Dottorato in MORFOGENESI E INGEGNERIA TISSUTALE

Titolo della tesi: Radioresistance mechanisms in a clinically relevant model of prostate cancer

Background: Long-term androgen deprivation in combination with radiotherapy (RT) currently represent the main option for the Prostate Cancer (PCa) treatment, but radio-resistance and relapse remain unsolved clinical problems. Response or non-response to radiotherapy (RT) treatment is based on the radiobiological concept of the “6Rs”, which are repair, redistribution, repopulation, reoxygenation, intrinsic radioresistance and reactivation of antitumor immune response by RT. Aim :the Aim of this study is to evaluate the potential molecular mechanisms underlying acquired radioresistance of PCa cells. Methods: we developed a clinically relevant radioresistant PCa cell line (PC3RR) by subjecting parental PC3 cells to a radiation treatment equivalent to a course of RT in a patient with PCa. By using different bioassays and molecular assays we assessed the radiobiology characterization of PC3RR cells with their isogenic background. Results: Using clonogenic assay it has been showed that PC3RR cells are more radioresistant compared to PC3 cells. PC3RR cells showed greater efficiency in DNA damage repair, downregulation of cell death markers, and an increased proliferation rate after RT. PC3RR cells were characterized by an in vitro pro-metastatic phenotype with high expression of mesenchymal markers, furthermore, they showed lower basal ROS levels with higher expression of antioxidant genes. These findings are in accordance with radioresistant phenotype of cancer cells, described in litterature. Unexpectedly PC3RR cells have showed grater sensitibility to chemotherapy treatment with docetaxel. Conclusion: Taken together, these data support the hypothesis that radiotherapy treatment selects a more aggressive and radioresistant PC3 subpopulation, which could mainly contain cells with stem-like phenotype. The ability to identify these cells in the primary tumor or circulation would provide prognostic information capable of driving prostate cancer treatment decisions. Further, the ability to target these CSCs could prevent tumor metastasis and relapse after radiation therapy.