Abstract C234: Decreasing ovarian tumor stromal signaling via SFRP2 mitigates ovarian cancer progression.

Abstract

Abstract The tumor microenvironment has been definitively shown to be a key player in tumor progression and metastasis in a variety of cancers, including ovarian cancer and provides a plethora of potentially significant therapeutic targets. As ovarian cancer is the deadliest gynecological disease due to a lack of reliable diagnostic testing and efficacious treatments, our objective was to determine how the ovarian cancer-associated fibroblasts (CAFs) are contributing to the propagation of ovarian cancer. Our lab has identified a distinct gene signature for the ovarian stromal component of high-grade late-stage (HGLS) serous ovarian cancer as compared to normal stroma, human ovarian surface epithelium, and ovarian tumor, and many of these genes are secreted proteins suggesting a paracrine role for the tumor microenvironment. Secreted frizzled related protein 2 (SFRP2), a protein integral to stemness and proliferation, is overexpressed in ovarian CAFs by over 10-fold. Quantitative RT-PCR and immunohistochemical staining validated the overexpression of SFRP2 in ovarian CAFs and also showed a clinical correlation for stromal SFRP2 overexpression with poorer overall survival and chemoresistance in patients with HGLS serous ovarian cancer. Furthermore, increased SFRP2 expression correlated with significantly higher microvessel density suggesting an angiogenic effect. In vitro functional studies illustrated increased ovarian cancer cell proliferation in response to recombinant SFRP2 that was dose and time dependent. Ovarian cancer cells overexpressing SFRP2 (autocrine signaling) also illustrated increased cell proliferation. Additionally, ovarian cancer cell co-cultured with ovarian CAFs induced increased SFRP2 expression in the CAFs. Using an allogenic mouse model, we determined that silencing stromal SFRP2 using a SFRP2 knockout mouse significantly decreased ovarian cancer cell growth, suggesting that eliminating tumor stromal signaling cues may mitigate ovarian cancer progression. Together, these results illustrate a direct and specific signaling linkage between ovarian tumor cells and their associated microenvironment, specifically CAFs, suggesting that elimination of this signaling linkage may slow ovarian cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C234.