Theories of pathogenesis of tumor growth. Stages of carcinogenesis
Moscow State University of Medicine and Dentistry A.I. Evdokimova
Department of Oncology and Radiation Therapy
Head of Department: MD, Professor Velsher Leonid Zinovievich
Teacher: Candidate of Medical Sciences, Associate Professor Gens Gelena Petrovna
Abstract on the topic:
Carcinogenesis.
Completed by: 5th year student,
medical faculty (student department),
Menshchikova E.V.
Moscow 2013
According to Virchow's theory, cell pathology underlies any disease. Carcinogenesis is a sequential, 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 responses. As a result, the cell acquires new qualities: immortalization ("immortality", i.e., the ability for unlimited division), the absence of contact inhibition, and the ability for invasive growth. In addition, tumor cells acquire the ability to avoid the action of factors of specific and nonspecific antitumor immunity 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:
Stage of initiation (changes in cellular oncogenes, shutdown of suppressor genes)
Metabolic activation phase (conversion of pro-carcinogens to carcinogens)
Phase of interaction with DNA (direct and indirect genotoxic effect)
The fixation phase of induced changes (DNA damage should appear in the progeny of target cells capable of producing a proliferative pool.)
Promotion stage
I (early) phase - phenotype rearrangement occurring as a result of epigenetic changes (i.e. gene expression) induced by the tumor promoter.
Change in gene expression, which enables 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 gene activity switching, culminating in the formation of neoplastically transformed cells (neoplastic transformation is a manifestation of signs that characterize the ability of cells to unlimited proliferation and further profession, i.e. accumulation malignant potential
Stage of progression: developed by L.Foulds in 1969. There is a constant staged progressive growth of the tumor with the passage of a number of qualitatively different stages in the direction of increasing its malignancy. In the course of tumor progression, its clonal evolution can occur, new clones of tumor cells appear as a result of secondary mutations. The tumor is constantly changing: there is a progression, as a rule, in the direction of increasing its malignancy, which is manifested by invasive growth and the development of metastases. Stage invasive tumor characterized by infiltrating growth. A developed vascular network and stroma appear in the tumor, expressed to varying degrees. There are no borders with the adjacent non-tumor tissue due to the germination of tumor cells into it. Tumor invasion proceeds in three phases and is provided by certain genetic rearrangements. First phase of tumor invasion is 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 adhesive 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. On the cell surface, the concentration of calcium ions decreases, which leads to an increase in the negative charge of tumor cells. The expression of integrin receptors increases, providing attachment of the cell 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 is repeated again.
The stage of metastasis 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 the lymphatic and blood vessels, perineurally, implantation, which became the basis for distinguishing the types of metastasis. The process of metastasis is explained by the theory of the metastatic cascade, according to which the tumor cell undergoes a chain (cascade) of rearrangements that ensure spread to distant organs. In the process of metastasis, the tumor cell must have the following qualities:
penetrate into adjacent tissues and lumen of vessels (small veins and lymphatic vessels);
separate from the tumor layer into the blood (lymph) flow in the form of individual cells or their small groups;
maintain viability after contact in the blood stream (lymph) with specific and non-specific factors of immune protection;
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 conditionally 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 (lymphatic flow);
settling in a new place with the formation of a secondary tumor.
Currently, there are several concepts of oncogenesis, each of which mainly affects the 1st and (or) 2nd stage of carcinogenesis.
Mutation theory of carcinogenesis A normal cell becomes a tumor cell as a result structural changes in the genetic material, i.e. mutations. The notion of a multi-stage process of carcinogenesis has become an axiom, the decisive prerequisite for which is the unregulated expression of a transforming gene, an oncogene that pre-exists in the genome.
The transformation of a proto-oncogene into an active oncogene is provided by the following mechanisms. 1. Attachment of a promoter to the proto-onokgene- a DNA region with which RNA polymerase binds, initiating the transcription of a gene, including the oncogene located immediately behind it. Such sites (promoters) are contained in large terminal repeats (LTR) DNA copies of RNA viruses. The role of a promoter can be played by transposing elements of the genome- mobile genetic elements that can move around the genome and integrate into its various parts
2. Insertion of an enhancer into the cell genome(enchancer - enhancer) - a section of DNA that can activate the work of a structural gene, located not only in its immediate vicinity, but also at a distance of many thousands of base pairs or even built into the chromosome after it. Amplifier properties are possessed by mobile genes, LTR DNA copies.
3. Chromosomal aberrations with translocation phenomena, whose role in the mechanisms of tumor cell transformation can be illustrated by the following example. With Burkitt's lymphoma, the end of the q-arm of chromosome 8, having separated from it, passes to chromosome 14: the homologous fragment of the latter moves to chromosome 8; but an inactive gene tuc(proto-oncogene), located in its 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 is called the Philadelphia chromosome.
4.Point mutations of the proto-oncogene, For example, C-H-raS, reportedly different from the normal gene (C-H-raS) only 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, having normally a small trace activity, causes an increase in their total activity to a level sufficient to initiate tumor transformation. It is known that clawed frog eggs contain about 5 million copies of the gene tuc. 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 ensures rapid cell division and embryo growth. In the cells of an adult frog, only single genes are detected tuc, while in the cancer cells of the same frog their number again reaches 20-50. 6. Transduction of inactive cellular genes (protooncogenes) into the retrovirus genome and their subsequent return to the cell: it is believed that the oncogene of a tumorigenic virus of cellular origin; when animals or humans are infected with such a virus, the gene “stolen” by it enters a different part of the genome, which ensures the activation of the once “silent” gene.
Oncoproteins can:
mimic 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 control system for the proliferation of clonogenic cells with activated oncogenes is disrupted. The main fact confirming the mechanism based on the violation of tissue homeostasis is the ability of tumor cells to normalize during differentiation. The study of transplanted keratinizing rat carcinoma by autographic analysis showed (Pierce, Wallace, 1971) that cancer cells during division can give normal offspring, that is, malignancy is not genetically fixed and is not inherited by daughter cells, as suggested by the mutation hypothesis and molecular genetic theory. There are well-known experiments on the transplantation of tumor cell nuclei into pre-enucleated germ cells: in this case, a healthy mosaic organism develops. Thus, contrary to the idea that transformed oncogenes are allegedly preserved in normalized tumor cells during differentiation, there is reason to question the relationship 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 the acquisition of malignancy, the cell is usually: 1) self-sufficient in terms of proliferation signals (which can be achieved by the activation of certain oncogenes, for example, H-Ras); 2) is insensitive to signals suppressing its growth (which occurs when the tumor suppressor gene Rb is inactivated); 3) able to reduce or avoid apoptosis (which occurs as a result of the activation of genes encoding growth factors); 4) tumor formation is accompanied by enhanced angiogenesis (which can be provided by activation of the VEGF gene encoding vascular endothelial growth factors; 5) genetically unstable; 6) does not undergo cellular differentiation; 7) does not undergo aging; 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 rather 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 genes, DNA repair, and some others). In the case of cell infection with oncogenic viruses, the proteins encoded by the viral genome, which have a transforming potential, disrupt normal cell 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 human oncogenic:
Hepatitis B and C viruses (Hepatitis B virus and Hepatitis C virus, HBV / HCV) that cause liver cancer; Genetic deletion occurs as a result of genetic changes X and some of the genes PreS2 , while liver cells become HBsAg-negative and finally go out of immunological control. Next comes the selection of cells in which HBV DNA is integrated and which contain 3 major 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 release other growth factors that stimulate hepatocyte proliferation in a paracrine manner. Increased proliferation of hepatocytes can lead to genetic damage that will promote the selection of cells with accelerated proliferation and the acquisition of signs of malignant transformation. In liver tumor cells, inactivation of the tumor suppressors p53, Rb, BRCA2, and E-cadherin often occurs. Telomerase activation was also noted in hepatic cells at the stage of their transformation into malignant and disruption of the functioning of a number of important signaling systems.
Certain types (16 and 18) of human papillomavirus (Human papillomavirus, HPV)- being the etiological agent of cervical cancer and some tumors of the ano-genital sphere; It has been established that transforming genes are mainly genes E6 and E7, less E5. The mechanism of the functioning of genes E6 and E7 is reduced to the interaction of the products of these genes with the products of 2 suppressor genes p53 and Rb and subsequent inactivation of the latter, which leads to uncontrolled growth of infected cells. contributes to the disruption of cell signaling pathways, an increase in its proliferative activity and the accumulation of additional genetic changes. It should be noted that therapeutic and prophylactic vaccines against HPV have been created. Which stimulate the immune system against E6 and / or E7 early viral proteins (tumor antigens), which prevent the entry of infected cells into apoptosis and the aging phase, and also generate virus-neutralizing antibodies specific for the HPV capsid.
Epstein-Barr virus (EBV)), which is involved in the occurrence of a number of malignant neoplasms; The mechanism of carcinogenesis is complex and poorly understood. In particular, the LMP1 protein, localized in the membrane, mimics 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 replication and maintain the episomal state of the EBV genome.
Human herpesvirus type 8 (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 adult T-cell leukemia, as well as tropical spastic paraparesis and a number of other non-oncological diseases. The mechanism of trans-activation of transcription of a number of viral and cellular genes (cytokines, their receptors, cyclins, etc.) HTLV-1 cells. The Tax protein can also trans-repress the transcription of certain genes by acting through the transcriptional co-activator p300. Tax 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)- not possessing transforming genes, but creating the necessary conditions (immunodeficiency) for the occurrence of cancer.
Despite the different organization of human oncogenic viruses, the unequal range 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 infected by them; 2) in persons infected with oncogenic viruses, the onset of a tumor is usually an infrequent event: one case of a neoplasm occurs among hundreds, sometimes thousands of infected people; 3) after infection before the onset of a tumor, there is a long latent period lasting for years, sometimes decades; 4) in most infected individuals, the occurrence of a tumor is not mandatory, but they may constitute a risk group, with a higher possibility of its occurrence; 5) malignant transformation of infected cells requires additional factors and conditions leading to 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 long enough time. The division into initiators and promoters to a certain extent corresponds to the division of carcinogens. 1. Genotoxic
Carcinogens direct action when dissolved, they decompose
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, the nucleotide associated with the carcinogen residue can be misread by DNA polymerase, resulting in mutation. (Ex: N-nitrosoalkylureas, nitrogen mustard, diepoxybutane, beta-propiolactone, ethyleneimine)
Carcinogens indirect action are low-reactive compounds activated by the action of enzymes.
DETOXIFICATION OF CHEMICAL CARCINOGENES (oxidation of a procarcinogen by cytochrome P-450 isoforms)
METABOLIC ACTIVATION (Some procarcinogens are activated, turning into direct carcinogens - highly reactive derivatives that covalently bind to 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, which is very important, continuously. A more or less prolonged break in their use is accompanied by
stopping carcinogenesis (new tumors no longer appear) or even regression of tumors that have arisen. They cause cell proliferation, inhibit apoptosis, 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) violation of intercellular gap junctions.
CARCINOGENIC CLASSES OF CHEMICAL COMPOUNDS:
Polycyclic aromatic hydrocarbons.
aromatic amines.
Amino azo 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 has been 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 the so-called adducts - complexes of DNA with the corresponding compound, including 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 the group of I. Liir together with J. Weiss, one of the leading experts in the study of metabolites of classical estrogens - catecholestrogens, in particular 2- and 4-hydroxyestrone and 2- and 4-hydroxyestradiol. The result of this long work was an original concept, the essence of which is as follows: classical estrogens can, to one degree or another, turn into catechol estrogens, which are involved in the reactions of the exchange-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 hormone-induced enhanced proliferation is not taken into account in the mentioned model. Nevertheless, direct experiments have shown that of all the studied estrogen derivatives, the most carcinogenic are 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 the data of H. Adlerkreutz's group, 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 Caucasoid populations, which also differ in the frequency of detection of oncological diseases of the reproductive system.
There is every reason to believe that two main types of hormonal carcinogenesis are possible: promoter or physiological, when the action of hormones is reduced to the role of specific cofactors that enhance cell division (promotion stage); and genotoxic, when hormones or their derivatives have a direct effect on DNA, contributing to the induction of mutations and the initiation of tumor growth. The reality of the first is evidenced by classical observations, and the idea of risk factors and hormonal-metabolic predisposition to the development of tumors, and numerous epidemiological and laboratory data. The latter is supported by an increasing number of works that demonstrate the ability of hormones (so far, mainly estrogens) to damage DNA: form adducts, enhance the unwinding of its chains, form breaks, etc., which can lead to other, more specific (problastomogenic) changes at the level of the cellular genome.
Antiblastoma resistance Antiblastoma resistance is the body's resistance to tumor growth. There are three groups of mechanisms of antiblastoma resistance.
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 the corresponding 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 of interferon, antibodies, etc. Anti-transformational mechanisms: maintenance of gene homeostasis due to DNA repair processes; synthesis of inhibitors of tumor growth, providing suppression of cell reproduction and stimulation of their differentiation (the function of anti-oncogenes).
anticellular mechanisms, aimed at inhibiting and destroying individual tumor cells, preventing the formation of their colony, i.e. tumors. These include immunogenic mechanisms - non-specific (EC reaction) and specific (reaction of immune T-killers; immune macrophages), - non-immunogenic factors and mechanisms (tumor necrosis factor, interleukin-1, allogeneic, contact, keylon inhibition - regulatory neurotrophic and hormonal influence, etc.).
Thus, the study of the processes of carcinogenesis is a key moment both for understanding the nature of tumors and for searching for new and effective methods of treating oncological diseases.
1. Induction (initiation) consists in the mutation of one of the genes that regulate cell reproduction (the proto-oncogene turns into an 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 chemicals that do not cause DNA damage and are not carcinogenic. Oncogenes begin their activity → oncoproteins are synthesized → the number of initiated cells increases.
3. Progression - along with an increase in the mass of the tumor, it constantly acquires new properties, "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 of unregulated growth. The primary transformed cell transfers its properties only to its descendants, i.e. "vertically". At the same time, normal cells surrounding the tumor are not involved in the process of degeneration. This idea is called the position of clonal origin of the tumor.
Clonal tumor heterogeneity develops due to the 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. Influence of a tumor on an organism.
Atypism(from a + Greek typicos - exemplary, typical) - a set of features that distinguish tumor tissue from normal, and make up 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 look like undifferentiated tissues.
The term was introduced due to a certain formal similarity of tumor cells with embryonic ones (intense 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 the surrounding adjacent tissues, destroying them, etc.
Lecture on pathological physiology
theme of carcinogenesis.
Carcinogenesis is the process of development of tumors of any type. The last stage of tumor growth, with visible manifestations, manifestation is called malignancy (cancerification). General signs of malignancy:
1. The cell acquires the ability for uncontrolled, uncontrolled reproduction, division
2. Hyperplasia in parallel with uncontrolled cell division, there is a violation of differentiation, remains immature, young (this property is called anaplasia).
3. Autonomy (independent of the body), from controlling, regulating the processes of vital activity of stimuli. The faster the tumor grows, the less differentiated the cells are, as a rule, and the more pronounced the autonomy of the tumor.
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 or squeezing the surrounding tissues. And malignant tumors are characterized by the 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 through the hematogenous, lymphogenous way and form foci of the tumor process. Metastases are a sign of a malignant tumor.
6. Tumor tissue has a negative impact on the body as a whole: intoxication caused by products of tumor metabolism, tumor decay. In addition, the tumor deprives the body of the necessary nutrients, energy substrates, and plastic components. The combination of these factors is called cancer cachexia (depletion of all life support systems). The tumor process is characterized by pathological proliferation (uncontrolled cell division), impaired cell differentiation, and morphological, biochemical, and functional atypism.
Atypism 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 atypism. 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 shorten. Embryonic proteins, unusual for mature cells, begin to be synthesized in the cell, the amount of phosphotyrosines increases. All this leads to a violation of the properties of contact inhibition, increases the lability, fluidity of the membrane. Normally, cells, coming into contact with each other, stop dividing (there is a self-regulation of the division process). In tumor cells, the absence of contact inhibition leads to uncontrolled proliferation.
Biochemical atypia. Atypism 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 does not decrease when changing from anaerobic conditions to aerobic ones, but persists (increased glycolysis in tumor cells causes their high survival rate under hypoxic conditions). The tumor actively absorbs nutrients. The phenomenon of substrate traps is observed, which consists in an increase in the affinity of the enzyme for the substrate (glucose), in tumor cells, the activity of hexokinase increases by 1000 times. Tumor cells are also a trap for protein, which also leads to cachexia.
The predominance of glycolysis leads to an increase in the concentration of lactic acid in the tumor cells, acidosis is characteristic, leading to a violation of the vital activity of the cell itself (the necrosis zone is usually located in the center of the tumor).
Atypism in the regulation of growth and differentiation of tumor cells. The processes of growth, differentiation of division are normally under the control of central endocrine regulation, which is carried out by somatotropic hormone, thyroid hormones, and insulin. In addition to these common 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 the growth factor with the growth factor receptor on the cell membrane (in a tumor cell, this stage may be disturbed). At the next stage, secondary messengers are formed - cyclic adenosine and guanosine monophosphate, and for normal growth and differentiation, the predominance of cyclic adenosine monophosphate (cAMP) is characteristic. The formation of cyclic guanosine monophosphate is combined with increased proliferation. This is a typical feature 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 for serine, threonine, and histidine. In tumor tissue, protein kinases are tyrosine-dependent, that is, protein phosphorylation proceeds via tyrosine. Stimulation of proliferation is associated with the formation of proteins phosphorylated by 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 inductor, it stimulates the formation of phosphotyrosine and enhances uncontrolled cell reproduction.
Theories of the 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 chimney sweeps suffered at the age of 30-35 years (the question of the localization of the tumor in the scrotum is still unclear). Chimney sweeps, cleaning chimneys, rubbed soot into their skin and after 10-15 years developed skin cancer . The explanation of the mechanisms of development of this form of cancer was the beginning of a new era in the study of the tumor process. It was found out 2 main factors causing the development of cancer - constant irritation, damage; the action of certain substances (soot), which have been called carcinogens. Many carcinogens are now known. This model of the disease was reproduced by Japanese scientists who rubbed soot into the ear of a rabbit for a year and got first a benign (papilloma) and then a malignant tumor.
Carcinogenic substances that are in the external environment are called exogenous carcinogens: benzpyrenes, phenanthrenes, polycyclic hydrocarbons, amino-azo 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, tryptophan conversion products. Cancer has even been obtained by injecting substances such as glucose, distilled water under certain conditions. Tumor processes belong to the group of polyetiological diseases, that is, there is no one main factor that would contribute to the development of a tumor. It occurs when a combination of multiple conditions and factors, hereditary predisposition or natural resistance matters. Nuller animal lines have been bred that never get cancer.
The action of carcinogens is very often combined with the action of physical factors - mechanical irritation, temperature factors (in India, skin cancer in carriers of vats of hot coal, in northern peoples there is a higher incidence of cancer of the esophagus due to the use of very hot food: hot fish. In smokers, the following factors contribute to the development of lung cancer - high temperature, which is created when smoking, chronic bronchitis - causing active proliferation, and tobacco contains methylcholanthrenes - strong carcinogens In seafarers, facial skin cancer is an occupational disease (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 the occurrence of cancer is the inoculation of a non-cellular filtrate of an animal with a tumor to a healthy one. The non-cellular filtrate contained the virus and the healthy animal became ill. From diseased chickens, leukemia was transplanted into healthy chickens; it was possible to cause leukemia in almost 100% of chickens. More than 20% of various viruses have been described that are capable of causing various forms of the tumor process in almost all experimental animals. Transmission of cancer-causing viruses through milk has been discovered. The offspring of low-cancer mice were placed in a high-cancer female (the mice belonged to low-cancer and high-cancer lines. Low-cancer lines did not spontaneously develop cancer, high-cancer lines developed cancer in almost 100% of cases.). this is how the milk factor of a viral nature was discovered, the virus that causes disease was discovered, and in humans - the Epstein-Barr virus (we cause lymphoma).
So, 3 main theories of carcinogenesis have been formulated, corresponding to the three main etiological groups:
1. carcinogens
2. physical factors
3. biological factors - viruses.
The main theories explaining the pathogenesis of cancer are:
· Mutational theory of carcinogenesis, which explains the development of the tumor process as a consequence of mutation. Carcinogenic substances, 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 disturbed. The epigenomic mechanism is based on derepression of normally inactive genes and depression of active genes. According to this theory, the basis of the tumor process is the derepression of ancient genes.
Virus theory. Viruses can persist in cells for a long time, being in a latent state, under the influence of carcinogens, physical factors, they are activated. The virus integrates into the cell 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 theory of oncogene expression. 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 encoding proteins. Normally, they are inactive, repressed, so they are called protoncogens. 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 one (malignancy). Oncogenes are denoted 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 are able to change: membrane ones move into the cytoplasm and vice versa. By function, 5 groups of oncoproteins are distinguished:
1. Nuclear DNA-binding proteins - mitogens. They perform the function of stimulating cell division. This group includes oncogene products myc, myt.
2. Guanosine triphosphate-binding oncoproteins. This group includes oncogene products of the ras family. Oncoproteins guanosine phosphate-binding contribute to 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. They contribute to the phosphorylation of proteins by tyrosine, increase the content of phosphotyrosines in the cell. The target for oncoproteins is vinculin, fibrinogen. Under the action of oncoprotein on these targets, the content of phosphotyrosines in them increases by 6-8 times. With an increase in phosphotyrosines in these proteins, which are part of the membrane, the properties of the cell membrane change. First of all, the adhesive property decreases, contact inhibition is disturbed.
4. Homologues of growth factors and growth factor receptors. Growth factors are formed outside the cell, are transferred by the hematogenous route, and interact with specific receptors. If an oncoprotein is formed that acts as 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 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 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, localized in the cell membrane, but unlike the normal receptor. The oncoprotein receptor begins to interact with any growth factor, loses its specificity, and cell proliferation is stimulated.
5. Altered membrane receptors (pseudoreceptors). This group includes proteins belonging to the group of tyrosine-dependent protein kinases, but there are others. In the pseudoreceptor, 2 functions are connected - the function of the growth factor and the growth factor receptor. In order for proteins to begin to perform their function, the expression of proto-oncogenes into oncogenes is necessary.
Mechanism of expression of proto-oncogenes.
The expression of proto-oncogenes is associated with the action of various carcinogenic factors - ionizing radiation, chemical carcinogens, viruses. There are 2 types of virus influence:
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 oncogene itself activates the insertion mechanism), and the 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 inserted 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 both chromosomal and gene. Chromosomal mutations include chromosomal aberrations, deletions, translocations, inversions - all options when a chromosome break occurs, which leads to the expression of oncogenes at the break site, since the oncogene is released from the compensatory 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 myelogenous leukemia, an altered Philadelphia chromosome 22 is found with very high 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. In the process of mutual translocation from chromosome 9 to chromosome 22, a promoter is transferred, which is inserted next to the oncogene. The consequence is the stimulation of the mus oncogene, a DNA-binding oncoprotein, the mitogen, is formed.
Point mutations can also lead to the expression of oncogenes, and point mutations are typical for some oncogenes (oncogenes of the ras family). Perhaps a mutation in the oncogene itself or in the regulator gene with a change in the repressor that 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 DNA and can be integrated into any site. Their physiological function is to increase the activity of a particular gene. Transposons can perform the function and expression of oncogenes by acting as promoters. It has been noted that in the process of carcinogenesis, the activity of the mutation process, 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 copies of the genes obtained to enhance the activity of the gene, up to 5, up to a maximum of 10 copies. Under the conditions of a carcinogen, the number of copies of oncogenes reaches hundreds (500-700 or more, this is an epigenomic mechanism of oncogene expression.
Another epigenomic mechanism is DNA demethylation. Under the influence of chemical carcinogens, active radicals, the process of DNA demethylation takes place. the demethylated site becomes active.
In order for a normal cell to become a tumor cell, a group of oncogenes must be activated (from 2 to 6-8 or more oncogenes. The mechanisms of interaction between oncogenes are now 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 action of carcinogens in the cell, a certain group of oncogenes is activated. At the stage of initiation, the expression of oncogenes mu and mut is most often observed (the products of these oncogenes are DNA-binding mitogens), uncontrolled proliferation is stimulated. differentiation does not occur, the function is preserved. This is a long latent - latent phase. The duration of the initiation phase is approximately 5% of the life span 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 is continuously, uncontrollably dividing. A cell in the initiation phase is called immortal (immortal) since it continuously reproduces itself, the initiation phase is called the immortalization phase. The cell in this phase can return to the path of normal development, or it can go to the next phase of development - the transformation phase.
Transformation occurs if the initiated cell continues to be affected by a carcinogenic factor and a new group of oncogenes is expressed. 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 at this phase. The expression of these oncogenes leads to the final malignancy of the cell - differentiation and proliferation are disturbed. The formation of single tumor cells does not yet lead to a tumor process. Tumor cells have the property of foreignness (antigens) for 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. A 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 composition of the tumor cell membrane. Embryonic proteins - alpha-ketoprotein, etc.
4. Divergence.
Appear in the tissues of antigenic components that are unusual for this 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 the tumor antigen:
1. the function of natural killers (natural killers) - they create the main antitumor protection. They recognize the 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 the complex of antibodies on the surface of tumor cells prevents the manifestation of 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 prolonged use of immunosuppressants, glucocorticoids.
The stage of tumor progression is already characterized by clinical manifestations - the mass of the tumor increases, infiltrative growth, metastasis is observed, and ends with cancer cachexia.
The process of vascular development in the tumor is controlled by the oncoprotein angiogenin (now they are 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 regression. In lizards, newts, tumors often form in the zone of active regeneration (tail), which are able to resolve themselves. Cases of resorption of tumors in humans are described, but the mechanism of this phenomenon has not yet been studied.
It has now been established that cancer, or a malignant neoplasm, is a disease of the genetic apparatus of a 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 transformation of a normal cell into a tumor cell is due to 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 action of free radicals, and under the influence of external causative factors of a chemical and physical nature.
Theories of carcinogenesis
The study of the mechanisms of tumor cell transformation has a long history. So far, many concepts have been proposed trying 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 made it possible to get closer to understanding why various etiological factors cause the same disease in essence. It was the first unified theory of the origin of tumors, which included achievements in the field of chemical, radiation and viral carcinogenesis.
The main provisions of the theory of oncogenes were formulated in the early 1970s. R. Huebner and G. Todaro (R. Huebner and G. Todaro), who suggested that in the genetic apparatus of every normal cell there are genes, with untimely activation or dysfunction of which a normal cell can turn into a cancer cell.
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;
- unmutated oncogenes act at the key stages of the implementation of the processes of proliferation, differentiation and programmed cell death, being under the control of the signaling systems of the body;
- genetic damage (mutations) in oncogenes lead to the release of the cell from external regulatory influences, which underlies its uncontrolled division;
- a mutation in one oncogene is almost always compensated, so the process of malignant transformation requires combined disturbances in several oncogenes.
Carcinogenesis has another side of the problem, which concerns the mechanisms of suppression of malignant transformation and is associated with the function of the so-called anti-oncogenes (suppressor genes), which normally have an inactivating effect on proliferation and favor the induction of apoptosis. Antioncogenes are able to induce reversal 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 anti-oncogenes, and genetic instability.
In general, carcinogenesis is considered at the present level as a consequence of a violation of normal cellular homeostasis, which is expressed in the loss of control over reproduction and in the strengthening of the mechanisms for protecting cells from the action of apoptosis signals, that is, programmed cell death. As a result of the activation of oncogenes and the shutdown of 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, takes place in several stages.
Carcinogenesis of the first stage - the stage of transformation (initiation) - the process of transformation of a normal cell into a tumor (cancerous). Transformation is the result of the interaction of a normal cell with a transforming agent (carcinogen). During stage I of carcinogenesis, irreversible disturbances in the genotype of a normal cell occur, 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. Cell damage can be either genetic or epigenetic in nature. Genetic changes are understood to mean any modifications in DNA sequences or in the number of chromosomes. These include damage to or rearrangement of the primary structure of DNA (for example, gene mutations or chromosomal aberrations), or changes in the number of copies of genes or the integrity of chromosomes.
Carcinogenesis of the second stage is the stage of activation, or promotion, the essence of which is the reproduction of a transformed cell, the formation of a clone of cancer cells and a tumor. This phase of carcinogenesis, in contrast to the initiation stage, is reversible, at least at an early stage of the neoplastic process. During promotion, the initiated cell acquires the phenotypic properties of the 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 the death of the body. Tumor induction requires a long and relatively continuous action of 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, activate membrane protein kinase, affect cell differentiation, and block intercellular communications.
A growing tumor is not a frozen, stationary formation with unchanged properties. In the process of growth, its properties are constantly changing: some signs are lost, some appear. This evolution of the properties of the tumor 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 effect on the tissue, organ and organism levels, creating in some cases conditions conducive to the survival of the transformed cell, as well as the subsequent growth and progression of neoplasms. According to some scientists, these conditions result from profound dysfunctions of the neuroendocrine and immune systems. Some of these shifts may vary depending on the characteristics of carcinogenic agents, which may be due, in particular, to differences in their pharmacological properties. The most common responses to carcinogenesis that are essential for the onset 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 hormone-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 violation of tissue growth, manifested in the uncontrolled reproduction of cells, which are characterized by atypism, or anaplasia.
Under atypisms understand the totality of features that distinguish tumor tissue from normal tissue and make up the biological characteristics 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 the development of tumors are various factors that can cause the transformation of a normal cell into a tumor. They are called carcinogenic or blastomogenic. These are agents of 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 provide tumor transformation of cells are mutagenicity (the ability to directly or indirectly affect the cell genome, which ultimately leads to mutations), the ability to penetrate through external and internal barriers, and the dosage of action, which provides minor damage to the cell, which allows it to survive.
Along with carcinogenic factors, there are a number of substances that, without causing mutations themselves, are mandatory participants in carcinogenesis - cocarcinogens And syncarcinogens. Cocarcinogens are non-mutagenic factors (promoters) that enhance the effect of carcinogenic agents. Cocanceogenesis is an enhancement of the mutagenic action of a carcinogen by compounds that stimulate cell proliferation by inactivating protein products of anti-oncogenes or enhancing the transmission of growth-stimulating signals. Syncarcinogens are carcinogenic factors that cause increased tumor formation under the combined action of several known carcinogens.
CHEMICAL CARCINOGENES
According to WHO, more than 75% of cases 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, final carcinogens. The final carcinogens are alkylating compounds, epoxides, diolepoxides, free radical forms of a number of substances.
Tumors are predominantly caused by tobacco combustion factors (approximately 40%); chemical agents that make up food (25-30%) and compounds used in various areas of production (about 10%). More than 1500 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, dimethylbenzanthracene have the highest carcinogenic activity. Every year, hundreds of tons of these and similar substances are emitted 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, nitrosomethylurea.
Amino azo compounds.
Among them, 4-dimethylaminoazobenzene and orthoaminoazotoluene are considered highly effective carcinogens.
Aflatoxins are metabolic products (coumarin derivatives) of mold fungi, mainly Aspergillus flavus (hence the name of the substances they produce).
Other organic substances with carcinogenic activity: epoxides, plastics, urethane, carbon tetrachloride, chloroethylamines 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 physical and chemical modification of the products of normal metabolism. 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 a physical nature are:
- ionizing radiation
A). α-, β- and γ-radiation, the source of which are radioactive isotopes (P 32, I 131, Sr 90, etc.),
b). X-Ray Radiation,
V). neutron flux,
- 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 have been repeatedly injected with the radioactive radiopaque substance Thorotrast). The incidence of thyroid cancer has risen sharply in individuals exposed to radioactive iodine during the Chernobyl accident.
Question
Types of oncogenic viruses
According to 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 incorporating into the genome of the target cell. A segment of the oncovirus DNA (the oncogene itself) integrated with the cell genome can carry out tumor transformation of the cell. It is also not ruled out that one of the oncovirus genes can play the role of a promoter of a cellular proto-oncogene.
Viral oncogenes and the cellular genes that control cell cycle and proliferation have both similarities and important differences. In this regard, they speak of proto-oncogenes and oncogenes.
Proto-oncogene- gene of the normal human genome; involved in the regulation of cell proliferation. Expression products of proto-oncogenes are in many cases important for normal cell differentiation and intercellular interactions. As a result of somatic mutations, a proto-oncogene can become oncogenic. In this case, the prefix c- (from cellular - cellular) can be added to the name of the proto-oncogene, viral homologues are marked with the prefix v- (from viral - 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. Many oncogenes have been identified (eg, ras [bladder tumors]); p53, a mutant gene on chromosome 17 (normally involved in the repair of UV-induced gene defects). Mutations in p53 are responsible for the development of breast, cervical, ovarian, and lung cancers; malignant effects of oncogenes can be enhanced by retroviruses, the so-called jumping genes, mutations. Oncogenes have been found in some DNA tumor viruses. They are necessary for virus replication (transforming gene). Oncogenes also include genes of a virus or retrovirus that cause malignant degeneration of the host cell, but are not necessary for virus replication.
Oncosuppressors
Transformed (tumor) cells divide uncontrollably and indefinitely. Oncosuppressors, or anti-oncogenes (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 the growth of cells in the G1 phase.
The p53 protein registers various signals when the cell is affected (viral infection, hypoxia) and the state of its genome (activation of oncogenes, DNA damage). With unfavorable information about the state of the cell, p53 blocks the cell cycle until the disturbances are eliminated. In damaged cells, the content of p53 increases. This gives the cell a chance to repair DNA by blocking the cell cycle. With gross damage, p53 initiates cell suicide - apoptosis. Tumors (almost 50%) are accompanied by mutations in the p53 gene. At the same time, despite possible genome disturbances (including changes in the number of chromosomes), cells do not enter apoptosis, but enter into a continuous cell cycle. The repertoire of mutations in the p53 gene 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-Fromeni syndrome, a congenital defect in p53 is the cause of the high incidence of carcinomas.
It also plays an important regulatory role p27 protein binds to cyclin and cyclin-dependent protein kinase proteins and blocks the entry of the cell into the S-phase of the cycle. A decrease in the level of p27 is a prognostically unfavorable sign. The determination of p27 is used in the diagnosis of breast cancer.
Stages of chemical carcinogenesis. By themselves, potentially carcinogenic substances 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, final carcinogens.
The end carcinogens are considered to be:
♦ alkylating compounds;
♦ epoxides;
♦ diolepoxides;
♦ free radical forms of a number of substances.
Apparently, they cause such changes in the genome of a normal cell, which lead to its transformation into a tumor cell.
There are 2 interrelated stages of chemical carcinogenesis:
1) initiations;
2) promotions.
Stage of initiation. 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 in a point mutation of the proto-oncogene;
2) the epigenomic mechanism is characterized by derepression of an inactive proto-oncogene. Under the action 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 process of initiation is already irreversible.
The initiated cell becomes immortalized (immortal, from the English immortality - eternity, immortality). It loses 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 is carried out;
2) there is an unlimited proliferation of a cell that has become genotypically and phenotypically tumor;
3) a neoplasm is formed.
biological carcinogens. These include oncogenic (tumor-native) 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 retrovirus oncogenes.
Stages of physical carcinogenesis
The target of carcinogenic agents of a physical nature is also DNA. Either their direct action on DNA is allowed, or through intermediaries - a kind of 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 action of agents of a physical nature on DNA. This causes either damage to its structure (gene mutations, chromosomal aberrations) or epigenomic changes. Both the first and the 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, the oncogene is expressed and the normal cell is modified into a cancer cell. As a result of successive cycles of proliferation, a tumor is formed.
