Abstract
Abstract Ovarian cancer is the most lethal gynecologic malignancy in the US. While major research efforts have been dedicated to identify disease related genes and mutations in cancer cells, the role of the stromal tumor microenvironment in disease progression is relatively unexplored. We previously reported that while ovarian cancer cells have minimal response to TGF-beta, TGF-beta induced secretory proteins from cancer associated fibroblasts (CAFs) promote ovarian cancer motility and invasion potential. The present study seeks to further evaluate the involvement of TGF-beta signaling in CAFs in the progression of ovarian cancer and the therapeutic potential of targeting such signaling in cancer treatment. By comparing the gene expression profiles of laser-microdissected ovarian tumor stromal tissues from high-grade serous ovarian cancer (HGSOC) patients with short and long survival, a differentially expressed gene signature was identified. Using the IPA platform, signaling pathways and upstream regulators activated in CAFs from patients with short survival were identified. TGF-beta signaling was found to be significantly activated (p = 2.47E-03), while the ligand TGF-beta 1 was identified as the most significant upstream regulator (Z-score = 5.189, p = 8.85E-29), suggested the involvement of CAF TGF-beta signaling in poor patient survival. Further immunohistochemistry and survival analyses revealed the clinical relevance of multiple TGF-beta regulated stromal genes, including VCAN, MFAP5 and COMP in poor disease prognosis. Subsequently, cell culture studies were performed to evaluate the effects of TGF-beta in ovarian cancer progression. While exogenous TGF-beta did not affect proliferation, motility and invasion potential of ovarian cancer cells directly, TGF-beta promoted ovarian cancer cells motility and invasion potential in a co-culture system of cancer cells and CAFs. Similarly, treatment of exogenous TGF-beta-induced CAF secretory proteins promoted ovarian cancer progression, suggested the presence of CAFs is required for TGF-beta mediated ovarian cancer progression and targeting such TGF-beta signaling in CAFs could be a novel modality of ovarian cancer treatment. To reprogram CAFs by targeting its TGF-beta signaling, multiple approaches were tested in co-culture systems. Using either siRNAs or small molecule inhibitors, TGF-beta signaling in CAFs was effectively suppressed and inhibited ovarian cancer progression was observed. Based on our current findings, animal studies will be performed to further evaluate the efficacy of targeting the CAF TGF-beta signaling pathway in ovarian cancer treatment. This study presents the paradigm which activation of TGF-beta signaling in ovarian CAFs is significantly associated to the poor clinical outcomes. Targeting such pathway activation in CAFs could effectively suppress tumor progression and thereby presented a novel approach in cancer treatment. Citation Format: Tsz-Lun Yeung, Cecilia S. Leung, Kwong-Kwok Wong, Samuel C. Mok. Reprogramming the TGF-beta signaling in cancer-associated fibroblasts inhibits ovarian cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5066. doi:10.1158/1538-7445.AM2015-5066
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