Tumor-derived mesenchymal stem cells promoted tumor development through CCR2-dependent recruitment of macrophages (66.40)

Abstract Mesenchymal stem cells (MSCs) residing in tumor stroma have been recognized to originate from normal tissues, such as bone marrow. Although they present as a major component of tumor stroma, the exact role they play in tumor progression and how they distinguish from normal tissue MSCs are largely unknown. In this report, we characterized the function of mesenchymal stem cells in promoting tumor development. Compared to BM-MSCs or tissue-MSCs, lymphoma-derived MSCs (L-MSCs) exhibited a strong tumor-promoting effect in a tumor transplantation model. While L-MSCs did not differ from BM-MSCs in their ability to suppress the adaptive immunity, they induced more abundant accumulation of CD11b+Gr-1+ myeloid suppressor cells and F4/80+ macrophages in tumors. Depletion of macrophages, but not myeloid suppressor cells, completely ablated the effect of L-MSCs, indicating that the tumor-promoting effect of L-MSCs was mediated via the recruitment of macrophages. Furthermore, chemokines CCL-2, CCL-7 and CCL-12, all of which utilize CCR2 as a receptor, were found over-expressed in L-MSCs. Correspondingly, the tumor-promoting effect of L-MSCs was largely abolished in CCR2-/- mice. Collectively, these data demonstrated that L-MSCs contribute to tumor development through CCR2-dependent recruitment of macrophages to tumor sites. Our findings thus established a mechanistic link between two major types of tumor stromal cells, providing critical implications for the future cancer therapy.