Investigating the Molecular Mechanism and Therapeutic Potential of Thrombomodulin in Regulating the Tumoral Stroma Tropism of Mesenchymal Stem Cells

Thrombomodulin (TM) is originally identified as an anti-coagulant and has been evidenced to play an important role in regulating tumor progressions. Currently, our studies further demonstrated that TM is a novel adhesion molecule, which modulates the adhesion of endothelial cells and monocytes via interacting with Lewis Y carbohydrate for controlling angiogenesis and atherosclerosis. The non-hematopoietic mesenchymal stem cells (MSCs) can specifically home into the developing tumors and become the active components of tumor stroma, which affect tumor’s growth, progressions, and therapeutic resistances; however, the mechanism regarding how the adhesion molecules guide the microenvironment interaction of MSCs into the tumor stroma is rarely understood, and the significance of TM expression in MSCs has never been investigated. Our unpublished study found that TM's expression was significantly up-regulated in MSCs while treating with tumor conditioned medium. Furthermore, TM knockout strategy was utilized for revealing the function of MSC's TM in regulating tumor progressions. The results showed that MSCs with TM knockout dramatically affected MSC’s in vitro cellular activities and diminished the recruitment of MSCs in B16F10 melanoma stroma and MSCs-promoted B16F10 melanoma growth in vivo, suggesting that TM expression may conduct the tumor tropism of MSCs for enhancing tumor growth. Therefore, this study will focus on the molecular mechanism and therapeutic potential-regarding how TM expression regulates the micro-environmental interaction of MSCs for tumoral stroma mobilization, and whether blocking TM-mediated MSC's tumor tropism endowed with the ability to inhibit the development of active tumor stroma for sensitizing melanoma to the therapies. In conclusion, we believe these aims may bring the new perspective on TM’s application for targeting MSC’s mobilization that can help tumor’s medication. This project, three specific aims are proposed as follows, including to investigate (1) the molecular mechanism of TM expression on governing the tumoral micro-environmental interaction of MSCs and endothelium-lined in tumor stroma in vitro, (2) the potential role of TM and specific domain of TM on regulating MSC’s tumor stroma tropism in vivo, and (3) the therapeutic effect of recombinant TM domain proteins via interfering with the tumoral tropism of MSCs for diminishing the development of active tumor stroma, which accelerates the conventional therapies in treating melanoma.

Project ID:PC10408-1729
External Project ID:MOST104-2320-B182-038