Role of the pro-inflammatory omental microenvironment in ovarian cancer progression

PROJECT SUMMARY/ABSTRACT High-grade serous ovarian cancer (HGSC) metastasizes preferentially to the omentum, which is a well- vascularized fold of peritoneal tissue covered by mesothelial cells and a major site of intra-abdominal fat accumulation. It was reported that HGSC and stromal cell-derived pro-inflammatory cytokines downregulate omentin (ITLN1), a novel mesothelial cell-derived adipokine to promote the invasive potential and proliferation of cancer cells in the omental microenvironment. Omentin has been shown to suppress ovarian cancer invasive potential and cell growth through suppressing MMP1 expression and cell traction force in cancer cells, and inducing a local rapid metabolic coupling between ovarian cancer cells and neighboring adipocytes. Besides, higher levels of pre-operative serum omentin in patients with HGSC were associated with longer survival times. In addition, mice treated with omentin had marked increase in activated CD8+ T cell density compared to the untreated control. These findings suggested that adipocytes play an important role in mediating the suppressive effect of omentin on the malignant phenotype of ovarian cancer cells, and the immune microenvironment. Therefore, we focus on secretory proteins that can be upregulated by omentin in mature adipocytes. A recent proteomic study demonstrated that an anti-inflammatory protein tumor necrosis factor-inducible gene 6 protein (TSG-6) was the top gene upregulated by omentin in adipocytes. Previous studies demonstrated that TSG-6 inhibits infiltration of immune cells during inflammation. It can also bind to specific chemokines such as CXCL12 and prevent them to bind to glycosaminoglycan (GAG)-rich tumor stroma and endothelial cell surface, suggesting that TSG-6-mediated blockade of these cytokines to suppress tumor growth, angiogenesis, and regulatory T cell trafficking. Based on these findings, we hypothesize that omentin normalizes the pro-inflammatory omental microenvironment in ovarian cancer through upregulating anti-inflammatory TSG-6 in adipocytes, which binds to pro-inflammatory cytokines secreted by cancer cells and various stromal cell types, which attenuate the immunosuppressive tumor microenvironment, prevent omental metastasis, and suppress tumor progression, and subsequently improve patients’ survival rate. To test this hypothesis, first, we propose to determine the roles of omentin in normalizing the immunosuppressive microenvironment and preventing tumor development in ovarian cancer. Second, we propose to determine the mechanisms by which omentin reprograms the immune landscape in ovarian tumor tissues and suppresses the invasive potential of ovarian cancer cell. Third, we propose to determine the efficacy of omentin administration alone or in combination with paclitaxel in ovarian cancer treatment, and determine the pharmacokinetics/pharmacodynamics and toxicity of omentin using various mouse models. Our studies will enable us to delineate the immune modulator role of omentin in HGSC pathogenesis, and to further develop omentin as a chemopreventive and therapeutic agent in the treatment of HGSC to improve patients’ survival rates.