Role and Therapeutic Potential of Thrombomodulin in Mscs-Mediated Active Stromal Microenvironment Establishment during Tumor Growth

Mesenchymal stem cells (MSCs) can specifically home into the developing tumor and become the active components of tumor stroma, which affect tumor’s growth, immunity, and progressions; however, the mechanism regarding how the molecule guide and modulate the microenvironment interaction and differentiation of MSCs for developing active stroma during tumor growth is rarely understood. Currently, our studies have demonstrated that thrombomodulin (TM) is a novel adhesion molecule, which interacts with Lewis Y carbohydrate for controlling cell-cell adhesion during angiogenesis and atherosclerosis. Our preliminary results found that MSC's TM expression was low in quiescent state but was significantly up-regulated while treating with tumor conditioned medium in the mechanism of platelet-derived growth factor signaling dependence. However, the significance of TM expression in MSCs has never been investigated. Due to the lethality of TM gene knockout during embryo development, loxP flanked TM gene targeting mouse-isolated MSCs and melanoma models will be utilized for revealing the role of TM in MSCs-mediated functions during tumor growth. Preliminary results showed that under tumor cell’s conditioning, TM gene knockout significantly affected MSC’s proliferation, migration, interleukin-6 secretion, and tumor-associated fibroblast differentiation in vitro. Furthermore, TM knockout notably diminished MSCs-mediated tumor growth and vasculogenesis, and MSC’s stromal trafficking in B16F10 melanoma xenograft in vivo. Moreover, TM knockout reduced the endothelial adhesion of MSCs, and recombinant TM lectin-like domain protein (rTMD1) notably blocked the chemotactic migration of MSCs. These results indicate that TM expression in MSCs is a critical event for MSC’s homing and differentiation, which promotes tumor progression, and rTMD1 might have the therapeutic potential via inhibiting MSC recruitment for diminishing the establishment of functional tumor stroma that might sensitize melanoma for current therapies. However, the functional significance that TM acts in MSCs, which regulates MSCs-tumor microenvironment interaction has never been studied. This subsequent project, three specific aims are proposed as follows: (1) to explore the molecular mechanism of TM expression on regulating the tumor microenvironment tropism of MSCs in vitro and in vivo, (2) to search the function of TM expression in MSCs-mediated active stromal microenvironment establishment during tumor growth, (3) to investigate the therapeutic potential of rTMD1 with the conventional chemo- or radio-therapies via targeting the functional tumor stroma for treating melanoma. In conclusion, we believe these aims will bring the new perspective on TM’s application via targeting tumor microenvironment that can help tumor’s medication.

Project ID:PC10608-2362
External Project ID:MOST106-2320-B182-034