Abstract
Abstract Ovarian cancer is the most lethal gynecologic malignancy. Although anti-angiogenic therapies look promising, no major strides have been made to improve ovarian cancer patient survival over the past decade. Therefore, finding new molecular targets that can improve therapeutic benefit from anti-angiogenic strategies are of paramount importance. Microfibrillar-Associated Protein 5 (MFAP5) was previously reported to be associated with prognosis and promoted ovarian cancer progression. In ovarian tumor samples, we identified a positive correlation between stromal MFAP5 and CD31 expressions which suggested a pro-angiogenic role of MFAP5. This study aims at delineating the mechanism of stromal MFAP5 in modulating tumor angiogenesis and investigating the potential of targeting MFAP5 as an anti-angiogenic therapy for ovarian cancer treatment. Increased motility and tube formation were observed in the presence of exogenous MFAP5 in both human microvascular endothelial cell 1 (HMEC-1) and telomerase immortalized microvascular endothelial cells (TIME). Besides, both anti-αVβ3 integrin antibody and cell permeant calcium chelator, BAPTA, attenuated MFAP5 stimulated motility. These suggested that MFAP5 exerts its biological activity through the αVβ3 integrin receptor and calcium signal transduction. In vivo, extensive CD34 positive tubular network was formed in the matrigel mixed with recombinant MFAP5 injected subcutaneously into mice. Further analysis using the Leica Metamorph software confirmed that there were significantly increases in the number of nodes, total tube area, number of tube segment and branch points in MFAP5 containing matrigel compared to control (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. 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. Finally, 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. To conclude, stromal MFAP5 acts on αVβ3 integrin receptor and modulates endothelial cell behavior through calcium signaling. It contributes to ovarian tumor angiogenesis and tumor progression. Hence, targeting stromal MFAP5 could be a potential anti-angiogenic 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 ovarian tumor angiogenesis through calcium dependent LPP signaling pathway. [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 1029. doi:10.1158/1538-7445.AM2014-1029
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