Abstract 5088: Fibroblast-derived factors enhance growth of ovarian cancer cells

Abstract

Abstract Background: Ovarian cancer is one of major cancers that affect female reproductive organs. Rapid progression of ovarian cancer without symptoms makes this disease difficult to clinically manage and mortal. Tumor microenvironment significantly contributes to tumor malignancy and targeting the tumor microenvironment is being explored as important cancer therapy. MAPK signal transduction pathways mediates cell response to paracrine factors derived from microenvironment. It is important to identify pathways that are specifically activated in response to microenvironment-derived signals and their relevance to pathogenesis of cancer in order to effectively target signaling derived from tumor microenvironment. We studied the effect of fibroblast-derived media on the growth of ovarian cancer cells and the role of three families of MAPK and AKT in fibroblast-induced increase in cancer cell growth. We also evaluated roles of IL-6, IL-8, MCP1, and CXCL1, highly secreted by fibroblasts, in mediating growth increase induced by fibroblasts. Methods: Ovarian cancer cells were cultured in media derived from human ovarian fibroblast (CM1 and CM2), serum free media (SF), and 4% FBS media (REF) and their growth rate and MAPK activation induced by different media were compared. In order to identify, MAPK family that is important in the enhancement of cancer cell growth, cell growth rate was compared in different media in the absence and presence of specific inhibitor. IL-6, IL-8, MCP1, and CXCL1 were treated and their effects on cell growth and MAPK activation were assessed. Results: CM1 and CM2 significantly enhanced cell growth compared to SF at 72 hr in ovarian cancer cells. In OVCAR3 and OVCAR4 cells, phosphorylation of both p38 and ERK were highly induced by both CM1 and CM2 compared to REF and SF. Phosphorylation of JNK and AKT was highly induced by CM1 and CM2 in OVCAR4 cells while that was less apparent in OVCAR3 cells. In contrast, phosphorylation of proteins in MAPK families and AKT was not specifically induced by CMs in SKOV3 cells. In OVCAR3 and OVCAR4 cells, pretreatment with a p38 inhibitor, selectively prevented the cell growth induced by CMs. Treatment of IL-6, IL-8, and MCP1 up to 1 ng/mL did not increase growth of any cancer cells. However, CXCL1 at 1 ng/mL significantly increased cell growth in OVCAR3 and OVCAR4 but not in SKOV3 cells. Treatment of CXCL1 also enhanced phosphorylation of p38, JNK in OVCAR3 and OVCAR4 cells whereas these effects of CXCL1 were not observed in SKOV3 cells. Furthermore, treatment of SB225002 (CXCR2 inhibitor) effectively prevented p38 activation and growth enhancement induced by CM1 and CM2 in OVCAR3 and OVCAR4 cells. Conclusion: Our study demonstrates that the growth of ovarian cancer cells is enhanced by factors derived from ovarian fibroblasts partly by activation of p38. CXCL1 is one of factors that is derived from fibroblast and increases growth of cancer cells. Citation Format: Youngjoo Kwon, Geun Yeong Park. Fibroblast-derived factors enhance growth of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5088.