Theories of the pathogenesis of tumor growth. Stages of carcinogenesis

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 estrogenic 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.

1. Induction (initiation) consists of a mutation in one of the genes that regulate cell reproduction (proto-oncogene turns into oncogene) → the cell becomes potentially capable of unlimited division; initiating factors are various carcinogens .

2. Promotion (acceleration) - stimulation of cell division by promoters, due to which a critical mass of initiated cells is created. Promoters are chemical substances that do not cause DNA damage and are not carcinogens. Oncogenes begin their activity → oncoproteins are synthesized → the number of initiated cells increases.

3. Progression - along with an increase in tumor mass, it constantly acquires new properties, “becomes malignant” - increasing autonomy from the regulatory influences of the body, destructive growth, invasiveness, the ability to form metastases (usually absent in the early stages) and, finally, adaptability to changing conditions.

A tumor is a progeny (clone) of one primary cell, which, as a result of a multi-stage process, has acquired the ability to grow unregulated. The primary transformed cell passes on its properties only to its descendants, i.e. "vertically". In this case, the normal cells surrounding the tumor are not involved in the process of degeneration. This idea is called the provision on clonal origin of the tumor.

Tumor clonal heterogeneity develops due to genetic instability of the tumor cell. This leads to the emergence of new clones that differ genotypically and phenotypically. As a result of selection, the most malignant clones are selected and survive. After chemotherapy, only 0.1% of tumor cells remain, but since the cell cycle is 24 hours, the tumor can recover after 10 days and be resistant to previous chemotherapy.

Properties of tumor growth. Atypisms. The effect of a tumor on the body.

Atypism(from a + Greek typicos - exemplary, typical) - a set of characteristics that distinguish tumor tissue from normal tissue and constitute the biological characteristics of tumor growth.

Anaplasia or cataplasia(from ana - reverse, opposite, kata - down + Greek plasis - formation) - a change in the structure and biological properties of the tumor, making them similar to undifferentiated tissue.

The term was introduced due to a certain formal similarity between tumor cells and embryonic cells (intensive reproduction, enhanced anaerobic glycolysis). At the same time, tumor cells are fundamentally different from embryonic ones. They do not mature, are capable of migration and invasive growth into surrounding neighboring tissues, destroying them, etc.

Lecture on pathological physiology

topic Carcinogenesis.

Carcinogenesis is the process of development of tumors of any type. The last stage of tumor growth, with visible manifestations, is called malignancy (malignancy). General signs of malignancy:

1. The cell acquires the ability for uncontrolled, unrestrained reproduction and division

2. Hyperplasia in parallel with uncontrolled cell division, a violation of differentiation is observed, remains immature, young (this property is called anaplasia).

3. Autonomy (independent of the body), from stimuli that control and regulate vital processes. The faster the tumor grows, the less differentiated the cells are, as a rule, and the more pronounced the autonomy of the tumor is.

4. A benign tumor is characterized by a violation of proliferation, there is no violation of differentiation; with the growth of a benign tumor, the cells simply increase in number, pushing apart or squeezing the surrounding tissues. And malignant tumors are characterized by so-called infiltrative growth, tumor cells germinate (like cancer cells) destroying surrounding tissues.

5. Ability to metastasize. Metastases are cells that can spread throughout the body by hematogenous, lymphogenous routes and form foci of the tumor process. Metastases are a sign of a malignant tumor.

6. Tumor tissue has a negative effect on the body as a whole: intoxication caused by the products of tumor metabolism and tumor decay. In addition, the tumor deprives the body of necessary nutrients, energy substrates, and plastic components. The combination of these factors is called cancer cachexia (exhaustion of all life support systems). The tumor process is characterized by pathological proliferation (uncontrolled cell division), impaired cell differentiation and morphological, biochemical and functional atypia.

Atypia of tumor cells is characterized as a return to the past, that is, a transition to more ancient, simpler metabolic pathways. There are many features that distinguish normal cells from tumor cells:

1. Morphological atypia. The main thing is the change in the cell membrane:

In tumor cells, the contact surface area decreases, the number of nexuses - contacts that ensure the adhesiveness of cell membranes - decreases, the composition of membrane glycoproteins changes - carbohydrate chains are shortened. Embryonic proteins that are unusual for mature cells begin to be synthesized in the cell, and the amount of phosphotyrosines increases. All this leads to a violation of the properties of contact inhibition, increasing the lability and fluidity of the membrane. Normally, cells that come into contact with each other stop dividing (self-regulation of the division process takes place). In tumor cells, the lack of contact inhibition leads to uncontrolled proliferation.

Biochemical atypia. Atypia of energy metabolism is manifested in the predominance of glycolysis, a more ancient metabolic pathway. In tumor cells, a negative Pasteur effect is observed, that is, intense anaerobic glycolysis when changing anaerobic to aerobic conditions does not decrease, but remains (increased glycolysis in tumor cells determines their high survival rate under hypoxic conditions). The tumor actively absorbs nutrients. The phenomenon of substrate traps is observed, which consists in increasing the affinity of the enzyme for the substrate (glucose), in tumor cells the activity of hexokinases increases 1000 times. Tumor cells are also protein traps, which also leads to cachexia.

The predominance of glycolysis leads to an increase in the concentration of lactic acid in tumor cells; acidosis is characteristic, leading to disruption of the vital functions of the cell itself (the necrosis zone is usually located in the center of the tumor).

Atypia in the regulation of growth and differentiation of tumor cells. The processes of growth and division differentiation are normally under the control of central endocrine regulation, which is carried out by somatotropic hormone, thyroid hormones, and insulin. In addition to these general factors, each tissue has its own growth and differentiation factors (epidermal growth factor, platelet factor, interleukin). Induction of growth and differentiation begins with the interaction of a growth factor with a growth factor receptor on the cell membrane (this stage may be disrupted in a tumor cell). At the next stage, secondary messengers are formed - cyclic adenosine and guanosine monophosphate, and normal growth and differentiation is characterized by the predominance of cyclic adenosine monophosphate (cAMP). The formation of cyclic guanosine monophosphate is combined with increased proliferation. This is a typical sign in tumor cells. At the next stage, active protein kinases are formed, the function of which is phosphorylation of cellular proteins. Normally, protein kinases phosphorylate proteins at serine, threonine, and histidine. In tumor tissue, protein kinases are tyrosine-dependent, that is, protein phosphorylation occurs on tyrosine. Stimulation of proliferation is associated with the formation of proteins phosphorylated at tyrosine.

Regulation of tumor cell growth and differentiation is also associated with calcium-dependent protein kinase. Normally, calcium-dependent protein kinase functions as a modulator and balances the processes of growth and differentiation. A tumor cell is always characterized by hyperreactivity of calcium-dependent protein kinase, while it acts as a proliferation inducer, it stimulates the formation of phosphotyrosine and enhances uncontrolled cell proliferation.

Theories of development of the tumor process.

In 1755, English scientists published a study “On cancer of the skin of the scrotum in chimney sweeps.” Cancer in this work was considered as an occupational disease that affected chimney sweeps at the age of 30-35 years (the question of the localization of the tumor in the scrotum still remains unclear). While cleaning chimneys, chimney sweeps rubbed soot into their skin and after 10-15 years they developed skin cancer . Explaining the mechanisms of development of this form of cancer marked the beginning of a new era in the study of the tumor process. 2 main factors causing the development of cancer were identified - constant irritation, damage; the effect of certain substances (soot) that have been called carcinogens. Many carcinogenic substances are now known. This model of the disease was reproduced by Japanese scientists who rubbed soot into a rabbit's ear for a year and obtained first a benign (papilloma) and then a malignant tumor.

Carcinogenic substances that are found in the external environment are called exogenous carcinogens: benzpyrenes, phenanthrenes, polycyclic hydrocarbons, aminoazo compounds, aniline dyes, aromatic compounds, asbestos, chemical warfare agents, and many others. There is a group of endogenous carcinogens - these are substances that perform a certain useful function in the body , but under certain conditions can cause cancer. These are steroid hormones (especially estrogens), cholesterol, vitamin D, and tryptophan conversion products. Cancer has even been obtained by administering substances such as glucose and distilled water under certain conditions. Tumor processes belong to the group of polyethylological diseases, that is, there is no one main factor that would contribute to the development of the tumor. It occurs through a combination of multiple conditions and factors, including hereditary predisposition or natural resistance. Lines of nuller animals have been bred that never get cancer.

The action of carcinogenic substances is very often combined with the action of physical factors - mechanical irritation, temperature factors (in India, skin cancer among porters of vats of hot coal, among northern peoples there is a higher incidence of esophageal cancer due to the consumption of very hot food: hot fish. In smokers contribute to the development of lung cancer the following factors - high temperature, which is created by smoking, chronic bronchitis - causing active proliferation, and tobacco contains methylcholanthrenes - strong carcinogens. An occupational disease among sailors is facial skin cancer (exposure to wind, water, ultraviolet radiation from the sun) , radiologists have an increased incidence of leukemia.

The third etiological group is viruses. One of the main confirmations of the viral theory of cancer is the inoculation of the non-cellular filtrate of an animal with a tumor into a healthy one. The non-cellular filtrate contained the virus and the healthy animal became ill. Leukemia was transferred from sick chickens to healthy chickens, and it was possible to induce leukemia in almost 100% of chickens. Over 20% of different viruses have been described, which are capable of causing various forms of the tumor process in almost all experimental animals. The transmission of cancer-causing viruses through milk has been discovered. The offspring of low-cancer mice were placed with a high-cancer female (the mice belonged to low-cancer and high-cancer lines. Low-cancer lines did not spontaneously develop cancer, while high-cancer lines developed cancer in almost 100% of cases). This is how the milk factor of a viral nature was discovered, a virus was discovered that causes disease in humans - the Epstein-Barr virus (we cause lymphoma).

So, 3 main theories of carcinogenesis have been formulated, corresponding to three main etiological groups:

1. carcinogenic substances

2. physical factors

3. biological factors - viruses.

The main theories explaining the pathogenesis of cancer are:

· mutation theory of carcinogenesis, which explains the development of the tumor process as a consequence of mutation. Carcinogenic substances and radiation cause a mutation process - the genome changes, the structure of cells changes, and malignancy occurs.

· Epigenomic theory of carcinogenesis. Hereditary structures are not changed, the function of the genome is disrupted. The epigenomic mechanism is based on derepression of normally inactive genes and depression of active genes. The basis of the tumor process, according to this theory, is the derepression of ancient genes.

· Viral theory. Viruses can persist in cells for a long time, being in a latent state; they are activated under the influence of carcinogens and physical factors. The virus is integrated into the cellular genome, introducing additional information into the cell, causing disruption of the genome and disruption of the cell's vital functions.

All these theories formed the basis of the modern concept of oncogenes. This is the oncogene expression theory. Oncogenes are genes that contribute to the development of the tumor process. Oncogenes were discovered in viruses - viral oncogenes, and similar ones discovered in cells - cellular oncogenes (src, myc, sis, ha-ras). Oncogenes are structural genes that encode proteins. Normally, they are inactive and repressed, which is why they are called protoncogenes. Under certain conditions, activation or expression of oncogenes occurs, oncoproteins are synthesized, which carry out the process of transforming a normal cell into a tumor cell (malignization). Oncogenes are designated by the letter P, followed by the name of the gene, say ras, and a number - the molecular weight of the protein in microdaltons (for example Pras21).

Lecture on pathological physiology.

Lecture topic: carcinogenesis (part 2).

Classification of oncoproteins.

Oncoproteins are classified by localization into the following groups: 1. Nuclear, 2. Membrane, 3. Cytoplasmic proteins.

Stable localization of only nuclear oncoproteins, while membrane and cytoplasmic ones can change: membrane proteins move to the cytoplasm and vice versa. Based on their function, there are 5 groups of oncoproteins:

1. Nuclear DNA-binding proteins - mitogens. They perform the function of stimulating cell division. This group includes the products of the oncogenes myc, myt.

2. Guanosine triphosphate-binding oncoproteins. This group includes products of the ras family of oncogenes. Guanosine phosphate-binding oncoproteins promote the accumulation of cyclic guanosine monophosphate in the cell, which contributes to the orientation of the cell towards tumor growth.

3. Tyrosine-dependent protein kinases. Promote tyrosine phosphorylation of proteins, increase the content of phosphotyrosines in the cell. The targets for oncoproteins are vinculin and fibrinogen. When the oncoprotein acts on these targets, the content of phosphotyrosines in them increases by 6-8 times. With an increase in phosphotyrosines in these membrane proteins, the properties of the cell membrane change. First of all, the adhesive property is reduced and contact inhibition is impaired.

4. Homologues of growth factors and growth factor receptors. Growth factors are formed outside the cell, transferred hematogenously, and interact with specific receptors. If an oncoprotein is formed that performs the function of a growth factor, it is formed in the cell itself as a result of oncogene expression, then interacts with receptors, leading to growth stimulation (the mechanism of autocrine growth stimulation). An example of such an oncoprotein is the product of the sis oncogene. The P28sis oncoprotein is nothing more than a platelet-derived growth factor, that is, in normal tissues it stimulates the formation of platelets; its targets are platelet precursor cells. In this case, the sis gene is weakly expressed, but if oncogene expression occurs, platelet-derived growth factor begins to form inside the cells and stimulates cell growth.

Oncoproteins can function as growth receptors; they are also formed in the cell as a result of oncogene expression and are localized in the cell membrane, but unlike a normal receptor. The oncoprotein receptor begins to interact with any growth factor, loses specificity, and stimulates cell proliferation.

5. Modified membrane receptors (pseudoreceptors). This group contains proteins belonging to the group of tyrosine-dependent protein kinases, but there are others. The pseudoreceptor combines two functions - the function of growth factor and growth factor receptor. In order for proteins to begin to perform their function, the expression of proto-oncogenes into oncogenes is necessary.

Mechanism of proto-oncogene expression.

The expression of proto-oncogenes is associated with the action of various carcinogenic factors - ionizing radiation, chemical carcinogens, viruses. There are 2 types of influence of viruses:

1. In the structure of the virus, the oncogene usually does not perform any function. When a viral oncogene is introduced into the cellular genome, it is activated (the insertion mechanism itself activates the oncogene), and oncoprotein is synthesized.

2. The virus can carry into the cell not an oncogene, but a promoter gene. A promoter is a factor that does not have a carcinogenic effect, but under certain conditions it can enhance this process. In this case, the promoter must be embedded near the cellular proto-oncogene.

Chemical and physical carcinogenic factors stimulate the mutational mechanism of oncogene expression. The mutation mechanism is based on somatic mutations, that is, mutations that occur in tissues and organs that are not inherited. By their nature, they can be either chromosomal or genetic. Chromosome mutations include chromosomal aberrations, deletions, translocations, inversions - all options when a chromosome break occurs, which leads to the expression of oncogenes at the site of the break as the oncogene is released from the compensating influence of the genome. In the process of chromosomal aberrations, the influence of a promoter gene can be revealed, which can be transferred from one chromosome to another, to another part of the chromosome. In chronic myeloid leukemia, an altered Philadelphia chromosome 22 is found with great constancy in leukocytes. It is characterized by the loss of part of the shoulder. It has been established that this mutation is a consequence of the mutual translocation of chromosomes 9 and 22, with the 9th chromosome receiving an excess of material, and the 22nd losing part of the arm. During the process of mutual translocation from chromosome 9 to 22, a promoter is transferred, which is inserted next to the oncogene. The consequence is stimulation of the oncogene myc, which produces a DNA-binding oncoprotein - mitogen.

Point mutations can also lead to the expression of oncogenes, and point mutations are typical for some oncogenes (oncogenes of the ras family). There may be a mutation in the oncogene itself or in the regulator gene with a change in the repressor, which regulates the activity of the oncogene, and the oncogene is activated. The next mechanism of oncogene expression is associated with the action of transposons. Transposons are moving, wandering or jumping genes. They move along the DNA and can be inserted into any site. Their physiological function is to enhance the activity of a particular gene. Transposons can function and express oncogenes by serving as promoters. It has been noted that during the process of carcinogenesis, the activity of the mutation process and the activity of transposons increases sharply, and the repair mechanisms sharply decrease.

Amplification is also a physiological mechanism for regulating genome activity. This is an increase in gene copies obtained to enhance gene activity, up to 5, to a maximum of 10 copies. Under carcinogen conditions, the number of copies of oncogenes reaches hundreds (500-700 or more; this is the epigenomic mechanism of oncogene expression.

Another epigenomic mechanism is DNA demethylation. Under the influence of chemical carcinogens and active radicals, the process of DNA demethylation occurs. the demethylated site becomes active.

In order for a normal cell to transform into a tumor cell, a group of oncogenes must be activated (from 2 to 6-8 or more oncogenes. The mechanisms of interaction of oncogenes are currently being studied. It is known that the mutual activation of oncogenes is a chain reaction, that is, the product of one oncogene activates a new oncogene etc.

Stages of carcinogenesis:

1. Initiation

2. Transformation

3. Tumor aggression

Under the influence of carcinogens, a certain group of oncogenes is activated in the cell. At the initiation stage, expression of the oncogenes myc and mut is most often observed (the products of these oncogenes are DNA-binding mitogens), and uncontrolled proliferation is stimulated. differentiation does not occur, the function is preserved. This is a long hidden - latent phase. The duration of the initiation phase is approximately 5% of the lifespan of the species (in humans, depending on the type of tumor - 5, 10, 12 years, sometimes much shorter). At the initiation stage, the Hayflick limit is removed. It is typical for a normally developing cell to perform no more than 30-50 mitoses, then division stops and the cell dies. This limitation on the number of mitoses is called the Hayflick limit. This is not the case in a tumor cell; the cell divides continuously and uncontrollably. A cell in the initiation phase is called immortal (immortal) since it continuously reproduces itself; the initiation phase is called the immortalization phase. A cell in this phase can return to the path of normal development, or it can move to the next phase of development - the transformation phase.

Transformation occurs if the initiated cell continues to be affected by a carcinogenic factor and expression of a new group of oncogenes occurs. In cell culture, the expression of oncogenes of the ras family characteristic of this phase is observed with the greatest constancy; the products of these oncogenes bind guanosine triphosphate. expression of the sis oncogene also occurs during this phase. The expression of these oncogenes leads to the final malignancy of the cell - differentiation and proliferation are impaired. The formation of single tumor cells does not yet lead to a tumor process. Tumor cells have the property of being foreign (antigens) to the body. It is believed that tumor cells are constantly formed, but with sufficient immune control they are destroyed. The transition to the stage of tumor progression depends on the state of immunological reactivity.

The antigenic properties of a tumor cell are manifested by several mechanisms:

1. antigenic simplification. The qualitative change in glycoproteins is especially important - carbohydrate chains are shortened.

2. Antigenic complication - the appearance of unusual components - an increase in phosphotyrosines.

3. Reversion (return to the past) - the appearance of embryonic proteins in the membrane of the tumor cell. Embryonic proteins - alpha-ketoprotein, etc.

4. Divergence.

Antigenic components appear in tissues that are unusual for the tissue. Divergence is like an exchange of antigenic fragments. Thus, there is no absolutely foreign antigen; all antigens are modifications of the body’s own tissue; these are weak mosaic antigens.

There are several levels of protection against tumor antigen:

1. function of natural killer cells (natural killer cells) - they create the main antitumor protection. They recognize a tumor cell by negative information - the absence of long glycoproteins, etc. the killer contacts the tumor cell and destroys it.

2. Sensitized killer T cells also destroy foreign cells. The role of humoral immunity is controversial. It is believed that a complex of antibodies on the surface of tumor cells prevents the killer effect.

It has been shown that with immunodeficiencies, the risk of developing tumors increases by 1000 times, and sometimes by 10,000 times, as well as with long-term use of immunosuppressants, gliocorticoids.

The stage of tumor progression is already characterized by clinical manifestations - the mass of the tumor increases, infiltrative growth and metastasis are observed, and ends with cancer cachexia.

The process of vascular development in a tumor is controlled by the oncoprotein angiogenin (they are now trying to use blockers of this protein to treat the tumor).

A constant sign of tumor growth is an increase in the number of T-suppressors in relation to T-helpers (it is not clear whether this is a primary or secondary mechanism).

It is known that tumors are capable of regrowth. In lizards and newts, tumors often form in the zone of active regeneration (tail), which are capable of resolving themselves. Cases of tumor resorption in humans have been described, but the mechanism of this phenomenon has not yet been studied.

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

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

Theories of carcinogenesis

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

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

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

• oncogenes - genes that are activated in tumors, causing increased proliferation and reproduction and suppression of cell death; oncogenes exhibit transforming properties in transfection experiments;
• non-mutated oncogenes act at key stages of the processes of proliferation, differentiation and programmed cell death, being under 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.

Question

Tumor - This is a typical tissue growth disorder, manifested in the uncontrolled proliferation of cells, which are characterized by atypia, or anaplasia.

Under atypisms understand the set of characteristics that distinguish tumor tissue from normal tissue and that constitute the biological features of tumor growth.

Anaplasia - a term emphasizing the similarity of a tumor cell with an embryonic one (increased reproduction, intensive process of glycolysis, etc.). But tumor cells are not identical to embryonic ones: they grow, but do not mature (do not differentiate), are capable of invasive growth into surrounding tissues with destruction of the latter, etc.

The causes of tumor development are various factors that can cause the transformation of a normal cell into a tumor cell. They are called carcinogenic or blastomogenic. These are agents of a chemical, physical and biological nature, and the main condition contributing to the implementation of their action (risk factor) is a decrease in the effectiveness of the body's antitumor defense mechanisms. This is largely determined by genetic predisposition. The properties of carcinogenic factors that ensure tumor transformation of cells are mutagenicity (the ability to directly or indirectly influence the cell genome, which ultimately leads to mutations), the ability to penetrate through external and internal barriers and the dosage of action, which ensures minor damage to the cell, which allows it survive.

Along with carcinogenic factors, there are a number of substances that, without causing mutations themselves, are obligatory participants in carcinogenesis - cocarcinogens And syncarcinogens. Cocarcinogens are non-mutagenic factors (promoters) that enhance the effect of carcinogenic agents. Cocarcinogenesis is the enhancement of the mutagenic effect of a carcinogen by compounds that stimulate cell proliferation by inactivating protein products of antioncogenes or enhancing the transmission of growth-stimulating signals. Syncarcinogens are carcinogenic factors that cause increased tumor formation through the combined action of several known carcinogens.

CHEMICAL CARCINOGENS

According to WHO, more than 75% of human malignant tumors are caused by exposure to chemical environmental factors. Potentially carcinogenic substances by themselves do not cause tumor growth. Therefore, they are called procarcinogens, or precarcinogens. In the body they undergo physical and chemical transformations, as a result of which they become true, ultimate carcinogens. Ultimate carcinogens are alkylating compounds, epoxides, diolepoxides, free radical forms of a number of substances.

Tumors are caused predominantly by tobacco combustion factors (approximately 40%); chemical agents included in food (25-30%) and compounds used in various areas of production (about 10%). More than 1,500 chemical compounds are known to have a carcinogenic effect. Of these, at least 20 are definitely the cause of tumors in humans. The most dangerous carcinogens belong to several classes of chemicals (Fig. 1).

Rice. 1 Main classes of chemical carcinogens.

Organic chemical carcinogens

Polycyclic aromatic hydrocarbons.

Among them, 3,4-benzpyrene, 20-methylcholanthrene, and dimethylbenzanthracene have the greatest carcinogenic activity. Every year hundreds of tons of these and similar substances are released into the atmosphere of industrial cities.

Heterocyclic aromatic hydrocarbons.

This group includes dibenzacridine, dibenzcarbazole and other compounds.

Aromatic amines and amides.

These include 2-naphthylamine, 2-aminofluorene, benzidine, etc.

Nitroso compounds. The most dangerous among them are diethylnitrosamine, dimethylnitrosamine, and nitrosomethylurea.

Aminoazo compounds.

Among them, 4-dimethylaminoazobenzene and orthoaminoazotoluene are considered highly effective carcinogens.

Aflatoxins are metabolic products (coumarin derivatives) of molds, mainly Aspergillus flavus (hence the name of the substances they produce).

Other organic substances with carcinogenic activity: epoxides, plastics, urethane, carbon tetrachloride, chlorethylamines and others.

Inorganic carcinogens

Exogenous: chromates, arsenic and its compounds, cobalt, beryllium oxide, asbestos and a number of others.

Endogenous. These compounds are formed in the body as a result of physicochemical modification of normal metabolic products. It is believed that such potentially carcinogenic substances are bile acids, estrogens, some amino acids (tyrosine, tryptophan), lipoperoxide compounds.

Question

PHYSICAL CARCINOGENIC FACTORS

The main carcinogenic agents of physical nature are:

1. Ionizing radiation

A). α-, β- and γ-radiation, the source of which is radioactive isotopes (P 32, I 131, Sr 90, etc.),

b). x-ray radiation,

V). neutron flux,

1. ultraviolet radiation.

Individuals chronically, periodically, or once exposed to these agents often develop various malignant neoplasms. In patients treated with drugs containing radioactive substances, neoplasms occur at a higher frequency than in the general population (for example, liver tumors in patients who were repeatedly injected with the radioactive contrast agent Thorotrast). The incidence of thyroid cancer increased sharply in individuals exposed to radioactive iodine during the Chernobyl nuclear power plant accident.

Question

Types of oncogenic viruses

Based on the type of viral nucleic acid, oncogenic viruses are divided into DNA-containing and RNA-containing.

DNA viruses

The genes of DNA oncoviruses are capable of directly inserting into the genome of the target cell. A section of DNA oncovirus (the oncogene itself), integrated with the cellular genome, can carry out tumor transformation of the cell. It is also possible that one of the oncovirus genes may play the role of a promoter of a cellular proto-oncogene.

Viral oncogenes and cellular genes that control the cell cycle and proliferation have both similarities and important differences. In this regard, they talk about proto-oncogenes and oncogenes.

Proto-oncogene- gene of the normal human genome; participates in the regulation of cell proliferation. The expression products of proto-oncogenes are in many cases important for normal cell differentiation and cell-cell interactions. As a result of somatic mutations, a proto-oncogene can become oncogenic. In this case, the prefix c- (from cellular) can be added to the name of the proto-oncogene; viral homologues are marked with the prefix v- (from viral).

Oncogene- one of the genes that, under normal conditions (i.e., as a proto-oncogene), encodes a protein that ensures the proliferation and differentiation of cell populations (protein kinases, nuclear proteins, growth factors). In tumor DNA viruses, oncogenes encode normal viral proteins; Oncogenes, however, can provoke - if they are mutated or activated by retroviruses - malignant growth. Numerous oncogenes have been identified (eg, ras [bladder tumors]); p53, a mutant gene on chromosome 17 (normally involved in the repair of ultraviolet-induced gene defects). Mutations of p53 are responsible for the development of breast, cervical, ovarian, and lung cancer; the malignant effects of oncogenes can be enhanced by retroviruses, so-called jumping genes, mutations. Oncogenes are found in some DNA tumor viruses. They are necessary for virus replication (transforming gene). Oncogenes also include viral or retroviral genes that cause malignant degeneration of the host cell, but are not necessary for viral replication.

Tumor suppressors

Transformed (tumor) cells divide uncontrollably and indefinitely. Oncosuppressors, or antioncogenes (for example, p53) inhibit their proliferation. Encoded by this gene p53 protein- one of the most important regulators of the cell cycle. This protein specifically binds to DNA and inhibits cell growth in the G1 phase.

The p53 protein registers various signals under influences on the cell (viral infection, hypoxia) and the state of its genome (activation of oncogenes, DNA damage). When there is unfavorable information about the state of the cell, p53 blocks the cell cycle until the disturbance is corrected. In damaged cells, the content of p53 increases. This gives the cell a chance to repair DNA by blocking the cell cycle. When severely damaged, p53 initiates cell suicide - apoptosis. Tumors (almost 50%) are accompanied by mutations of the p53 gene. Moreover, despite possible genomic disturbances (including changes in the number of chromosomes), cells do not enter apoptosis, but enter a continuous cell cycle. The repertoire of p53 gene mutations is wide. They lead to uncontrolled proliferation of cells in cancer of the colon, liver, lung, esophagus, breast, glial tumors of the brain, tumors of the lymphoid system. In Li-Fromeny syndrome, a congenital defect in p53 is responsible for the high incidence of carcinomas.

Also plays an important regulatory role p27 protein binds to cyclin and cyclin-dependent protein kinase proteins and blocks the cell from entering the S-phase of the cycle. A decrease in p27 levels is a prognostically unfavorable sign. Determination of p27 is used in the diagnosis of breast cancer.

Stages of chemical carcinogenesis. Potentially carcinogenic substances themselves do not cause tumor growth. Therefore, they are called procarcinogens or precarcinogens. In the body they undergo physical and chemical transformations, as a result of which they become true, ultimate carcinogens.
The ultimate carcinogens are considered to be:
♦ alkylating compounds;
♦ epoxides;
♦ diolepoxides;
♦ free radical forms of a number of substances.
Apparently, they cause changes in the genome of a normal cell that lead to its transformation into a tumor cell.
There are 2 interrelated stages of chemical carcinogenesis:
1) initiation;
2) promotions.
Initiation stage. At this stage, the final carcinogen interacts with DNA loci containing genes that control cell division and maturation (such loci are also called proto-oncogenes).
There are 2 interaction options:
1) the genomic mechanism consists of a point mutation of the proto-oncogene;
2) the epigenomic mechanism is characterized by derepression of an inactive proto-oncogene. Under the influence of chemical carcinogens, the proto-oncogene is converted into an oncogene, which subsequently ensures the process of tumor transformation of the cell. And although such a cell does not yet have a tumor phenotype (it is called a latent tumor cell), the initiation process is already irreversible.
The initiated cell becomes immortalized (immortal, from the English immortality - eternity, immortality). It is deprived of the so-called Hayflick limit: a strictly limited number of divisions (usually about 50 in mammalian cell culture).
Promotion stage. The promotion process is induced by various carcinogenic agents, as well as cellular growth factors. At the promotion stage:
1) oncogene expression occurs;
2) unlimited proliferation of the cell occurs, which has become genotypically and phenotypically tumorous;
3) a neoplasm is formed.
Biological carcinogens. These include oncogenic (tumor-related) viruses. The role of viruses in carcinogenesis attracts attention, on the one hand, as an independent problem, and on the other hand, because a large number of cellular proto-oncogenes are similar to retroviral oncogenes.

Stages of physical carcinogenesis

The target of carcinogenic agents of a physical nature is also DNA. Either their direct effect on DNA is allowed, or through intermediaries - unique mediators of carcinogenesis. The latter include free radicals of oxygen, lipids and other organic and inorganic substances.

The first stage of physical carcinogenesis is the initiation of tumor growth. It consists in the direct or indirect impact of agents of physical nature on DNA. This causes either damage to its structure (gene mutations, chromosomal aberrations) or epigenomic changes. Both the first and second can lead to the activation of proto-oncogenes and subsequent tumor transformation of the cell.

The second stage is promotions. At this stage of carcinogenesis, oncogene expression and modification of a normal cell into a cancer cell occur. As a result of successive cycles of proliferation, a tumor is formed.