Abstract A49: Adipocytes promote ovarian cancer cell chemoresistance

Ovarian cancer is the most lethal cancer of the female reproductive system and the fifth leading cause of cancer death among women. One of the reasons for the high death rate among women with ovarian cancer is the resistance to chemotherapy. The majority of the ovarian cancer patients who show an initial response to chemotherapy will succumb to resistance and cancer recurrence. Previous studies have demonstrated that abdominal omental adipocytes promote local ovarian cancer metastasis by attracting cancer cells and acting as an energy source for their growth. However, it is not known whether adipocytes have any effects on the sensitivity of ovarian cancer cells to chemotherapeutic drugs. To address this question, we treated human ovarian cancer cells with the conditioned media of either human abdominal subcutaneous adipocytes or visceral adipocytes and examined the viability of the cells in the presence of cisplatin, paclitaxel and doxorubicin. We found that the viability of OVCAR-5 cells was significantly increased when treated with conditioned media from subcutaneous adipocytes. Similar results of preliminary studies were obtained with other human ovarian cancer cells (e.g. OVCAR-8 and SKOV-3) and with conditioned media from visceral adipocytes. Increased chemoresistance was also observed in ovarian cancer cells co-cultured with adipocytes in a transwell system. These data suggest that soluble factors secreted from adipocytes, i.e. adipokines, are protective against chemotherapeutic drugs. We then examined the downstream pathways activated in ovarian cancer cells by adipocyte-conditioned media and found that phosphorylated Akt and Stat3 levels were significantly increased in the presence of the adipocyte-conditioned media whereas phosphorylated Erk and p38 levels were not changed. Given that IL-6 is secreted by adipocytes and can activate both Akt and Stat3, we blocked IL-6 in adipocyte-conditioned media with a neutralizing antibody and found that Stat3 activity was inhibited in ovarian cancer cells treated with adipocyte-conditioned media deficient of IL-6 but Akt activity was not affected. However, IL-6 neutralizing antibody did not affect the protective effects of adipocyte-conditioned media on ovarian cancer cells, suggesting that IL-6 and its downstream Stat3 pathway were not involved. Interestingly, the protective effects of adipocytes against cisplatin were abolished when Akt activation was inhibited in ovarian cancer cells by LY294002 treatment, indicating the critical function of Akt pathway in adipocyte-induced chemoresistance. The identity of the adipokine(s) that activates Akt in ovarian cancer cells and confers chemoresistance is currently under investigation. Taken together, these findings demonstrate that abdominal adipocytes enhance the survival of ovarian cancer cells against chemotherapeutic drugs by secreting soluble factor(s) that activates the Akt pathway and identify abdominal adipocytes and associated adipokines as important mediators of ovarian cancer chemoresistance. (This work is supported by the Weitzman Family Fund.) Citation Format: Jiang Yang, Marsha A. Moses. Adipocytes promote ovarian cancer cell chemoresistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A49.