Genetic instability of a multicellular organism: inherent in the immune system and neoplasia

Abstract

            One of the key properties of a tumor cell, unlike a normal one, is a high level of genetic instability. The cause and main driving force of tumor growth and progression is the instability of the genome of tumor cells and, due to this, the extraordinary plasticity of their properties. Genetic instability forms the properties of tumor cells that distinguish them from normal ones: independence of proliferation from external stimuli, resistance to growth inhibitory signals, torpidity to apoptosis, inability to adequately maintain connections with cells of the same species, potential immortality, invasion and metastasis. Cytogenetically determined chromosomal abnormalities are typical for many types of tumors. The cells of a malignant neoplasm borrow the properties that normally belong to the cells of the immune system, namely the acquisition of the ability to rearrange the genome, express class II histocompatibility antigens, and migrate. The most studied phenomenon of genome rearrangement in normal cells is the process of genetic rearrangements, without which adequate functioning of the immune system is impossible. In the Nobel lecture delivered in Stockholm on December 8, 1987. S. Tonegawa spoke about the main provisions of the discovery made by his group. Scientists have shown that the variable and constant parts of immunoglobulin genes are closer in plasma cells compared to germ line cells. For the first time, RNA splicing was described, in which a sequence that is unnecessary in the mature immunoglobulin RNA is cut out. In general, it was shown for the first time that the genome is not a conservative, frozen body, but is characterized by rearrangements.It was also shown that the mutational process is an integral part of the functioning of the immune system of higher eukaryotes. The results of the discovery were published in 1983.At the same time, the group O. K. Frolov on the basis of the Donetsk Medical Institute named after M. Gorky, cytogenetic data were obtained on the genetic instability of lymphocytes as one of the phases of a productive immune response to vaccination models with smallpox, mumps, and typhoid vaccines. The dependence of the "disintegration" of associations of nucleoli-forming acrocentric chromosomes on the rate of lymphocyte proliferation was shown. The number of chromosomal mutations in lymphocytes was directly correlated with the height of the humoral immune response. It was concluded that the immune response is impossible without the mutation process and during it the location of chromosomes in the nucleus changes. These works were published in 1973 in the journal "Cytology and Genetics".The rearrangement of the genome is most often carried out with the direct participation of repetitive sequences. After the completion of the "Human Genome" project, it became clear that genes coding for proteins account for up to 2% of the total volume. 98% of the genome consists of non-coding DNA. LTR sequences account for 9.24%, non-LTR structures account for 35.19%. ALU repeats represent 10.76%, L1 — 17.88%, MIR — 2.93%, L2 — 3.62%.It is interesting that the appearance of some types of non-coding DNA in the genome coincides with evolutionary aromamorphoses. For example, L1 determines the appearance of the placenta in animals. It is believed that normally L1 works in the cells of the genital tract and embryogenesis, involved in cell differentiation.Activity is regulated by methylation and specific Piwi miRNAs. L1 insertions play a role in tumor progression, as they are able to activate oncogenes and inactivate tumor suppressor genes. Lee and colleagues described 183 L1 insertions in prostate, colon, and ovarian tumor cells. Hypomethylation of the L1 promoter has been reported in myeloma, chronic myeloid and chronic lymphocytic leukemia, lung cancer, colorectal cancer, urothelial cancer, liver and pancreatic cancer. Genetic instability of L1 cells is induced by homologous and non-homologous recombination, deletions, and translocations.ALU repeats are also mediators of genome reorganization and the phenomena of homologous and non-homologous recombination, as a result of which such cytological disorders as translocations, duplications, deletions and inversions are observed. Normally, ALU repeats regulate gene activity. During tumor growth, the activity of ALU repeats increases, which provokes genetic instability. Along with systems that maintain the gene pool in an unchanged state, without variability, the existence of higher eukaryotes would simply be impossible due to the use of the mutational process by immunocompetent cells as a tool to create variable centers of immunoglobulins and cellular receptors.Along with systems that maintain the gene pool in an unchanged state, without variability, the existence of higher eukaryotes would simply be impossible due to the use of the mutational process by immunocompetent cells as a tool to create variable centers of immunoglobulins and cellular receptors. The payoff for perfection is the emergence of malignant tumors that use the genetic instability normally inherent in the immune system for their own growth and development.