Abstract AP17: OVARIAN TUMOR STIMULATION CONVERTS NORMAL OVARY AND OMENTAL MESENCHYMAL STEM CELLS INTO TUMOR–PROMOTING CARCINOMA–ASSOCIATED MESENCHYMAL STEM CELLS

Abstract

Abstract BACKGROUND: Ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs) are multipotent cells which influence the creation of the ovarian tumor microenvironment. CA-MSCs strongly promote ovarian cancer growth, cancer stem cell-like cells and chemotherapy resistance. CA-MSCs lack tumor associated somatic mutations, however compared to normal MSCs, CA-MSCs have a unique expression profile which mediates their pro-tumorigenic properties. The origin of CA-MSCs is unknown. We hypothesized that CA-MSCs are derived from local tissue MSCs reprogrammed by the ovarian tumor to become pro-tumorigenic CA-MSCs. METHODS: We define a “CA-MSC-like expression profile” of 6 genes significantly and reproducibly differentially expressed between normal human MSCs (from bone marrow (BM), omentum (OM) or ovary (OV)) and patient-derived CA-MSCs. Three normal MSC populations were grown with human ovarian cancer cells and analyzed to determine if tumor stimulation can induce a CA-MSC-like expression profile. Tumor stimulated MSCs were functionally analyzed to determine if acquisition of a CA-MSC-like expression profile correlates with development of pro-tumorigenic functions. Methylation array analysis of normal MSCs versus CA-MSCs was performed to explore the role of epigenetic regulation in the formation a CA-MSC. RESULTS: Tumor stimulation of normal OV and OM MSCs but not BM MSCs yield expression changes which approximate the CA-MSC-like expression profile. In vivo tumor stimulation of normal OM MSCs most effectively induces a CA-MSC-like expression profile. The development of a CA-MSC-like expression profile correlates with gain of pro-tumorigenic functions including induction of cancer cell chemotherapy resistance, enrichment of the ovarian cancer stem cell-like pool and enhancement of tumor growth. In contrast, tumor stimulated BM MSCs--which do not develop a CA-MSC-like expression profile--fail to gain pro-tumorigenic functions. Further, methylation array analysis demonstrates significant global differences in methylation patterns of CA-MSCs versus normal MSCs, indicating that epigenetic alterations may drive the development of the CA-MSC phenotype. CONCLUSIONS: Collectively we demonstrate that normal OV and OM MSCs are capable of becoming CA-MSCs through in vivo tumor stimulation with development of a distinct CA-MSC-like expression profile with corresponding pro-tumorigenic functions. These findings highlight the critical influence of the tumor on the normal host environment, manipulating normal cells to become cancer-supporting cells. The differential capacity of OV and OM MSCs but not BM MSCs to become CA-MSCs also highlights the heterogeneity of MSCs and may factor into the intraperitoneal tropism of ovarian cancer spread. Ultimately, understanding how tumor stimulation drives the development of CA-MSCs may identify powerful targets to disrupt the formation and function of the ovarian tumor microenvironment. Citation Format: Coffman, LG and Buckanovich, RJ. OVARIAN TUMOR STIMULATION CONVERTS NORMAL OVARY AND OMENTAL MESENCHYMAL STEM CELLS INTO TUMOR–PROMOTING CARCINOMA–ASSOCIATED MESENCHYMAL STEM CELLS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP17.