor cells, destroying them in tissue culture.