Carcinogenesis: theories and stages

It has now been established that cancer, or malignant neoplasm, is a disease of the cell's genetic apparatus, which is characterized by long-term chronic pathological processes, or, more simply, carcinogenesis, which develop in the body over decades. Outdated ideas about the transience of the tumor process have given way to more modern theories.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 occurrence of these damages occurs as a result of endogenous causes, such as replication errors, chemical instability of DNA bases and their modification under the influence of free radicals, and under the influence of external causal factors of a chemical and physical nature.

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Theories of carcinogenesis

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

The basic principles of the oncogene theory were formulated in the early 1970s by R. Huebner and G. Todaro, who suggested that the genetic apparatus of every normal cell contains genes whose untimely activation or dysfunction can cause a normal cell to become cancerous.

Over the past ten years, the oncogenic theory of carcinogenesis and cancer has acquired its modern form and can be reduced to several fundamental postulates:

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

Carcinogenesis has another side to the problem, which concerns the mechanisms of inhibition of malignant transformation and is associated with the function of the so-called antioncogenes (suppressor genes), which normally have an inactivating effect on proliferation and favor the induction of apoptosis. Antioncogenes are capable of causing a reversion of the malignant phenotype in transfection experiments. Almost every tumor contains mutations in antioncogenes in the form of both deletions and micromutations, and inactivating damage to suppressor genes occurs much more often than activating mutations in oncogenes.

Carcinogenesis involves molecular genetic changes that comprise the following three main components: activating mutations in oncogenes, inactivating mutations in antioncogenes, and genetic instability.

In general, carcinogenesis is considered at the modern level as a consequence of the disruption of normal cellular homeostasis, expressed in the loss of control over reproduction and in the strengthening of cell defense mechanisms against the action of apoptosis signals, i.e. programmed cell death. As a result of the activation of oncogenes and the shutdown of 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 a cancer cell concern groups of genes responsible for the control of proliferation, apoptosis, angiogenesis, adhesion, transmembrane signals, DNA reparation and genome stability.

What are the stages of carcinogenesis?

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

Stage I carcinogenesis - the transformation (initiation) stage - is the process of converting a normal cell into a tumor (cancerous) cell. Transformation is the result of the interaction of a normal cell with a transforming agent (carcinogen). During stage I carcinogenesis, irreversible disturbances in the genotype of a normal cell occur, as a result of which it passes into a state predisposed to transformation (latent cell). During the initiation stage, the carcinogen or its active metabolite interacts with nucleic acids (DNA and RNA) and proteins. Damage to the cell can be genetic or epigenetic in nature. Genetic changes are understood to be any modifications in DNA sequences or the number of chromosomes. These include damage to or reorganization of the primary structure of DNA (for example, gene mutations or chromosomal aberrations), or changes in the number of gene copies or the integrity of chromosomes.

Stage II carcinogenesis is the activation or promotion stage, 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 the early stage of the neoplastic process. During promotion, the initiated cell acquires the 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 a tumor disease and the death of the organism. Long-term and relatively continuous exposure to the promoter is necessary for tumor induction.

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

A growing tumor is not a frozen, stationary formation with unchanging properties. In the process of growth, its properties are constantly changing: some features are lost, some appear. This evolution of tumor properties 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 cell genotype, but also has a variety of effects at the tissue, organ, and organism levels, creating in some cases conditions that promote the survival of the transformed cell, as well as subsequent growth and progression of neoplasms. According to some scientists, these conditions arise as a result of profound dysfunctions 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, essential for the occurrence 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, the hormonally mediated increase in cellular proliferation, as well as disturbances in carbohydrate and lipid metabolism, and changes in the function of various parts of the immune system.