The Role Of MTOR In Macrophage Induced Neoangiogenesis

Aim:Macrophages have multifaceted roles in tumor growth and development, and are closely associated with angiogenesis. Tumor-associated macrophages (TAM, M2phenotype) promote tumor angiogenesis, but the mechanism of how monocytes differentiate to TAMs is unclear. The purpose of the study is to investigate the role of mTOR pathway in monocytes differentiation and macrophages induced hepatoma's angiogenesis.Methods and method:In human peripheral monocytes stimulated by lipopolysaccharide (LPS), mTOR was inhibited by rapamycin or activated by RNAi-mediated knockdown of the mTOR repressor TSC2. Cytokine secretion(IL-12p40, IL-12p70, IL-10,1L-6, TNF-a and MCP-1), M2macrophages'cell surface marker expression(CD206), angiogenesis of induced by macrophages both in vitro and in vivo were examined. And the role of STAT3in these process were also detected. Results:Rapamycin caused the monocytes to differentiate into Ml macrophages releasing more IL-12and less IL-10, whereas TSC2knockdown caused the monocytes to differentiate into M2macrophages releasing less IL-12and more IL-10. In parallel fashion, angiogenic properties were promoted or reduced in HUVEC cells co-cultured with TSC2-deficient monocytes or rapamycin-treated monocytes, respectively. Furthermore, tumor angiogenesis and growth in murine xenografts were promoted or reduced by infusion of hosts with TSC2-deficient or TSC2-overexpressing monocytes, respectively, and in vivo depletion of macrophages was sufficient to block the anti-angiogenesis effects of rapamycin on tumors. Inhibition of STAT3by NSC74859could block mTOR activated macrophages promoted angiogenesis in vitro while rapamycin could inhibit STAT3activation, and NSC74859could block hepatoma's angiogenesis in vivo.Conclusions:In the present study, the TSC2-mTOR pathway was identified as a key regulator in differentiation of monocytes into the M1or M2phenotype and angiogenesis induced by macrophages. And mechanismly, STAT3may mediate the effect of TSC2-mTOR in differentiation of monocytes.