Involvement of PAFR activation during chemotherapy in the melanoma repopulation phenomenon

Abstract

One of the biggest challenges faced in cancer treatment is the process of tumor repopulation.In this process, cells that are refractory to therapy, are able to proliferate and reconstitute the tumor. Despite its clinical frequency and its contribution to treatment failure, the molecular and cellular events involved in this phenomenon are still poorly understood. The comprehension of these events is important to prevent the repopulation and improve the current therapies. In the unique model proposed, known as Phoenix Rising, apoptotic cells (derived from chemotherapy or radiotherapy), provide proliferative signals to other tumor cells, in a mechanism dependent on caspase 3 and phospholipase A2 (pLA2). The platelet activating factor, PAF, is a bioactive lipid originated from pLA2 with several physiological roles. In tumors, the activation of its receptor (PAFR) is related to processes that favor tumor growth and metastasis. Furthermore, PAFR is involved in housekeeping events, such as phagocytosis of apoptotic cells by macrophages that are polarized towards an immunosuppressive phenotype. Previous results from our group showed that cells exposed to hypoxia were more resistant to cisplatin-induced cell death and that PAFR antagonist, WEB 2086, sensitized these cells in this context. Besides that, the combined treatment was synergic and induced, approximately, 50% of cell death. In vivo experiments showed that in hypoxic tumor areas, the expression of PAFR was increased. It is already known that tumor cells submitted to hypoxia are more resistant to treatment and might contribute to tumor repopulation. Therefore, the aim of this project is to evaluate if in conditions of hypoxia/re-oxygenation, nutrient deprivation and exposure to cytotoxic agents, the PAFR activation is involved in tumor repopulation, triggering mechanisms related to tumor survival (e.g. autophagy) and cell proliferation.