Bezdieniezhnykh N. Factor of the epithelial-mesenchymal transition of cells in the tumor process and sensitivity to medication therapy (experimental study)

The dissertation is aimed on determination of biological features and immunophenotypic status of tumor cells of different histogenesis under the conditions of action of exo- and endogenous modifiers for evaluation of the value of the epithelial-mesenchymal transition (EMT) in tumor progression and sensitivity of malignantly transformed cells to cytostatics. The study utilizing in vitro experimental system with the use of cells from tumor material of patients with tumors of different histogenesis has established the plasticity of the tumor cell phenotype in the dynamics of cultivation and the shift from the dominance of mesenchymal characteristics to the epithelial phenotype under conditions of cell growth ex vivo. The reduction of malignancy patterns of tumor cells after their exposure to chemotherapeutic drugs (cisplatin, irinotecan) at subtoxic doses and IFN-alpha were revealed using the invasion test and the test for colony-formimg ability. The inhibition of the expression of EMT associated markers and the marker of cancer stem cells (CD44) under prolonged exposure of the tumor cells to IFN has been established. Antitumor and antimetastatic effects of IFN-beta were established using in vivo models: prolonged exposure of melanoma cells to this cytokine significantly inhibited tumor growth in mice and causes a 100-fold reduction in metastasis volume and 10-fold reduction of metastases numbers. The cells of breast cancer, ovarian cancer, lung cancer, and colorectal cancer cells with epithelial phenotype have been found to be less sensitive to antimetabolites (fluorouracil, methotrexate). In addition, the breast cancer cells with epithelial phenotype were significantly more sensitive to gemzar than the cells with a predominance of mesenchymal features, which indicated the feasibility of assessing EMT status of tumor cells as a predictive marker for improving the efficacy of medication therapy.