Abstract 4799: Identification and characterization of stromal factors with clinical significance in the ovarian tumor microenvironment

Abstract

Abstract Ovarian cancer is the most lethal gynecologic malignancy in the United States. While the tumor microenvironment has been shown to play important roles in cancer pathogenesis, large-scale transcriptome profiles of the stromal component of ovarian tumors and the identification of stromal prognostic markers and therapeutic targets are lacking. This study seeks to identify secreted stromal factors and evaluate their clinical significance. Transcriptome profiling and clustering analysis on microdissected ovarian cancer associated fibroblasts (CAFs) samples from 83 patients revealed a heterogeneous gene expression pattern. Since CAFs can be derived from mesenchymal stem cells (MSCs), we compared transcriptome profiles of MSC samples obtained from healthy individuals with those from CAFs. Results showed that CAF expression profiles could be classified into two major subtypes. The MSC subtype, which has gene expression pattern highly resembling to that of undifferentiated MSCs, is significantly associated with poorer patient survival when compared to the non-MSC subtype. Further analyses identified two expression clusters within the MSC subtype: 1) the CAF-C cluster which expressed high level of MSC chondrogenic differentiation associated genes including CSPG2, SFRP2 and COMP, and 2) the CAF-O cluster which expressed high level of osteogenic differentiation associated genes including RUNX2 and BGN. Survival analysis showed that patients with the CAF-O expression subtype had overall survival rates comparable to those with the non-MSC subtypes, while the CAF-C subtype is associated with worst clinical outcomes. Pathway analyses revealed strong interactions among these stromal genes. Among them, SFRP2, which has been shown to inhibit osteogenic differentiation of MSCs by inhibiting Wnt signaling and subsequently suppress RUNX2 expression, was selected for further validation studies. Stromal SFRP2 and RUNX2 protein expression levels were evaluated by immunohistochemistry on paraffin tissue sections from 94 patients. Results showed that high levels of stromal SFRP2 were significantly associated with poor patient survival (p < 0.001), while high levels of stromal RUNX2 were significantly associated with improved patient survival (p < 0.001). A significant inverse correlation between SFRP2 and RUNX2 expression levels was also observed (r = -0.279, p = 0.037), suggested that the interactions among these genes may generate different landscapes in the tumor microenvironment, which modulate MSC differentiation and subsequently cancer cell aggressiveness. This study presents a new paradigm of which osteogenic-like and chondrogenic-like CAF signatures are associated with better and poorer patient survival respectively. Understanding the relationship between the expression patterns of stromal factors and MSC differentiation would provide us with new insights into ovarian cancer pathogenesis. Citation Format: Tsz-Lun Yeung, Cecilia S. Leung, Kwong-Kwok Wong, Samuel C. Mok. Identification and characterization of stromal factors with clinical significance in the ovarian tumor microenvironment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4799. doi:10.1158/1538-7445.AM2014-4799