Date of Graduation
12-2013
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Honami Naora
Committee Member
Elsa R. Flores
Committee Member
Hui-Kuan Lin
Committee Member
Ju-Seog Lee
Committee Member
Mong-Hong Lee
Abstract
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among women in the United States. The high lethality of EOCs stems from rapid peritoneal involvement. EOCs frequently colonize peritoneal surfaces that overlie connective and adipose tissues. However, the mechanisms that enable ovarian cancer cells to readily adapt to the peritoneal environment are poorly understood. HOXA9, a homeobox gene that is normally expressed in the developing female reproductive tract, is aberrantly expressed in EOCs and controls the morphologic features of these tumors. The differentiation pattern of a tumor is an important determinant of its clinical behavior and prognosis. The overall goal of this project is to determine the clinical significance of HOXA9 and its mechanisms in the biological behavior of EOC. In this study, I demonstrated that expression of HOXA9 is strongly associated with poor outcomes in EOC patients and in mouse xenograft models of EOC. Whereas HOXA9 promoted EOC growth in vivo, HOXA9 did not stimulate autonomous tumor cell growth in vitro. On the other hand, HOXA9 was found to be associated with increased abundance of cancer-associated fibroblasts (CAFs) in mouse xenograft models of EOCs and with a CAF-like gene signature in human tumors. However, HOXA9 did not induce CAF-like features in EOC cells. Expression of HOXA9 in EOC cells induced normal adipose and bone marrow-derived mesenchymal stem cells (MSCs) as well as normal peritoneal fibroblasts to express markers of CAFs and to stimulate growth of EOC and endothelial cells. These effects of HOXA9 were due in substantial part to its transcriptional activation of TGF-beta2 that acted in a paracrine manner on peritoneal fibroblasts and MSCs to induce CXCL12, IL-6 and VEGF-A expression. These results demonstrate that HOXA9 promotes progression of EOC by ‘educating’ the stroma to become permissive for tumor growth.
Keywords
epithelial ovarian cancer, HOXA9, cancer-associated fibroblast