Abstract B61: Leptin induces a pro-inflammatory macrophage-cancer cell reinforcement loop that favors high-grade serous ovarian cancer progression among overweight/obese women.
Authors: Mauricio A. Cuello, Lorena Abarzua-Catalan, Sumie Kato, Isidora Solar, Claudia Arancibia
Journal: Clinical Cancer Research (2016)

Abstract Introduction: High-grade serous ovarian cancer remains as the most lethal gynecologic cancer. Despite achieving optimal debunking using ultra-radical surgery followed by platinum-based chemotherapy, in the long term, most of the patient will die from their disease, mainly due to extensive carcinomatosis, bowel obstruction and cachexia. Recently our group has provided biological evidence supporting the role of obesity in impairing ovarian cancer prognosis. Obesity is considered as a chronic low-grade inflammation state where leptin can play a major role in modulating cancer behavior. In the present work we explore the effects of leptin levels found in ascites, comparing lean and obese population, in cytokine profile released from macrophages and cancer cells and its impact in macrophage behavior and invasiveness of ovarian cancer cells. Methods: Ascites from patients undergoing primary cytoreductive surgery for advanced stage high-grade serous ovarian cancer were collected to establish primary tissue cultures and measuring leptin levels by ELISA kit. A database was built up for clinical variables, and patients were stratified by body mass index (BMI) using the WHO classification. Three ovarian cancer cells (e.g. HEY, UCI 101 and SKOV3) were used to establish in vitro spheroids and assessing the effects of leptin alone or conditioned media (CM) collected from leptin-treated macrophages in migration/invasion of cancer cells in matrigel Boyden chamber assays. IL-6, IL-10 and IL-12 release were measured in both cancer cells and macrophages upon leptin treatment, at similar concentrations than those found in ascites collected from lean, overweight and obese patients. Monocyte THP-1 cells were PMA-transformed into macrophages and the IL-10/IL-12 release ratio was used to identify M1 or M2 polarization induced either by leptin alone or CM collected from leptin-treated cancer cells. Results: Ascites collected from obese patients express significantly higher leptin levels compared with ascites from lean patients (13 ±4 ng/ml vs. 4±2 ng/ml; p&amp;lt;0,05). In addition, supplementation with ascites containing higher leptin levels significantly speeds up spheroid formation and increases the spheroid number. Moreover, ascites from obese patients also fosters formation of denser spheroids compared with ascites from lean patients. Adding leptin to the media at concentrations found in obese patients results in significantly increase in cytokine release from both ovarian cancer cells and macrophages. In terms of ovarian cancer cells, leptin fosters the faster formation of spheroids and increase the spheroid number. These cancer cells tend also to migrate and invade more than those not supplemented. In relation to macrophages, leptin induce an increase in the IL-10/IL-12 release ratio, reflecting preferred polarization to a M2 phenotype. Adding CM from macrophages, treated with leptin, induces epithelial mesenchymal transition (EMT) and significantly increases migration and invasion of ovarian cancer cells in matrigel Boyden chamber assays. Conclusions: Our findings support a role of leptin as one of the factors driving the detrimental effect of obesity in high-grade serous ovarian cancer. Leptin induces a pro-inflammatory reinforcement loop between cancer cell and macrophage that favors ovarian cancer progression by turning the macrophage tumor-suppressive phenotype into a pro-tumorigenic one and prompting an inflammatory microenvironment. (Research funded by Fondecyt 1120292). Citation Format: Mauricio A. Cuello, Lorena Abarzua-Catalan, Sumie Kato, Isidora Solar, Claudia Arancibia. Leptin induces a pro-inflammatory macrophage-cancer cell reinforcement loop that favors high-grade serous ovarian cancer progression among overweight/obese women. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B61.