Сергей Алексеевич Шалин
Pathogenesis of cancer
Important and undeniable statements:
– malignant cells are more similar to each other than normal cells are to each other;
– malignant cells have fewer differences between themselves than the differences between malignant cells and normal cells;
– not a single property that malignant cells possess is possessed by epithelial cells, and not a single function of the epithelium (integumentary, protective, exocrine) is transferred to malignant cells;
– the basic principles of the “birth” of a malignant cell, the growth of the primary focus and the development of the malignant process of various organs and tissues are completely identical.
The question of which cell can lay claim to the role of the progenitor cell of the primary malignant stem cell of solid tumors remains controversial. When analyzing all the cells of the human body, only Mononuclear cells (Monocytes) can claim this role, and there is every reason for this statement, they are:
1. They are somatic proliferating cells.
2. They have a long life cycle (months).
3. They have sufficient autonomy: they are able to move freely throughout the host body through the blood stream, penetrate and migrate in various organs and tissues.
4. They are an intermediate development option in the red bone marrow and bloodstream, and in tissues they are transformed into tissue macrophages.
5. In anaerobic conditions, they can independently switch to the anaerobic type of energy production.
6. They can take on the phenotype of microenvironmental cells – mesenchymal-epithelial transition.
7. They have the ability to influence various vital processes: hematopoiesis, homeostasis, immunity, proliferation, maturation and differentiation of cells, etc. Thus, a mononuclear cell (Monocyte) is a cell that can lay claim to the role of a precursor cell of the primary malignant stem cell of solid tumors.
STEPS
The stages of formation and successive change of generations of malignant stem cells during mononuclear oncogenesis correspond to the stages of formation and successive change of generations of stem cells during embryonic hematopoiesis. The presented comparative analysis of the stages of formation and sequential change of generations of stem cells during embryonic hematopoiesis and Mononuclear oncogenesis shows that Mononuclear oncogenesis is a pathological form of embryonic hematopoiesis in the postnatal period of human development.
Comparative analysis of the stages of formation and change of generations of stem cells during embryonic hematopoiesis and mononuclear oncogenesis.
– The first phase – Mesoblastic, the first generation of stem cells – in the wall of the yolk sac of the embryo, the “birth” of blood stem cells occurs – the first generation.
– The first generation of stem cells – Cytoblastic – in an isolated microcavity formed like the yolk sac of an embryo, the “germination” of a malignant stem cell occurs. Due to proliferation, mass accumulation occurs and the first generation of malignant stem cells is formed. Second phase.
– The second phase – Hepatolienal, second generation of stem cells – blood stem cells emerge from the yolk sac and populate the liver, which becomes the main organ of embryonic hematopoiesis. The second generation of blood stem cells is formed in it. Liver blood stem cells then colonize the thymus, spleen and lymph nodes.
– The second generation of stem cells Primary-focal – the malignant stem cells exit beyond the isolated micro cavity into the intercellular space and colonize it. Due to proliferation, appositional and invasive growth they organise a primary focus, where the second generation of the malignant stem cells is formed.
– The third phase Medullar (marrow) – the blood stem cells colonize the red bone marrow, where their third generation is formed – this is the final phase of the embryonic haematopoiesis. Medullar (marrow) – the blood stem cells colonize the red bone marrow, where their third generation is formed – this is the final phase of the embryonic haematopoiesis.
– The third and subsequent generations of stem cells Secondary-focal or metastatic – due to the invasive growth and angioneogenesis the malignant stem cells penetrate into the bloodstream and colonize the lymph nodes, the bone marrow, liver, lungs etc., followed by organisation of the secondary malignant focus – mature metastasis, where the third generation of the malignant stem cells is formed. Later, subsequent generations of the malignant stem cells may form.
PROTOTYPES
Mononuclear oncogenesis uses known processes and structural organizations as prototypes, according to the principle “all this was already in the body, only at a different time, in a different place and with other cellular and non-cellular elements.” The prototype of the “pretumor” bed, presented as an isolated microcavity, is the structural organization and functioning of the yolk sac of the embryo. In this case, conditions close to embryonic ones arise inside the microcavity, and the “nascent” malignant stem cell conditionally repeats the beginning of embryonic hematopoiesis. The prototype of the structural organization and functioning of the primary malignant focus is the structural organization and functioning of the red bone marrow. In this case, the primary malignant focus is presented as an independent structural unit containing all the classical characteristics of the tissue, possessing autonomy of reproduction and the ability to spread in the host organism. A prototype of the relationships between the structural elements that make up the malignant process and the relationships At the same time, the malignant process is presented as an independent system, which is characterized by its own control over the proliferation, differentiation and maturation of malignant cells, their spread and metastasis, as well as the subordination of vital organs and systems of the host body.The prototype of the emergence, growth and development of a malignant process is embryonic hematopoiesis. In this case, the malignant process conditionally repeats in a distorted form all the stages of formation and successive changes in generations of stem cells of embryonic hematopoiesis.
BASE
The basis for the growth and development of Mononuclear oncogenesis is a malignant stem cell, and the basis for the “generation” of a malignant stem cell is the return of a tissue Mononuclear cell, which has genotypic and epigenetic changes, to the embryonic state during mitosis, a block of differentiation at the pluripotent or unipotent level and transformation. In the red bone marrow, under carcinogenic effects (ionizing radiation, exo- and endocarcinogens, viruses), a characteristic spectrum of disorders occurs at the gene, chromosomal and genomic levels: amplification (increase in the copy number of genes), deletions, insertions, translocations, micromutations (point substitutions, microdeletions, microinsertions), etc., a pluripotent precursor cell of the ancestor of myelopoiesis with subsequent development into a monocytic germ (class II) or a unipotent precursor cell of the ancestor of Monocytes (class III) according to a recessive trait. As a result, an initiated cell appears in the host organism – a mononuclear cell, which has genotypic changes in nuclear DNA, but is phenotypically presented as a normal cell (Promonocyte, Monocyte). The initiated cell, maintaining the stages of its development in the red bone marrow and vascular bed, enters the focus of chronic inflammation and finally enters an isolated microcavity. Here, surrounded by an aggressive oxygen-free environment, she develops structural changes in the cell membrane and chemical changes in the cytoplasm – epigenetic changes. A tissue mononuclear cell appears, which has genotypic and epigenetic changes – this is the potential precursor cell of the primary malignant stem cell of solid tumors. Such a mononuclear cell 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 every Promonocyte and 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. The promonocyte or Monocyte, having genotypic and epigenetic changes, attempts to transform into a 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 – tissue mononuclear cell (Promonocyte, 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 the bone marrow cell occurred at the level of the pluripotent progenitor cell of the ancestor of myelopoiesis with subsequent development into a monocytic lineage (class II), then the tissue mononuclear cell is transformed into a pluripotent malignant stem cell, which has 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 Mononuclear cell is transformed into a unipotent malignant stem cell with minimal phenotypic heterogeneity.
The “nascent” malignant stem cell, through proliferation, creates a clone of true malignant cells. Under the influence of growth factors secreted by true malignant cells into the intercellular space, “conditionally malignant cells” appear – phenotypically altered integumentary or glandular epithelium. True malignant cells are the trigger, regulator and activator of the growth and development of the malignant process.
