Abstract
Abstract
Ovarian cancer is the most lethal gynecologic malignancy and the 5th leading cause of cancer related deaths among women in the USA. Most patients eventually succumb to chemoresistant disease and the purpose of this study is to understand the mechanism of development of chemoresistance and disease relapse. Cancer stem cells (CSCs) consist of a small subpopulation in the tumor that are resistant to cytotoxic chemotherapy and cause relapse. The tumor microenvironment can potentially provide an optimal cancer stem cell niche for cancer stem cell growth and maintenance. Cancer associated fibroblasts (CAFs) are one of the main constituents of the tumor microenvironment in ovarian tumors, promoting tumor progression and chemoresistance. We have studied the potential role of CAFs in maintaining CSC population and enhancing chemoresistance with an objective to develop effective approaches to overcome chemoresistance and tumor relapse. Co-culture of high grade serous ovarian cancer cells with CAFs resulted in increased resistance to carboplatin. ALDH1A1 is a well-established marker for ovarian cancer CSCs and the ALDH+ population was significantly increased upon co-culture with CAFs. Similarly, CAFs also enhanced spheroid formation of ovarian cancer cells seeded in ultralow adhesion plates in CSC medium. Interestingly, co-culturing ALDH- ovarian cancer cells with CAFs resulted in the induction of ALDH+ cells within 6 days. Analysis of the signaling pathways activated in ovarian cancer CSCs and the gene expression profiles of ovarian cancer CAFs indicated the potential role of Wnt signaling in the productive cross-talk between CAFs and ovarian cancer CSCs. Treatment with Wnt inhibitors abrogated the induction of CSCs by CAFs. By selectively silencing porcupine, a protein involved in Wnt ligand lipidation and secretion, we further confirmed that CAF derived Wnts are responsible for the induction of CSC. Studies are ongoing to identify the specific Wnt ligand involved in the cross-talk and downstream pathways activated during CSC induction and maintenance by CAFs. Our results indicate that CAF-derived Wnt ligands are instrumental in ovarian cancer CSC growth and maintenance. In the long term, our studies will broaden the understanding of CSC maintenance by the tumor microenvironment and contribute towards the development of novel therapeutic approaches to prevent ovarian cancer chemoresistance and relapse.
Citation Format: Yiming Fang, Mohamed A. Abd El Aziz, Kartikeya Tiwari, Anirban K. Mitra. Cancer associated fibroblasts promote ovarian cancer chemoresistance by inducing cancer stem cells through Wnt signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4685.