Oncogenic viruses (oncoviruses)

To explain the nature of cancer, two dominant theories have been proposed - mutational and viral. In accordance with the first cancer is the result of successive mutations of a number of genes in one cell, ie, it is based on changes that occur at the gene level. This theory was completed in 1974 by F. Burnett: a cancer tumor is monoclonal from a single original somatic cell, mutations in which are caused by chemical, physical agents and viruses that damage DNA. In the population of such mutant cells, an accumulation of additional mutations increases the capacity of cells to unrestricted reproduction. However, the accumulation of mutations requires a certain time, therefore the cancer develops gradually, and the probability of the appearance of the disease depends on the age.

The virus genetic theory of cancer was most clearly formulated by the Russian scientist LA Zilber: cancer causes oncogenic viruses, they integrate into the chromosome of the cell and create a cancer phenotype. The complete recognition of the viral genetic theory has for some time been hampered by the fact that many oncogenic viruses have an RNA-genome, so it was not clear how it integrates into the chromosome of the cell. After such reverse transcriptase has been found in such viruses, capable of reproducing DNA-provirus from virion RNA, this obstacle has disappeared and the virus-genetic theory has been recognized along with a mutational one.

A decisive contribution to the understanding of the nature of cancer introduced the discovery in the oncogenic viruses of the malignant gene, the oncogene and its precursor, found in human, mammalian and avian cells, the protooncogene.

Proto-oncogenes are a family of genes that perform vital functions in a normal cell. They are necessary for regulating its growth and reproduction. The products of proto-oncogenes are various protein kinases, which carry out phosphorylation of cellular signaling proteins, as well as transcription factors. The latter are proteins - the products of proto-oncogenes c-myc, c-fos, c-jun, c-myh and cell suppressor genes.

There are two types of oncoviruses:

• Viruses containing an oncogene (one + viruses).
• Viruses that do not contain an oncogene (viruses one ").
• One + viruses can lose an oncogene, but this does not disturb their normal functioning. In other words, the oncogene itself is not needed by the virus.

The main difference between one + and one viruses is the following: the virus one +, penetrating into the cell, does not cause its transformation into cancer or causes extremely rare. "One" viruses, getting into the nucleus of the cell, transform it into a cancerous one.

Therefore, the transformation of a normal cell into a tumor cell is due to the fact that the oncogene, when introduced into the chromosome of the cell, gives it a new quality that allows it to reproduce in the body uncontrollably, forming a clone of cancer cells. This mechanism of the transformation of a normal cell into a cancerous cell resembles a bacterial transduction, in which a moderate phage, integrating into the chromosome of bacteria, gives them new properties. This is all the more believable that oncogenic viruses behave like transposons: they can integrate into the chromosome, move in it from one site to another, or move from one chromosome to another. The question is: how does a proto-oncogene turn into an oncogene when it interacts with a virus? First of all, it is necessary to note the important fact that in the case of viruses, due to the high rate of their proliferation, promoters work with much greater activity than promoters in eukaryotic cells. Therefore, when one-virus is integrated into the chromosome of the cell next to one of the proto-oncogenes, it subordinates the work of this gene to its promoter.When exiting the chromosome, the viral genome snatches a protooncogene out of it, the latter becomes an integral part of the viral genome and turns into an oncogene, and the virus from one - into one + -virus .. Integrating into the chromosome of another cell, this already onc-virus simultaneously transduces into it and the oncogene with all the consequences. This is the most frequent mechanism of formation of oncogenic (one +) viruses and the beginning of the transformation of a normal cell into a tumor cell. Other mechanisms are possible for the conversion of the proto-oncogene into an oncogene:

• translocation of the proto-oncogene, as a result of which the protooncogene is in the neighborhood of a strong viral promoter, which takes it under its control;
• amplification of the proto-oncogene, as a result of which the number of copies of it increases, as well as the amount of the product synthesized;
• the conversion of the proto-oncogene into an oncogene is due to mutations caused by physical and chemical mutagens.

Thus, the main reasons for the transformation of the proto-oncogene into an oncogene are as follows:

• Inclusion of the proto-oncogene into the genome of the virus and the conversion of the latter into one + virus.
• The entry of a proto-oncogene under the control of a strong promoter, either as a result of the integration of the virus, or due to the translocation of the gene block in the chromosome.
• Point mutations in the protooncogene.

Amplification of proto-oncogenes. The consequences of all these events can be:

• a change in the specificity or activity of the oncogene protein product, especially since very often the inclusion of a protooncogene into the genome of the virus is accompanied by protooncogene mutations;
• loss of cell-specific and temporal regulation of this product;
• an increase in the amount of the protein product of the oncogene being synthesized.

Oncogene products are also protein kinases and transcription factors, so the disturbances in the activity and specificity of protein kinases are considered as initial triggers for the transformation of a normal cell into a tumor cell. Since the family of proto-oncogenes consists of 20-30 genes, the family of oncogenes obviously includes no more than three dozen variants.

However, the malignancy of such cells depends not only on the mutations of proto-oncogenes, but also on changes in the effect on genes from the genetic environment as a whole, characteristic of a normal cell. This is the modern gene theory of cancer.

Thus, the primary reason for the transformation of a normal cell into a malignant one is the mutation of the proto-oncogene or its entry into the control of a powerful viral promoter. Various external factors inducing the formation of tumors (chemical substances, ionizing radiation, UV irradiation, viruses, etc.). Act on the same target - protooncogen. They are found in the chromosomes of the cells of each individual. Under the influence of these factors, one or another genetic mechanism that leads to a change in the function of the proto-oncogene is included, and this, in turn, gives rise to the degeneration of a normal cell into a malignant one.

A cancer cell carries on itself viral viral proteins or its own altered proteins. It is recognized by T-cytotoxic lymphocytes and is destroyed with the participation of other mechanisms of the immune system. In addition to T-cytotoxic lymphocytes, cancer cells are recognized and destroyed by other killer cells: NK, Pit-cells, B-killers, and also K-cells, whose cytotoxic activity depends on antibodies. As K-cells, polymorphonuclear leukocytes can function; macrophages; monocytes; thrombocytes; mononuclear cells of lymphoid tissue, devoid of markers of T- and B-lymphocytes; T-lymphocytes having Fc-receptors for IgM.

An antitumor effect is possessed by interferons and some other biologically active compounds formed by immunocompetent cells. In particular, cancer cells are recognized and destroyed by a number of cytokines, especially such as tumor necrosis factor and lymphotoxin. They are related proteins with a wide range of biological activity. The tumor necrosis factor (TNF) is one of the main mediators of the inflammatory and immune reactions of the body. It is synthesized by various cells of the immune system, mainly macrophages, T-lymphocytes and Kupffer cells of the liver. TNOa was discovered in 1975 by E. Karswell and his co-workers; it is a polypeptide with a mass of 17 kD. It has a complex pleiotropic effect: it induces the expression of MHC class II molecules in immunocompetent cells; stimulates the production of interleukins IL-1 and IL-6, prostaglandin PGE2 (it serves as a negative regulator of the mechanism of TNF secretion); has a chemotactic effect on mature T-lymphocytes, etc. The most important physiological role of TNF is the modulation of cell growth in the body (rostrigulating and cytodifferentiating functions). In addition, it selectively inhibits the growth of malignant cells and causes their lysis. It is assumed that the growth modulating activity of TNF can be used in the opposite direction, namely, to stimulate the growth of normal and suppress the growth of malignant cells.

Lymphotoxin, or TNF-beta, is a protein with a mass of about 80 kD, is synthesized by some T-lymphocyte subpopulations, and also has the ability to lyse target cells carrying foreign antigens. Other peptides are also capable of activating the functions of NK cells, K cells, macrophages, neutrophilic leukocytes, in particular peptides that are fragments of IgG molecules, for example, taftene (a cytophilic polypeptide derived from a CH2 domain), Fab fragments, Fc, etc. Only thanks to the constant interaction of all immunocompetent systems, antitumor immunity is provided.

Most people do not suffer from cancer, not because they do not have mutant cancer cells, but because the latter, having emerged, are timely recognized and destroyed by T-cytotoxic lymphocytes and other parts of the immune system before the malignant offspring have time to do so. In such people, the antitumor immunity works reliably. In contrast, in cancer patients mutant cells are not recognized in time or destroyed by the immune system, but multiply uncontrollably and uncontrollably. Consequently, cancer is a consequence of immunodeficiency. What link of immunity suffers at the same time, it is necessary to find out, in order to outline more effective ways of fighting the disease. In this regard, much attention is paid to the development of cancer biotherapy methods based on the integrated and consistent use of modulators of biological and immunological reactivity, i.e., chemicals synthesized by immunocompetent cells that are capable of modifying the reactions of the organism's interaction with tumor cells and providing antitumor immunity. With the help of such immunological reactivity modifiers, it is possible to influence both the immune system as a whole and selectively its individual mechanisms, including those controlling the formation of activation factors, proliferation, differentiation, the synthesis of interleukins, tumor necrosis factors, lymphotoxins, interferons, etc. ., to eliminate the state of immunodeficiency in cancer and improve the effectiveness of its treatment. Cases of human myeloma cure with the help of lymphokine-activated killers and interleukin-2 have already been described. In the experimental and clinical immunotherapy of cancer, the following trends were outlined.

• Introduction of activated cells of the immune system into tumor tissues.
• Use of lymphatic and / or monokines.
• The use of immunomodulators of bacterial origin (the most effective LPS and peptidoglycan derivatives) and products induced by them, in particular TNF.
• Use of antitumor antibodies, including monoclonal antibodies.
• Combined use of different directions, for example, first and second.

The prospects for using immunologic reactivity modulators for cancer biotherapy are unusually wide.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10]