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What is a precancer?
Who is the author of the term "precancer" is still unknown. Different authors call different names of the inventor of this term. According to T. Venkei and J. Sugar (1962), for the first time it is found in the work of dermatologist V. Dyubreylya (1896).
Until now, it is also unclear what a precancer is. According to the meaning and meaning, a precancer must meet two criteria: always precede a cancer and turn into cancer inevitably, i.e. in all cases. Otherwise it is not a predrak.
If a precancer meets these two criteria, then its meaning is clear to everyone: the diagnosis of a precancer and its elimination should prevent cancer. This is the only way to reduce the number of cancer patients. Currently, it is extremely necessary, because Standard cancer treatment methods - surgical, radiation and drug - allow you to remove and destroy only part of the cancer cells, but not all, i.e. prolong the patient's life.
According to the theory of R. Virchow, the basis of any disease is the pathology of the cell or cells. Cell - the smallest unit of life, susceptible to disease. From here it will not be a mistake if we use the expression “diseased cell”.
Cancer in a broad sense is a population of malignant cells from any tissue whose cells have ominous properties - invasions and metastasis. The cancer formation process in the form of a scheme can be represented as follows1:
1 According to the same scheme, a non-cancerous tumor is formed.
Target cell 1
> Cancer cell
> Cancer (clone or population of cancer cells)
The diagram shows that cancer is the end result of a target cell disease. But cancer itself arises from a cancer cell due to its unlimited division. It also follows from the scheme that if there is a precancer, then its place should be between the target cell and the cancer cell. That which may be in this place must be a precancer. Let's call it while “something”, which we learn from the subsequent presentation.
Even Aristotle wrote: "To know any thing, you need to know its origin and development." For us, this means finding out how a normal target cell turns into a cancer cell, i.e. we need to turn to carcinogenesis. However, you should first give some information about the cell and its properties.
The life of the cell and its properties are determined by the genotype. Each gene through its product - protein, creates some kind of property of the cell. All properties of a cell are its phenotype. The genotype of a cell is disturbed by exposure to a carcinogen cell - chemical, physical or biological - a virus. In this case, the cell phenotype also changes: the previous properties change or disappear, new ones appear. Properties of cancer cells: the ability to invade and metastasize - the main reasons for the difficulties in curing cancer. Thus, a target cell can become a tumor only after exposure to its carcinogen genotype.
It has now been found that genetic disorders that result in a target cell becoming a cancer cell can include: 1) derepression of a number of fetal genes in it — epimutations; and 2) changes in suppressor genes, DNA repair, in the cell cycle genes, apoptosis and immune response in the cell - epimutations and mutations.
Although the picture of gene causes is still incomplete, but now existing knowledge can be used in practice.
1 A “target cell” is a tissue cell exposed to a carcinogen.
The main method for detecting cell epimutations is the methyl-specific polymerase chain reaction (MS – PCR), for the detection of mutations the polymerase chain reaction by the method of molecular colonies (PCR – MMC). Such methods make it possible to identify cancer cells by changes in their genes in the biopsy material, as well as in samples from biological fluids from the patient - blood plasma, etc.
Carcinogenesis is the process of turning a normal cell into a tumor cell. Only immature cells of the tissue can be involved in it, and more often when they are in the division stage. There are two ways of carcinogenesis: 1) "de novo"
- from a target cell of a normal tissue and 2) “on the soil” (“against the background”) - from a target cell, a tissue altered by some influence of the tissue; there is more dividing cell pool in the altered tissue than in normal tissue.
The experiment proved that carcinogenesis in the tissue of any organ consists of two stages: 1st - initiation and 2nd - promotion. These stages were first discovered by I. Birnblum (1947, 1956), G.P. Rusch, B.E. Klein (1950) et al. On the skin of mice, and then confirmed on various tissues of other organs and other animals.
Scheme of the two-stage concept of carcinogenesis
(J. Berenblum, P. Shubik, 1947)
1) for the induction of a tumor, it is necessary to respect the sequence of effects - a carcinogen, then a promoter;
1 These stages occur in any type of carcinogenesis. A non-malignant tumor cell arises from them.
2) initiation is reversible and can be carried out in a matter of hours or days;
3) promotion is reversible, but requires prolonged and repeated exposure of the agent;
4) later, at a genetic level, the inclusion of various genes at stages of carcinogenesis was shown (H. Land, IF Parada, RA Weinberg, 1983).
The concept of carcinogenesis will be clearer from an example of animal experience.
Experience on the skin of mice. Once lubricated area of the subliminal skin, i.e. the minimum dose of carcinogen, which in itself does not cause a tumor. After some time - from a week to several months, the same place on the skin begins to be lubricated with a non-carcinogenic substance.
- Croton oil, which also does not in itself cause cancer. This lubrication is carried out for a certain minimum period of several weeks. As a result, multiple papillomas and cancer are formed on the skin.
1) in the experiment croton oil was used as a promoter - a non-specific irritant, causing irritation of the tissue, leading to pronounced proliferation of the cells of this tissue;
2) if a carcinogen is used as a promoter, then tumors appear at an earlier time than from a nonspecific irritant.
The initiation stage is caused only by a specific irritant, i.e. carcinogen, so it is called the initiator. The period of time from the first exposure of a carcinogen to a tissue to the appearance of a tumor visible to the eye is called latent. The promotion stage can be caused by both a carcinogen, its non-specific part of properties, and various non-specific stimuli. An irritant that causes a promotion stage is called a promoter. The role of the promoter is twofold: increased proliferation of “dormant” tumor cells or increased proliferation of immature cells of the original tissue.
In stage 1, exposure to a carcinogen causes a violation of the genotype in the target cell, i.e. the tumor genotype, and then the tumor phenotype, i.e. the cell becomes tumor. It performs at least one cycle of division, and these cells remain in the tissue in such a state - as if “slumber”; for their activation requires the effects of the promoter. At this carcinogenesis ends. This is the stage of dormant tumor cells.
In the 2nd stage, only under the influence of a promoter, even of a non-carcinogenic character, for example, croton oil, dormant tumor cells are activated and they proliferate, leading to the formation of a tumor visible to the eye. From these data, I. Birnblum concluded that “dormant” tumor cells are a precancer.
However, later by a number of authors (V.V. Khudoley, 1985; J.G. Ehrenpreis, 1986-1987; I.F. Seitz, 1986), additions were made to the essence of the stages: the target cell does not immediately become a tumor. In the 1st stage, epigenetic changes occur in the cell under the influence of a carcinogen - a tumor genotype. This state persists after the termination of the action of the carcinogen, but a change in the signs of initiation is possible, the cell still retains a normal phenotype, i.e. it is a precancerous cell. It is divided at least once, and the resulting cells remain until such time as they are not affected by the promoter. This is the stage of the initiated cells (Y.G. Ehrenpreis, 1986).
In the 2nd stage, under the influence of the promoter, the initiated cells, i.e. precancerous, acquire tumor phenotype, i.e. turn into cancer cells. At this carcinogenesis ends. After that, cancer cells divide indefinitely, forming a tumor. When the number of cells is 108-109 in a tumor, it is distinguished by the naked eye.
From the analysis of the essence of the stages, it follows that in the 1st stage the target cell first becomes precancerous, and in the 2nd stage, the promotion stage, acquiring a tumor phenotype, turns into cancer. So, “something” is an initiated cell or cells in a tissue, i.e. precancer (1st stage - the stage of initiated cells). In this regard, the missing stage should be added to the cancer pattern between the target cell and the cancer cell -
pre-cancerous cell stage:
Normal Target Cell
> Pre-cancerous cell (s)
Cancer (clone or cancer population
Evaluation of experiments on mice I.
Birnblum (1947, 1956) was carried out according to the final result, i.e. on the formation of cancer. From here the conclusion followed logically: a precancer is a “dormant” tumor cell.
However, in the experiments:
1) the state of the cells in the interval between a single smearing of the skin with a carcinogen and the action of a promoter was not studied. This is the reason that the stage of a precancerous cell was unnoticed;
2) the precancerous cell has a tumor genotype, but a normal phenotype. Therefore, it cannot be distinguished by morphological methods from normal tissue cells. This requires PCR - a method that was developed only in 1983.
It follows that a precancer today is a precancerous cell, and the definition: a precancer is a “dormant” tumor cell, now it is not accurate.
Thus, for such a long period of time - from the proposal of the term "precancer" to the present, many scientists tried to figure out what preoccupation is, but they did not succeed in achieving this goal. The main reason is that the precancer was sought in isolation from carcinogenesis. The basis of this approach is the principle: if cancer occurs in any local tissue change, for example, leukoplakia, then such a change is a precancer. On this and taking into account the degree of atypia of tissue cells - A, B, C (T. Venkei and J. Sugar, 1962), classifications of "precancerous diseases" were created - skin, mucous membrane and red border of lips of prof. A.L. Mashkilleyson (1970) and the Committee for the Study of Head and Neck Tumors (1977), as well as other authors. But this is an erroneous approach.
Currently, any local tissue change is not considered a precancerous disease and is referred to as the “background process”.
In oncology, so far there are two criteria for precancer: a nidus of grade III dysplasia that occurs in any part of the background process and is detected by morphological methods, and a precancerous cell. But dysplasia of the III degree by some signs does not meet the criteria of precancer. This is clear from the characteristics of dysplasia:
- it is interpreted differently - the center of immature cells or the center of immature cells with atypia of cells and tissue structure;
- by morphology, this is the closest to the cancer cell change and often grade III dysplasia turns into cancer;
- it is detected in the tissue by morphological methods, but they cannot determine the genotype of its cells;
- in each case, its fate is unknown: becoming a cancer or regress;
- A grade III dysplasia as a precancer is recommended to be used for any tissue. The question arises: if the focus of dysplasia of the III degree is a precancer, then why no one says that its cells are precancerous?
ON. Krajewski and co-authors (1993) write: "A pathologist sees under a microscope either a normal cell or a tumor cell, and with a picture that is considered a precancer, he does not have four morphological data to ascertain his true nature." It is not yet clear what the genotype of grade III dysplasia cells is. To do this, dysplasia cells must be investigated using PCR – MMC and MS – PCR methods. It is clear that without a tumor genotype of cells of the center of dysplasia of the third degree, it cannot be considered a precancer.
A new approach to answering the question of what a precancer is, appeared with the discovery of stages of carcinogenesis. From the analysis of stages, a precancer is an initiated cell.
in a particular fabric. Its characteristics meet the two criteria for precancer, which we mentioned at the beginning of this section.
It is not the tissue that is involved in the stages of carcinogenesis, but only the cell of this tissue. If it has a tumor genotype, but a normal phenotype, it is a precancerous cell. It is also important that in any tissue a precancer is a precancerous cell of a given cell type. From here: there is a precancer, but there is no precancerous diseases. (A.I. Rukavishnikov, 1994, 1999).
About the relationship of precancer with the 1st stage - the stage of initiation, before we said prof. V.M. Dilman (1986). He emphasized: 1) “the presence of the initiation stage can be interpreted as a state of biological precancer, since during this period the cell is already genetically different from normal, but not yet cancerous”;
2) “... after the action of the initiating agent on the cell, it is no longer normal, since the initiation phase is predominantly irreversible. But this cell is not malignant either, since the tumor process does not manifest itself outside the promotion. Consequently, a cell that has undergone changes under the influence of an initiating agent is already precancerous ”(cited in: IF Seits, 1986).
So, a precancerous cell has a defective genotype, but a normal phenotype. Normally, such a cell in the body should be destroyed by apoptosis, i.e. suicide, as defective, and cells of the immune system, as alien.
Acad. V.P. Skulachev (2002) writes about this as follows: “Pre-cancerous cells destroy themselves by apoptosis. In half of the cases, cancer appears when it breaks? The wt53 gene, encoding a p53 protein, that? for DNA breakage. When they are detected, it sends a signal to a pre-cancerous cell with a modified genetic material? To commit suicide? ”
The body's immune cells, cytotoxic T-lymphocytes, "recognize and destroy foreign pre-cancerous cells." "But if suddenly changes in the genetic apparatus of the cell have gone too far and are going
a failure in the immune system, a precancerous "cell is reborn into a cancer cell."
The focus of precancerous cells in the tissue under the experimental conditions (1st stage of initiation) is similar to the focus of grade III dysplasia detected by morphological methods in the tissue from the patient. Both the one and the other at the very beginning of the process represents a small group or nodule of cells in a tissue 1-2 mm in diameter. It is tempting to find out if they will turn out to be identical in their genotype and phenotype of their cells. Such an assumption can be verified by PCR – MMC and MS – PCR in such cells of the biopsy material from suspicious sites in the background process. In the case of coincidence of genotypes and phenotypes of their cells, we can conclude: the precancer in the experiment is the same as the focus of grade III dysplasia from the precancerous cells, but under conditions of a macroorganism. So far, we have not encountered any work in which the third degree dysplasia cells from the patient’s background process were tested by PCR – MMC and MS – PCR.
A.V. Liechtenstein, G.I. Potapova (2005) write that “the practice of identifying and destroying an already existing cancer, established to date, is the moment when the battle? pretty much lost. From this point of view, the array of mutant cells preceding a cancer is a much more gratifying target for therapeutic effects, which does not yet have all the properties of malignancy. ” Such mutant cells are nothing more than precancerous cells - Approx. - A.P.
In oncology, the following terms are still used: obligate and facultative precancer. They are included in monographs and in all textbooks, in which there is a section of oncology.
In this case, a precancer is understood as a modified tissue as a whole, and not a focus of degree dysplasia and not a precancerous cell in the tissue. The term “obligate” means that this altered tissue in all cases turns into cancer, and “facultative” does not always. These ideas about a precancer, as well as the terms denoting it, do not correspond to the level of knowledge about the precancer and therefore should be excluded from the medical literature.
Search for precancerous cells and cancer in suspicious places in the background process is carried out on the material of a fragment of tissue from these sites, taken during biopsy. Any background process on the skin or mucous membrane, or elsewhere in the body and the precancerous cell in the tissue is oncopathology, and this patient belongs to the 1B clinical group of follow-up at the oncologist.
In our opinion, for patients with a background process and a precancer, a precancerous center should be organized in each major city. In such a center, the following should be organized: PCR laboratory, cell culture laboratory, stem cell laboratory, etc.
In the presence of a precancerous center, the contribution of a dentist or a doctor of a different profile of polyclinics in relation to patients with a background process and precancer will be reduced to two tasks: 1) diagnose the patient’s background process using clinical methods and send it to the precancerous center. In the absence of a precancerous center, the patient should be referred to a specialist in an oncologic dispensary. In it, the oncologist will perform a biopsy from suspicious places in the background process and the material will be studied by morphological methods, and in the future, PCR – MMC and MS – PCR methods.
Для лечения пациента с фоновым процессом и предраком на слизистой оболочке и коже применяются два метода: криодеструкция жидким азотом и иссечение. Иссеченный материал направляют на исследование в патогистологическую лабораторию. Такое лечение должно выполняться в условиях онкологического учреждения. Это уже закреплено в лечебно-диагностической тактике врача-стоматолога выпускника в «Программе по хирургической стоматологии для студентов стоматологических факультетов медицинских учебных заведений. М., 1996 г.»:
Лечебно-диагностическая тактика врача-стоматолога выпускника
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