Carcinogenesis: theories and stages

It has now been established that cancer, or malignant neoplasm, is a disease of the genetic apparatus of a cell that is characterized by prolonged chronic pathological processes, or, more simply, carcinogenesis, which has developed in the body for dozens of years. Obsolete ideas about the transience of the tumor process gave way to more modern theories.

The process of transformation of a normal cell into a tumor cell is caused by the accumulation of mutations caused by damage in the genome. The appearance of these lesions occurs as a result of endogenous causes, such as replication errors, chemical instability of DNA bases and their modification under the action of free radicals, and under the influence of external causative factors of chemical and physical nature.

[1], [2], [3], [4], [5], [6], [7], [8]

Theories of carcinogenesis

The study of the mechanisms of tumor cell transformation has a long history. To date, many concepts have been proposed that attempt to explain carcinogenesis and the mechanisms for converting a normal cell into a cancerous one. Most of these theories have only a historical interest or are part of the universal theory of carcinogenesis, the theory of oncogenes, accepted by most pathologists today. The oncogenic theory of carcinogenesis has made it possible to come closer to an understanding of why different etiological factors cause one inherently disease. It was the first unified theory of the origin of tumors, which included achievements in the field of chemical, radiation and viral carcinogenesis.

The main provisions of the theory of oncogenes were formulated in the early 1970s. R. Huebner and G.Todaro (R. Huebner and G.Todaro) who suggested that in the genetic apparatus of every normal cell there are genes, if untimely activation or disturbance of the function of which the normal cell can turn into cancerous.

Over the past ten years, the oncogenic theory of carcinogenesis and cancer has acquired a modern look and can be reduced to several basic postulates:

• oncogenes - genes that are activated in tumors, causing increased proliferation and reproduction and suppression of cell death; oncogenes display transforming properties in transfection experiments;
• unmutated oncogenes act at key stages of the proliferation, differentiation and programmed cell death processes, being under the control of the body's signal systems;
• genetic damage (mutations) in oncogenes lead to the release of the cell from external regulatory influences, which underlies its uncontrolled division;
• mutation in one oncogene is almost always compensated, therefore the process of malignant transformation requires combined disorders in several oncogenes.

Carcinogenesis also has the other side of the problem, which concerns the mechanisms for restraining malignant transformation and is associated with the function of the so-called anti- oncogenes (suppressor genes), which normally have an inactivating effect on proliferation and favor the induction of apoptosis. Antioncogenes can cause a reversal of the malignant phenotype in transfection experiments. Virtually every tumor contains mutations in antioncogenes, both in the form of deletions and micromutations, and inactivating damages of suppressor genes occur much more often than activating mutations in oncogenes.

Carcinogenesis has molecular genetic changes, which comprise the following three main components: activating mutations in oncogenes, inactivating mutations in antinocogenes, and genetic instability.

In general terms, carcinogenesis is considered at the present level as a consequence of the disturbance of normal cellular homeostasis, expressed in loss of control over reproduction and in the enhancement of mechanisms for protecting cells from the effects of apoptosis signals, that is, programmed cell death. As a result of activation of oncogenes and switching off the function of suppressor genes, the cancer cell acquires unusual properties, manifested in immortalization (immortality) and the ability to overcome the so-called replicative aging. Mutational disorders in the cancer cell concern groups of genes responsible for controlling proliferation, apoptosis, angiogenesis, adhesion, transmembrane signals, DNA repair and genome stability.

What stages does carcinogenesis have?

Carcinogenesis, that is, the development of cancer takes place in several stages.

Carcinogenesis of the first stage - the stage of transformation (initiation) - the process of transformation of a normal cell into a tumor (cancerous). Transformation is the result of the interaction of a normal cell with a transforming agent (carcinogen). During the first stage of carcinogenesis irreversible disturbances of the genotype of the normal cell take place, as a result of which it passes into the state predisposed to transformation (latent cell). During the initiation phase, the carcinogen or its active metabolite interacts with nucleic acids (DNA and RNA) and proteins. Damage in the cell can have a genetic or epigenetic nature. Genetic changes are understood as any modification in DNA sequences or in the number of chromosomes. These include damage or rearrangement of the primary structure of DNA (eg, gene mutations or chromosomal aberrations), or changes in the number of copies of genes or the integrity of chromosomes.

Carcinogenesis of the second stage - the stage of activation, or promotion, the essence of which is the proliferation of the transformed cell, the formation of a clone of cancer cells and a tumor. This phase of carcinogenesis, unlike the initiation stage, is reversible, at least at an early stage of the neoplastic process. During the promotion, the initiated cell acquires phenotypic properties of the transformed cell as a result of altered gene expression (epigenetic mechanism). The appearance of a cancer cell in the body does not inevitably lead to the development of tumor disease and the death of the organism. For the induction of the tumor, a prolonged and relatively continuous action of the promoter is necessary.

Promoters have a variety of effects on cells. They affect the state of cell membranes that have specific receptors for promoters, in particular, activate membrane protein kinase, affect cell differentiation, and block cell-cell bonds.

A growing tumor is not a frozen, stationary formation with unchanged properties. In the process of growth, its properties are constantly changing: some signs are lost, some arise. This evolution of the properties of the tumor is called "tumor progression." Progression is the third stage of tumor growth. Finally, the fourth stage is the outcome of the tumor process.

Carcinogenesis not only causes persistent changes in the genotype of the cell, but also has a multifaceted influence on the tissue, organ and organism levels, creating in a number of cases conditions conducive to the survival of the transformed cell, as well as the subsequent growth and progression of the neoplasms. According to some scientists, these conditions arise as a result of profound violations of the functions of the neuroendocrine and immune systems. Some of these shifts may vary depending on the characteristics of carcinogenic agents, which may be due in particular to differences in their pharmacological properties. The most common reactions to carcinogenesis, which are essential for the onset and development of a tumor, are changes in the level and ratio of biogenic amines in the central nervous system, in particular in the hypothalamus, affecting, among other things, hormone-mediated enhancement of cell proliferation, as well as disorders of carbohydrate and fat exchange, changes in the function of various parts of the immune system.