Сергей Алексеевич Шалин - Pathogenesis of cancer

transform into cells of the microenvironment, and transform into a Macrophage. And although irreversible genotypic changes are an absolute necessity for transformation into a malignant stem cell, this is completely insufficient. Genotypic changes in the DNA of the Monocyte nucleus will wait patiently until optimal conditions arise for their manifestation, and then the “nascent” descendants — malignant stem cells — will dominate the host organism.

For the “birth” of a malignant stem cell, subsequent growth and development of the malignant process, “super conditions” are required, creating an isolated state of the progenitor cell from the influence of the body. These conditions can be called a “pre-tumor” bed in pathologically altered local tissues against the background of pre-tumor diseases of the macroorganism. A “pretumor” bed can be an isolated microcavity, the formation of which during chronic inflammation is a natural process. However, it is not at all necessary that the formed isolated microcavity will become the place where the “birth” of a malignant stem cell will occur. Formation of an isolated microcavity: during the process of inflammation, small blood clots and dead tissue are reabsorbed. Large tissue defects resulting from fibrinous-necrotic inflammation are replaced by scar tissue. Small defects that occur between cells within the stroma first become lumens and then turn into microcavities. In response to tissue damage and under the influence of pathogenetic inflammatory factors, pluripotent poorly differentiated connective tissue cells, called “peripheral blood fibrocytes” or fibroblast-like cells, migrate from the bloodstream. Their immunophenotypic characteristics, combined with the ability to give rise to representatives of fibroplastic cell differential, suggest that they are multipotent mesenchymal stromal cells (MMSCs), constantly circulating in the blood in small quantities. It is these fibroblast-like cells that participate in the formation of the insulating shell of the microcavity, which acts as a “graveyard” for dead cells. Due to chemotaxis, a certain number of Monocytes enter an isolated microcavity, because not all of them are subsequently transformed into a malignant stem cell, but the transformation process never occurs from single cells. Once in an isolated microcavity, the Monocyte finds itself surrounded by an aggressive oxygen-free environment. He develops structural changes in the cell membrane and chemical changes in the cytoplasm — epigenetic changes. A tissue monocyte appears, which has genotypic and epigenetic changes — this is the potential precursor cell of the primary malignant stem cell of solid tumors. Such a Monocyte remains outwardly normal as long as it is in interphase, but as soon as it begins Mitosis, all changes will become obvious and manifest themselves. It is known that each Monocyte in tissues turns into an organ- and tissue-specific Macrophage during the process of transformation. Transformation is a series of cell divisions during which its phenotypic changes occur sequentially under the influence of the microenvironment. A monocyte, having genotypic and epigenetic changes, attempts to transform into a Macrophage (macrophage blast, promacrophage, tissue macrophage) and begins the process of mitosis, during which a return to the embryonic state occurs. However, after mitosis, the level of genotypic changes appears, as a result of which a block of differentiation of daughter cells occurs and transformation, during which the nature of genotypic changes in nuclear DNA appears. As a result, an unstable active system is “born” — a malignant stem cell, which has retained many of the basic abilities and capabilities of the mother cell — the tissue Monocyte, which has not completely left the embryonic state and acquires new abilities of its new life: the possibility of uncontrolled division, autonomous regulation, immortality of the population, etc. A malignant stem cell is a proliferating somatic cell that has a certain level of potency, which corresponds to the level at which genotypic changes occurred in the bone marrow cell during hematopoiesis:

1. If genotypic changes in a bone marrow cell occurred at the level of a pluripotent progenitor cell of the ancestor of myelopoiesis with subsequent development into a monocytic lineage (class II), then the tissue monocyte is transformed into a pluripotent malignant stem cell with pronounced phenotypic heterogeneity and the possibility of the appearance of a “chimera” cell. with multiple differentiation.

2. If genotypic changes in the bone marrow cell occurred at the level of the unipotent progenitor cell of the ancestor of Monocytes (class III), then the tissue Monocyte is transformed into a unipotent malignant stem cell with minimal phenotypic heterogeneity. The “nascent” malignant stem cell, due to proliferation, creates a clone of malignant cells, which are the trigger, regulator and activator of the growth and development of the malignant process.

Thus, the following Monocytes and different groups of cells derived from Monocytes are possible in the human body:

1. The main group is normal Monocytes, which arose from the bone marrow cell and continued on their way into the bloodstream, and then entered the tissues and turned into macrophages.

2. The group of future cancer cells are Monocytes that received genotypic changes in their DNA in the germinal zone, penetrated into the blood, and then into an isolated microcavity in the infected tissue, where they were exposed to the environment. They eventually turned into cancer cells. In the future, contacts are possible between former Monocytes that have turned into Macrophages and former Monocytes that have turned into cancer cells. Most likely, these contacts will not be harmful to cancer cells, because They have the same basis and therefore there is no point in “fighting” among themselves.

3. The group with genotypic changes are Monocytes that received genotypic changes in their DNA in the germinal zone, but did not change phenotypically, although they changed some of their properties. Ultimately, in tissues they turned into macrophages and their derivatives.

MONONUCLEAR ONCOGENESIS PROGRAM

According to the modern theory of molecular genetic mechanisms of multistage carcinogenesis, the “birth” of a malignant cell occurs in three stages: initiation, promotion and progression. The program of the emergence, growth and development of mononuclear oncogenesis in the carrier organism consists of many regular, evolutionarily determined and successively changing periods and stages, separated in time, space and local changes in the cell (nucleus, cell membrane, cytoplasm). Detailed information about the molecular genetic mechanisms of oncogenesis is available in the available literature, so let us summarize and analyze its main provisions. To create the theory of “Mononuclear oncogenesis” as a natural mechanism of the emergence, growth and development of a malignant process, we considered it possible to question the existing theory about the origin of the primary malignant stem cell of solid tumors from cambial cells of the integumentary or glandular epithelium. After all, the question of what cellular and/or tissue substrate the malignant stem cells of solid tumors originate from is still debatable, and the range of cells that could lay claim to the role of the precursor cell of the primary malignant stem cell has not yet been precisely determined.

The first period is the formation of a “pre-tumor” bed.

The first stage:

— is the emergence and development of general diseases of the body, both basic and accompanying: nonspecific changes in tissues of an inflammatory, dystrophic and dishormonal nature; --">