Abstract 3777: Low physiological fluid shear exposure induces metastatic potential of chondrosarcoma cells via MMP-12 activation.

Abstract

Abstract Interstitial flow in and around tumor tissue affects the mechanical microenvironment to modulate tumor cell metastasis. We investigated the roles of flow-induced shear stress in modulating chondrosarcoma cell metastatic potential such as cell invasiveness and motility, and the underlying mechanisms. Using human chondrosarcoma cell lines as a model system, we demonstrated that low fluid shear (2 dyn/cm2), but not high fluid shear (20 dyn/cm2), exposure for 48 h remarkably induced MMP-12 mRNA by ∼35-fold and significantly triggered it proteolytic activity among all MMP members. The molecular basis of the shear effect was further analyzed, and our data revealed that low fluid shear stress induces the rapid synthesis of VEGF-B, VEGF-D and IGF-2, which in turn transactivates MMP-12 expression via PI3K and p38 MAPK-dependent pathways. Furthermore, highly induced MMP-12 markedly enhanced chondrosarcoma cell invasion and motility by using chemtaxis transwell chambers in conjunction with time-lapse micro-channel assays. Collectively, our data suggest that the induction of IGF-2, VEGF-B, and VEGF-D under low fluid shear, which in turn upregulates MMP-12 via PI3K and p38 MAPK signaling pathways, leading to the enhanced invasive and migratory capabilities of chondrosarcoma cells. Our findings provide insights into the mechanism by which shear stress induces chondrosarcoma metastatic potential and demonstrate the importance of mechanical environments in modulating molecular signaling, gene expression and functions in tumor cells. Citation Format: Shih-Hsun Chen, Pu Wang, Wei-Chien Hung, Konstantinos Konstantopoulos. Low physiological fluid shear exposure induces metastatic potential of chondrosarcoma cells via MMP-12 activation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3777. doi:10.1158/1538-7445.AM2013-3777