TNFSF15 facilitates the differentiation of CD11b(+) myeloid cells into vascular pericytes in tumors

OBJECTIVE: Immature vasculature lacking pericyte coverage substantially contributes to tumor growth, drug resistance, and cancer cell dissemination. We previously demonstrated that tumor necrosis factor superfamily 15 (TNFSF15) is a cytokine with important roles in modulating hematopoiesis and vascular homeostasis. The main purpose of this study was to explore whether TNFSF15 might promote freshly isolated myeloid cells to differentiate into CD11b(+) cells and further into pericytes. METHODS: A model of Lewis lung cancer was established in mice with red fluorescent bone marrow. After TNFSF15 treatment, CD11b(+) myeloid cells and vascular pericytes in the tumors, and the co-localization of pericytes and vascular endothelial cells, were assessed. Additionally, CD11b(+) cells were isolated from wild-type mice and treated with TNFSF15 to determine the effects on the differentiation of these cells. RESULTS: We observed elevated percentages of bone marrow-derived CD11b(+) myeloid cells and vascular pericytes in TNFSF15-treated tumors, and the latter cells co-localized with vascular endothelial cells. TNFSF15 protected against CD11b(+) cell apoptosis and facilitated the differentiation of these cells into pericytes by down-regulating Wnt3a-VEGFR1 and up-regulating CD49e-FN signaling pathways. CONCLUSIONS: TNFSF15 facilitates the production of CD11b(+) cells in the bone marrow and promotes the differentiation of these cells into pericytes, which may stabilize the tumor neovasculature.