103. Molecular genetic bases of carcinogenesis. Protooncogenes, suppressor genes, apoptosis regulator genes, their role in tumor development and progression.

Genetic rearrangements can occur under the influence of carcinogenic agents in both the somatic and germ cells. At the same time, four classes of genes are targets of carcinogenic agents: proto—oncogenes — regulators of cell proliferation and differentiation; tumor suppressor genes (anti-oncogenes) that inhibit cell proliferation; genes involved in cell death by apoptosis; genes responsible for DNA repair processes.

The appearance of a tumor is a multi–stage process, including 3 stages (stages). Stage 1 – initiation (transformation) – acquisition by the initial normal cell of the ability to multiply indefinitely. All the theories that prepared the basis for the discovery of the molecular mechanisms of carcinogenesis proceeded from the general premise that the transformation of a normal cell into a tumor cell is the result of persistent changes in the cell genome – a mutation of one of the genes regulating cellular reproduction. As a result, the cell becomes initiated (potentially capable of unlimited reproduction), but requires a number of additional conditions for the manifestation of this ability.

Various carcinogens that cause DNA damage can serve as initiating factors.

It has been established that in normal cells in DNA there is a site homologous in nucleotide composition to the oncogene of viruses, in other words, for each of the 20 known retroviral oncogenes in the genome of normal and tumor cells of various animal species there is a cellular analogue. In normal cells, the cellular analogue of the viral oncogene is inactive and is called a proto-oncogene. It is active in tumor cells and is called a cellular oncogene. The transition of inactive cellular oncogene 8 (proto-oncogene) to an active cellular oncogene occurs under the influence of chemical, physical and biological carcinogens. The following main mechanisms of activation of proto-oncogenes are distinguished.

When considering various theories of tumor development, it can be concluded that a variety of carcinogenic agents, differing in their mechanisms of action, always lead to the same result — the development of tumors. This phenomenon has been explained only in recent decades, when cancer began to be considered as a genetic disease. Genetic rearrangements can occur under the influence of carcinogenic agents, both in the somatic and in the germ cell. At the same time, four classes of genes are targets of carcinogenic agents: proto—oncogenes — regulators of cell proliferation and differentiation; tumor suppressor genes (anti-oncogenes) that inhibit cell proliferation; genes involved in cell death by apoptosis; genes responsible for DNA repair processes

104. Appearance and features of growth of tumors, The concept of the progression of tumors. Stages, types and ways of metastasis.

The appearance of the tumor is diverse: it can have the shape of a knot, a mushroom cap, or be in the form of cauliflower. Its surface is smooth, bumpy or papillary. The tumor is located in the thickness of the organ or on its surface. In some cases, it diffusely penetrates the organ, and then its boundaries are not defined, in others it is located on the surface of the organ (mucous membrane) in the form of a polyp. In compact organs, the tumor protrudes above the surface, germinates and destroys the capsule, corrodes (corrodes) blood vessels, resulting in internal bleeding. It often necrotizes and ulcerates (cancerous ulcer). On the incision, the tumor has the appearance of a homogeneous, usually white-gray or gray-pink tissue, sometimes resembling fish meat. Sometimes the tumor tissue is mottled due to the presence of hemorrhages and necrosis foci in it. A tumor in the form of a polyp may have a fibrous structure in some organs (for example, in the ovaries)- cystic. The size of the tumor depends on the speed and duration of its growth, origin and location, consistency - on the predominance of parenchyma or stroma in the tumor: in the first case, it is soft, in the second - dense. Secondary changes in the tumor are represented by foci of necrosis and hemorrhages, inflammation, ossification and lime deposition (petrification). Sometimes they occur in connection with radiation and chemotherapy. The microscopic structure of tumors is very diverse. However, all tumors have some common features. They consist of parenchyma and stroma, the ratios of which vary greatly. The tumor parenchyma is formed by cells that characterize the type of tumor and determine its morphological specificity. The stroma also has a tumor origin. There are complex connections between the parenchyma and the tumor stroma, and the features of the tumor parenchyma largely determine the nature of its stroma. This ability of tumor cells is largely determined by their genetic properties. It is not equally expressed in tumors of different histological structure, which explains the different content of fibrous structures in the tumor stroma. The cells of the tumor parenchyma not only induce the activity of fibroblasts, but they themselves can produce the intercellular substance of the stroma, or extracellular matrix (for example, collagen type IV of the basement membranes). Tumor cells. In addition, they produce a specific substance of a protein nature - angiogenin, under the influence of which capillaries are formed in the tumor stroma.

TUMOR GROWTH

Depending on the degree of differentiation, there are three types of tumor growth: expansive, appositional, infiltrating (invasive).

With expansive growth, the tumor grows out of itself, pushing aside the surrounding tissues. Parenchymal elements of the tissue surrounding the tumor atrophy, stroma collapse develops, and the tumor becomes surrounded by a capsule (pseudocapsule).

The expansive growth of the tumor is slow, typical for mature, benign tumors. However, some malignant tumors (kidney cancer, thyroid cancer, fibrosarcoma) can also grow expansively.

The appositional growth of the tumor occurs due to the neoplastic transformation of normal cells into tumor cells that are located in the tumor field.

With infiltrating (invasive) growth, tumor cells grow into the surrounding tissues and destroy them (destructive growth). Invasion usually occurs in the direction of least resistance along the interstitial tissues, along the course of nerve fibers, blood and lymph vessels. Tumor cell complexes destroy the walls of blood vessels, penetrate into the blood and lymph flow, grow into loose connective tissue. If an organ capsule, membrane and other dense tissues are found along the path of tumor invasion, tumor cells first spread along their surface, and then, germinating the capsule and membranes, penetrate into the depths of the organ. The boundaries of the tumor with its infiltrating growth are not clearly defined. Infiltrating tumor growth is rapid, characteristic of immature, malignant tumors.

In relation to the lumen of the hollow organ, tumor growth can be endophytic or exophytic. Endophytic growth is the infiltrating growth of a tumor deep into the wall of an organ. In this case, the tumor from the mucous membrane (for example, stomach, bladder, bronchus, intestines) is almost invisible; on the section of the wall it is visible that a tumor is germinating. Exophytic growth is the expansive growth of a tumor into the cavity of an organ (for example, stomach, bladder, bronchus, intestines). In this case, the tumor can fill a significant part of the cavity, connecting to the wall with its leg.

Depending on the number of foci of the tumor, they talk about unicentric (one focus) and multicentric (multiple foci) growth.

Progression is a change in the totality of tumor signs (genotype, karyotype and phenotype of tumor cells, including various features of their morphological, biochemical or other differentiation) in the direction of an increasing increase in malignancy.

The increase in malignancy is associated with the consistent appearance of cellular subpopulations with geno- and phenotypic differences from their predecessors, which are represented by such properties and signs as invasiveness, a change in growth rate, the ability to metastasize, the appearance of a new karyotype, other sensitivity to hormones and antitumor drugs. Therefore, despite the fact that initially most malignant neoplasms have a monoclonal origin, by the time of their clinical detection, the cells that make up their parenchyma are characterized by pronounced heterogeneity in geno- and phenotypic terms.

Metastasis is the formation of secondary foci of tumor growth (metastases) as a result of the spread of cells from the primary focus to other tissues. Metastases arise only from malignant neoplasms.

The factors contributing to the development of metastases include

-weak intercellular contacts

-high mobility of tumor cells

-higher hydrostatic pressure in the tumor node compared to the surrounding tissues

-lower pH values in the tumor tissue (acidified environment) compared to the surrounding tissues (cell movement is carried out along the pH gradient)

-isolation of numerous proteases by tumor cells, for example, collagenase.

Metastasis consists of 4 stages:

penetration of tumor cells into the lumen of a blood or lymphatic vessel;

transfer of tumor cells by blood or lymph flow;

stopping tumor cells in a new place (metastasis – from the Greek meta stateo – otherwise I stand);

the output of tumor cells into the perivascular tissue;