Abstract 915: Thrombomodulin expression regulates the tumor stroma differentiation of mesenchymal stem cells for controlling tumor growth

Abstract

Abstract Introduction: Thrombomodulin (TM), a thrombin receptor on endothelial cell surface, acts as an anti-coagulant factor in thrombin-catalyzed protein C activation and inhibits the pro-coagulant functions of thrombin. Owing to TM’s widely expression patterns on various cell types, our studies have demonstrated that beside anti-coagulation, TM also participates in controlling cell-cell adhesion, tumor growth, inflammation, angiogenesis, and atherosclerosis. However, the significance of TM expression in mesenchymal stem cells (MSCs) has never been investigated. The non-hematopoietic MSCs could specifically home into the developing tumors and becomes the active components of tumor stroma, which affects tumor’s growth, immunity, progression, and therapeutic resistance. Recently, we investigated the role of TM on the tumor microenvironment differentiation of MSCs for establishing the active stroma that assists tumor growth. Materials & methods: Normal and TM gene-targeting transgenic mice-isolated bone marrow-derived MSCs were used as the research models to investigate the expressing significance of TM on MSC’s biological activities and differentiations during mouse melanoma B16F10 cell’s conditioning in vitro and in vivo. Results: Our data showed that MSC's TM expression was low in the quiescent state but was up-regulated while treating with B16F10 cell’s conditioned medium in the mechanism of plate-derived growth factor signaling dependence. Accordingly, using conditional gene knockout strategy, under the condition of tumor cell other than normal culture resulted in that TM gene knockout significantly affected MSC’s proliferation, migration, interleukin-6 secretion, angiogenic activity, and tumor-associated fibroblast differentiation in vitro. Furthermore, TM knockout notably reduced the capacity of MSCs on regulating the growth, vasculogenesis, and active stroma establishment of B16F10 melanoma xenograft in vivo. Conclusion: These results indicate that the secretion of tumor-associated plate-derived growth factor is a critical event for MSC’s TM expression that controls MSC’s stroma differentiation for developing active tumor microenvironment, which promotes tumor progression. This study further suggests that the modulation of TM expression on MSCs has the therapeutic potential via diminishing the establishment of functional tumor stroma that sensitizes tumor for the therapies. Citation Format: Tsung-Hsien Shih, Jhy-Ming Li, Guey-Yueh Shi, Hua-Lin Wu. Thrombomodulin expression regulates the tumor stroma differentiation of mesenchymal stem cells for controlling tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 915. doi:10.1158/1538-7445.AM2017-915