Abstract 2395: Leptin induces an IL-6 mediated interaction between macrophages and ovarian cancer cells that prompted invasiveness and migration
Authors: Sumie Kato, Lorena Abarzua-Catalan, Isidora Solar-Costabal, Karen García, Jorge Branes, Gareth I. Owen, Mauricio A. Cuello
Journal: Cancer Research (2015)

Abstract Introduction: The current knowledge in ovarian epithelial carcinogenesis grants a major role for chronic inflammation in driving the multiple steps in the natural history of the most deadly gynecological cancer. Different environmental stimuli have been associated with an increased ovarian cancer risk. Growing evidence has become to support the potential role of obesity as one of the conditioning factors. Leptin, an adipokine, controlling metabolism and energy expenditure and normally circulating at higher serum levels among overweight women, has been syndicated as the pro-inflammatory mediator in obesity. So far, few are known about the role of and how leptin modulate cells to cells interactions among the different components of tumor microenvironment. Goal: In the present study we investigated the leptin effect in prompting a pro-inflammatory microenvironment, the communication between macrophages and ovarian cancer cells and the impact of this interaction in cancer cell migration and invasion. Methods: HEY ovarian cancer cell line and the THP-1 monocyte cell line were used. THP-1 cells were differentiated to macrophages by using PMA (Phorbol 12-myristate 13-acetate) 200 nM for 24h. Upon differentiation macrophages were exposed to a time course of leptin (100 ng/ml, 6h to 24h). Upon control or leptin exposure, conditioned medium was collected from macrophages (MCM), and used to measure IL-6 release to the medium and to treat HEY cell line for 24h. Secreted IL-6 was used as inflammation marker and measured by ELISA assay. Protein extracts were obtained from HEY cells upon control and MCM exposure and used to quantify epithelial mesenchymal transition (EMT) marker vimentin by Immunoblotting and Immunocytochemistry. The effects of leptin and MCM in HEY migration and invasion was assessed by Boyden chamber assay without or with matrigel, respectively. Results: Upon leptin treatment both HEY and macrophages significantly increased IL-6 release to the medium. More importantly, incubation of MCM with HEY cells resulted in a synergistic increase of IL-6 release, (from a basal release of 13,4±2 pg/mL to 2,3×104 pg/mL upon MCM exposure). Moreover, HEY cells exposure to MCM resulted in phenotypic changes that were associated to changes in vimentin expression (mainly upon exposure to 6h leptin incubated MCM). Finally, this exposure to leptin-incubated MCM significantly increased migration and invasion of HEY cells. Conclusions: Our findings support a role of leptin in prompting a pro-inflammatory microenvironment that involved an increase in IL-6 release from the macrophages. These changes induced by leptin in macrophages resulted in a cytokine secretion pattern, which consequentially modified cancer cells phenotype favoring migration and invasion and a more aggressive epithelial ovarian cancer behavior. (Funding: FONDECYT 1120292 and 3140335) Citation Format: Sumie Kato, Lorena Abarzua-Catalan, Isidora Solar-Costabal, Karen García, Jorge Branes, Gareth I. Owen, Mauricio A. Cuello. Leptin induces an IL-6 mediated interaction between macrophages and ovarian cancer cells that prompted invasiveness and migration. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2395. doi:10.1158/1538-7445.AM2015-2395