Pathogenesis of cancer - Сергей Алексеевич Шалин
— the malignant process impacts haemopoiesis, homeostasis, immunity etc.
Solid Tumours are the largest in quantity, heterogeneous group of malignant diseases, which develop through multi-stage malignant transformation of a normal proliferating somatic cell into a malignant stem cell:
— the origins of malignant cells are not known, as the precursor of the malignant stem cells is not known. It is supposed that the precursors are normal somatic proliferating cells — cambial cells, which are located in the area of the crypts’ floor, glands’ neck, periosteum and perichondrium, along the blood vessels’ flow and also in the area of intense restorative proliferation;
— it is not known where and how both stages (initiation and promotion) of the “birth” of a malignant stem cell take place. It is supposed, in the area of intensive proliferation of cells;
— also it is not known what process underlies the “birth” of a malignant stem cell. It is supposed that a normal somatic proliferating cell transforms into the malignant stem cell;
— the mechanism of the “birth” of a malignant stem cell is not known. It is supposed that following the carcinogenic impact the genotype and epigenetic changes of a normal proliferating somatic cell take place, and these are a launching mechanism for its transformation into the malignant stem cell;
— a malignant focus starts with the “birth” of one malignant stem cell (in 80 % cases), two or more malignant stem cells (20 %), which then form a clone of malignant cells;
— the malignant process is manifested through forming the primary malignant focus, which can be located in different organs and tissues, and it increases by proliferation of cells, appositional and invasive growth;
— the malignant process is developed by the haematogenous and lymphogenous spread in the host body while forming the secondary foci — metastases;
— the malignant process impacts haemopoiesis, homeostasis, immunity etc.
Thus, the contemporary notions:
1. The difference between haemoblastosis (leucosis and lymphoma) on the one hand and solid tumours on the other, is in the mechanism of the “birth” of a malignant stem cell;
— in the case of haemoblastosis, following the carcinogenic impact the genotype and epigenetic changes of a pluripotent or unipotent stem cell of myelo- or lymphopoiesis, a block of differentiation and its transformation into a malignant stem cell take place;
— it is supposed that in the case of solid tumours, following the carcinogenic impact genotype and epigenetic changes of a normal proliferating somatic cell take place, which are a launching mechanism for its transformation into a malignant stem cell.
2. The difference between leucosis on the one hand and lymphoma and solid tumours on the other, is in the manifestation of the malignant process:
— in the case of leucosis, the disease manifests itself by the affection of the red marrow, but the primary malignant focus is not formed. The “birth” of a malignant stem cell requires 2–4 genotype alterations of the nuclear DNA of a pluripotent or unipotent stem cell of myelo- or lymphopoiesis. Epigenetic alterations are of secondary importance, that is why changes in the living conditions and microenvironment of the precursor are not a prerequisite;
— in the case of lymphoma and solid tumours, the disease manifests itself by necessary forming of the primary malignant focus. The “birth” of a malignant stem cell requires 7–8 genotype alterations of the nuclear DNA of the precursor of the malignant stem cell. The genotype and epigenetic alterations are of equal importance, that is why changes in the living conditions and microenvironment of the precursor are a prerequisite. The large number of genotype alterations of nuclear DNA and the equally important genotype and epigenetic alterations determine the length of pre-clinical evolution of the disease.
3. The features of tumorous growth of lymphoma are common with those of solid tumours — they form the primary malignant focus and metastasis, as well as with leucosis; they can form the states, which are analogous to lymphoid leucosis. That is why the lymphoma is considered as an intermediate variant of the malignant process development.
4. Given that in the case of haemoblastosis the first stage (initiation) of the “birth” of a malignant stem cell takes place in the red marrow, it would be logical to suppose that in the case of solid tumours the first stage (initiation) of the precursor of a malignant stem cell also takes place in the red marrow. So the following second stage (promotion) occurs in the organs and tissues where the “birth” of a malignant stem cell takes place and it forms the primary malignant focus.
ONCOGENESIS
The basis for the growth and development of oncogenesis is a malignant stem cell, and the basis for the “generation” of a malignant stem cell is the return of a tissue Monocyte, which has genotypic and epigenetic changes, to the embryonic state during mitosis, a differentiation block at the pluripotent or unipotent level and transformation. Monocyte — with a diameter of 16–18 microns, various morphological variations in the nature and intensity of coloring of the nucleus and cytoplasm. The kernels may approach round, bean-shaped shapes. The cytoplasm is grayish or pale blue in color and may contain numerous dust-like azurophilic granules. Differentiation of Monoblast into Monocyte occurs in the red bone marrow within 5 days. A monocyte stays in the bone marrow for an average of 3 days, then divides and, without forming a bone marrow reserve, enters the peripheral blood. In the blood, the Monocyte is the largest blood cell, here it matures, the nucleus becomes from round, first bean-shaped, then clawed, and the chromatin structure changes. Various levels of monocyte differentiation were found in peripheral blood, with more mature monocytes predominating in healthy people. In the blood, monocytes are distributed into parietal and circulating pools, exchanging with each other, the quantitative ratios of which may vary. In humans, the circulating pool of Monocytes is normally 18x10 to the 6th degree cells/kg body weight, and the marginal pool, which currently does not take part in the
