Abstract
Abstract High-grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy. Although most patients respond to chemotherapy, relapse often occurs as chemoresistance disease. We previously reported the tumor-promoting role of Microfibrillar-Associated Protein 5 (MFAP5) in ovarian cancer. Follow up studies suggested a pro-angiogenic and chemo-protective role of MFAP5. Based on these findings, the present study aims at delineating the mechanism by which stromal MFAP5 modulates tumor angiogenesis and chemoresistance, and evaluating the potential of targeting MFAP5 as therapy for ovarian cancer. Immunostaining of HGSOC tissue sections revealed a significant correlation between stromal MFAP5 expression and intratumoral microvessel density. Further endothelial cell motility and tube formation assays on human endothelial cells demonstrated the pro-angiogenic roles of exogenous MFAP5. Furthermore, anti-αVβ3 integrin antibody and cell permeant calcium chelator, BAPTA, attenuated MFAP5's effects, suggesting that MFAP5 exerts its biological activity on endothelial cells through the αVβ3 integrin receptor and calcium signaling. In vivo studies showed that extensive tubular network was formed in the matrigel mixed with MFAP5 injected into mice (p<0.01). Co-injection of MFAP5 overexpressing fibroblasts and cancer cells subcutaneously into mice led to increased tumor size and number of CD34 positive intratumor microvessels. Microarray analysis on endothelial cells invaded into Matrigel plug identified a set of motility promoting genes that were associated with calcium signaling. Among them, upregulation of Lipoma-Peferred Partner (LPP), an actin cytoskeleton protein, was validated by qRT-PCR and western blot analyses. Silencing LPP by siRNA abolished MFAP5 stimulated motility in both HMEC-1 and TIME. Further western blot analyses showed that MFAP5 modulated endothelial cell motility and invasion potential through calcium dependent ERK/CREB/LPP signaling pathways. In an orthotopic mouse model, silencing of stromal MFAP5 by siRNA delivered by nanoparticles demonstrated a significant reduction in tumor weight (p<0.001) and intratumor microvessel densities. In addition, analysis on stromal gene expression profiles revealed that stromal MFAP5 expression is significantly increased in the group of patients with shorter progression-free survival when compared to those with longer progression-free survival. Further cell survival assays showed that pretreating to HGSOC cell lines with recombinant MFAP5 confers resistance to ovarian cancer cells towards paclitaxel treatment. RNA-Seq analysis was performed to delineate the underlying mechanism of such induced chemoresistance. To conclude, stromal MFAP5 contributes to ovarian tumor angiogenesis and chemoresistance. Hence, targeting stromal MFAP5 could be a potential therapy for ovarian cancer treatment. Citation Format: Cecilia S. Leung, Tsz-Lun Yeung, Kay-Pong Yip, Kwong-Kwok Wong, Anil K. Sood, Michael J. Birrer, Samuel C. Mok. CAF-derived MFAP5 promotes tumor angiogenesis and confers paclitaxel resistance in high-grade serous ovarian cancer. [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 4184. doi:10.1158/1538-7445.AM2015-4184
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