Impact of Aged Tumor Microenvironment and Chemosensitivity on Sub-types of Ovarian Cancer

Ovarian cancer (OC) is the most lethal female reproductive cancer––with a 5-year survival rate of 50.9%––and is diagnosed on average in patients in their 60s. Often OC patients enter an initial remission following chemotherapeutic or surgical interventions; however, ~75% of patients experience chemotherapy-resistant OC recurrence. This study aims to investigate the impact of aging on the tumor microenvironment (TME) and chemosensitivity of various subtypes of ovarian cancer (OC) to therapies targeting slower proliferating OC cells, which often lie dormant in patients and lead to disease recurrence. We have found slower proliferating OC cells exhibited a statistically significant higher sensitivity to the chemotherapy treatment ibrutinib compared to faster-proliferating cells in high-grade serous ovarian carcinomas (HGSOCs) in vitro. Cisplatin-resistant HGSOC cell lines displayed increased chemosensitivity to ibrutinib compared with the cisplatin-sensitive HGSOC cell lines. In clear cell ovarian carcinomas (CCOCs), we did not see dose-dependent chemosensitivity to duvelisib or ibrutinib, but there was an increased sensitivity when compared to the fast-proliferating HGSOC control. CCOC cell lines JHOC5 and TOV21-G showed increased responses to higher doses of UCN-01, but OVISE, the slowest proliferating CCOC did not. When looking at OC cell proliferation in conditioned medium from aged versus young WI-38 fibroblasts, OC cells were less proliferative in aged WI-38 medium when compared with the OC cells in young WI-38 medium in both HEYA8 and CAOV2 cell lines. Furthermore, we found that older WI-38 fibroblast coculture increased chemosensitivity for M41 HGSOC cells treated with duvelisib but not carboplatin. Future directions will be focused on the mechanisms of chemosensitivity in varying tumor microenvironments.