Herashchenko B. Proliferative and adaptive cell responses induced by ionizing radiation and chemotherapy drugs

The structural and functional constancy of self-renewing cell populations is usually controlled by homeostasis mechanisms aimed to replace cells that have died naturally or under the influence of external stressors. It is known that some physical and chemical factors at certain doses lead to the damage of genetic apparatus of cells, activating the mechanisms of its repair. Incomplete and/or incorrect repair of the genetic apparatus results in the two main consequences: cell death or oncogenic transformation. Cell death can be favorable only if the dead cells are actively replaced by the cells that have adapted and successfully recovered after the action of genotoxic agents. It is possible that such processes are implemented through polyploidization involving the mechanism of self-renewal inherent in stem cells, resembling post-traumatic regeneration of the liver parenchyma. According to in vitro studies, a similar scenario of response to genotoxic stress has been previously documented for some types of tumor cells. It has been proven for the first time that the formation of PBR can only be implemented under condition when the direct intercellular contact is established, and neither gap junctions nor long range factors that can be released into the intercellular milieu from irradiated cells play a major role in this process. It has also been found that PBR are implemented in cells acutely irradiated with 137Cs γ-rays from the outside as well as in cells prolongedly irradiated with 3 Н β-particles from the inside, and these responses are enhanced by increasing the ratio of irradiated cells to unirradiated cells, regardless of the type of applied radiation. The fact of involvement of cellular defense, proliferation and metabolism in PBR has been proven by the character of changes in the protein profile of bystander cells. Experiments with directly irradiated normal stem-like cells such as WB-F344 have first demonstrated that an adaptive response, which can be the basis of their radioresistance, is implemented through polyploidization with concomitant expression of stem cell factors OCT4 and NANOG responsible for self-renewal of cell populations. It has been found that after X-irradiation with doses within the range of 1.0–10.0 Gy even the large polyploid cells with ploidy of 8C and above can proliferate, as determined by Ki-67 marker, and can divide by regular mitosis. Similar to WB-F344 cells, tumor cells in some breast cancer cases (particularly near-triploid and triple-negative cases) have been found to respond to the genotoxic stress by polyploidization and self-renewal, although instead of IR doxorubicin with paclitaxel was used. In addition, the vast majority of polyploid cells that are also positive for the marker of invasiveness (CD44) can depolyploidize, producing the daughter cells with the same phenotype. DNA-cytometry has been proposed for the detection and quantitative evaluation of polyploid cells in a tumor before and after anti-tumor therapy, aiming to substantially expand the understanding of the course of the disease and the therapeutic effect.