Investigating senescence and senescence-escape in cancer cells
Despite the general concept that therapy-induced senescence (TIS) has a tumour-suppressive role, the presence of senescent tumour cells and the ability of cancer cells to escape from senescence could potentially lead to therapy resistance and tumour recurrence. While a wide range of chemotherapeutic drugs are known to induce senescence in cancer, the effect of TIS in tumour progression is still not completely understood. The project was focused on the development of in vitro senescence and senescence-escape models, along with the investigation of a cell surface protein dipeptidyl-peptidase 4 (DPP4/CD26) as a potential marker of senescence in cancer, and the establishment of a treatment strategy exploiting TIS. Three different drugs were used to induce senescence in MCF-7 and MDA-MB-231 breast cancer cell lines, and the expression of various senescence markers were investigated. To identify and isolate senescence-escaped cells and to evaluate the senescence-escaping ability of the cells, new methods were established by using a Ki-67 staining, crystal-violet staining and CellTrace CFSE staining. Our results revealed a variability in the expression of different senescent markers and in the senescence-escaping ability of the cells, depending on the drug used for senescence-induction and the cell type as well. Importantly, the expression of DPP4/CD26 was significantly increased in both senescent MCF-7 and MDA-MB-231 cells. Investigating the function of DPP4/CD26 in senescent cancer cells indicated that its expression is not essential for senescence-induction, however, it exhibited a potential role to promote senescence-escape in MCF-7 cells, but not in MDA-MB-231 cell. Our results also demonstrated that targeting senescent cancer cells with a senolytic drug and a DPP4 inhibitor resulted in a synergistic effect in MCF-7 cells, by decreasing the viability of senescent cells and reducing the number of senescence-escaped cells. Although further research should be conducted, our results and the established methods could contribute to the investigation of the mechanism of senescence-escape and the identification of potential therapeutic targets. Moreover, DPP4/CD26 could be a promising marker and a novel target to be exploited in cancer diagnosis and treatment.
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