Сергей Шалин
Pathogenesis of cancer

We can talk about the pathogenesis of cancer only by determining the primary mutation of the nuclear DNA of the genome of the precursor cell of the cancer cell. It is possible to theoretically substantiate which cell can lay claim to the role of a precursor cell of a cancer cell if we take into account the functional abilities of the cancer cell received from a somatic cell and the pathological state of the tissues that created optimal conditions for the emergence of a malignant stem cell, the growth and development of the malignant process. Key words: initiation, promotion, monocyte, malignant stem cell, mutation.

Key words: initiation, promotion, monocyte, malignant stem cell, mutation.

INTRODUCTION

Carcinogenesis or oncogenesis is a multi-stage mechanism of the emergence, growth and development of a malignant process. According to the modern theory of carcinogenesis, the occurrence of a malignant tumor is the result of the sequential accumulation of mutations in the somatic cells of the body that are not inherited. When the number of mutations becomes critical, the formation of a primary malignant stem cell occurs. The weak link of this theory is the absence of a cancer cell precursor cell. In a morphological study, it looks like this: a healthy normal cell, next to it a malignant cell, there is no transitional variant or precursor cell to a cancer cell.

MALIGNANT DISEASES

All human malignant diseases are divided into two main groups: hemoblastoses and solid tumors. The principle of division is based on the different localization of the malignant process and some similarity between malignant cells and normal cells of the microenvironment. The cytogenesis of malignant diseases of hematopoietic and lymphoid tissue is considered the most studied, which is based on the doctrine of stem and semi-stem precursor cells of hematopoiesis. Cytogenesis of solid tumors has not yet been studied; there is no clear idea from which progenitor cells malignant cells arise. That is why we will mainly consider issues related to solid tumors, drawing a possible analogy with hemoblastoses.

General signs of hemoblastoses and solid tumors.

1. Etiology: chemical agents (endo- and exocarcinogens), ionizing radiation.

2. Pathogenesis: nuclear DNA mutations and epigenetic changes – damage to the structure of the cell membrane and chemical processes in the cytoplasm of the cell. 3. Diagnostics: clinical, laboratory and instrumental research methods with mandatory morphological verification of the diagnosis (histological and cytological studies).

4. Complications: infectious, thrombotic, disruption of the normal mechanism of osteogenesis, gastrointestinal complications (nausea, vomiting, hiccups, constipation, diarrhea and mucositis), intoxication and psychological changes (anxiety, depression, aggressiveness and suicide).

5. Principles of pathogenetic therapy: influences that suppress the proliferation of malignant cells (X-ray, chemotherapy, hormone therapy and immunotherapy); vitamin therapy; auxiliary therapy (blood transfusion, relief of infection, treatment of thrombosis and bleeding); bone marrow transplantation.

6. Causes of death: cachexia, secondary infection, severe anemia, thromboembolic complications, massive bleeding and hemorrhage.

7. The main symptoms of a malignant neoplasm: transmission of all properties by inheritance, preservation of the principle of malignant progression, uncontrolled cell division, invasive growth and metastasis. Thus, the general similarity of hemoblastoses and solid tumors is established at the genetic level. General signs of hemoblastoses and solid tumors.

Differences between haemoblastosis and solid tumours

Let us consider each group of malignant diseases separately and also split haemoblastosis into two sub-groups: leucosis and lymphoma. Based on studies of the onsets of all malignant diseases, we can draw the following conclusions:

Leucosis is a numerous and heterogeneous group of malignant diseases, which emerge from haemopoietic (blood forming) cells and affect red marrow.

– the precursors of malignant stem cells are pluripotent or unipotent stem cells of the foci of myelo- or lymphopoiesis in the red marrow;

– both stages (initiation and promotion) of the “birth” of a malignant stem cell take place in the same location – in the red bone marrow;

– the basis of a malignant stem cell “birth” is the block of differentiation and transformation of a pluripotent or unipotent stem cell of myelo- or lymphopoiesis;

– the mechanism of a malignant stem cell “birth” lies in the genotype and epigenetic changes of a pluripotent or unipotent stem cell of myelo- or lymphopoiesis following the carcinogenic impact;

– the malignant process starts from the “birth” of one malignant stem cell, which then forms a clone of malignant cells;

– the disease is manifested through growth of the malignant process in the red marrow, but at that time a primary malignant focus is absent;

– the malignant process develops by the proliferation of malignant cells within the red marrow, and by haematogenous and lymphogenous spread in the host body;

– the malignant process impacts haemopoiesis, homeostasis, immunity etc.

Lymphoma is a group of malignant haematological diseases of lymphatic tissue characterised by malignant transformation of lymphoid cells;

– the precursors of malignant stem cells are pluripotent or unipotent stem cells of lymphopoiesis located in the red marrow;

– the first stage (initiation) of the “birth” of a malignant stem cell takes place in the red marrow, the second stage (promotion) in the location of the primary malignant focus;

– the basis of a malignant stem cell “birth” is a block of differentiation and transformation of a pluripotent or unipotent stem cell of lymphopoiesis;

– the mechanism of a malignant stem cell “birth” is the genotype and epigenetic changes of a pluripotent or unipotent stem cell of lymphopoiesis following the carcinogenic impact;

– the malignant process starts from the “birth” of one malignant stem cell, which then forms a clone of malignant cells;

– the malignant process is manifested through forming the primary malignant focus located in the lymph nodes (nodal involvement) or in any other organs and tissues (extra nodal involvement);

– the malignant process is developed by lymphogenous spread in the host body, sometimes cells of lymphoma are detected in the blood, but usually they tend to form thick tumours in the lymphatic system or in the internal organs (liver, stomach, nervous system or in other places);

– 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 circulation, adjacent to the inner wall of the microvessel, is 3.5 times larger (63x10 to the 6th degree of cells/ kg body weight). In general, the total pool of peripheral blood monocytes constitutes from 1 to 10% of all leukocytes (80–600 x 109/l). Monocytes circulate in the blood from 36 to 104 hours (1.5 – 4.5 days) and then leave it according to a stochastic principle, interacting with specialized adhesion molecules on endothelial cells. Monocyte migration from the vascular bed to the focus of chronic inflammation occurs through areas of the microcirculatory bed with the second type of endothelium – these are postcapillaries and venules. Once in the focus of chronic inflammation, monocytes migrate. Cell migration is a process of passive displacement of cells or active movement of cellular complexes and isolated cells, caused by complex selective interactions of cellular receptors on the membranes of migrating cells and their microenvironment. Genotypic changes in the Monocyte can occur at different stages of hematopoiesis and the higher, according to the hematopoietic scheme, the greater potency the malignant stem cell will have. Therefore, it is important to know not only what genotypic changes in the nuclear DNA of the Monocyte arose, but also at what level of hematopoiesis they arose, i.e. Not only the nature of genotypic changes (spectrum of disturbances) of nuclear DNA is important, but also the level of genotypic changes (class according to the hematopoiesis scheme). For the “germination” of a malignant stem cell in solid tumors, the most likely levels of potency are:

1. Class II – pluripotent progenitor cell of the ancestor of myelopoiesis, common to 4 lineages (CFU-GEMMeg) with subsequent development in the direction of the Monocytic lineage.

2. Class III – unipotent progenitor cell of the monocytes (CFU-M). It must be emphasized that genotypic changes in nuclear DNA occur according to a recessive trait, therefore these changes do not manifest themselves in any way in the red bone marrow.

During the process of differentiation, genotypic changes are laid down in the genetic apparatus of the future Monocyte, which morphologically will not differ from a normal bone marrow cell. The acquisition of genotypic changes in nuclear DNA for a Monocyte is not decisive in the possibility of transformation into a malignant stem cell, because it can divide, mature, differentiate, 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.

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