The Molecular and Therapeutic Significances of Thrombomodulin-Expressed in Mesenchymal Stem Cells for Regulating the Active Stroma Establishment of Tumor

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, immunity, progression, and therapeutic resistance; however, the mechanism regarding how the adhesion molecule guide and modulate the microenvironment interaction of MSCs for the development of active tumor stroma microenvironment 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. However, the significance of TM expression in MSCs has never been investigated. Accordingly, TM knockout strategy was utilized for revealing the role of TM in MSCs-mediated functions for tumor progression. The 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. TM knockout notably diminished the growth, vasculogenesis, and trafficking of MSCs 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 the therapies. However, the role that TM acts in MSCs for regulating MSCs-tumor microenvironment interaction, which assists tumor progression has never been studied. This project, four specific aims are proposed as follows: (1) to explore the signaling pathways involved in TM up-regulation and TM-associated signaling pathways in MSCs under tumor cell’s conditioning, (2) to search the function of TM expression in MSCs-mediated host anti-tumor immunity for affecting tumor progression, (3) to examine the molecular mechanism of TM expression for regulating MSC’s stroma homing, which aids melanoma progression in vitro and in vivo, and (4) 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 may bring the new perspective on TM’s application for targeting MSC’s mobilization and differentiation that can help tumor’s medication.

Project ID:PC10507-0630
External Project ID:MOST105-2320-B182-038