血管生成
糖酵解
PI3K/AKT/mTOR通路
下调和上调
癌症研究
缺氧(环境)
调节器
巨噬细胞
转移
肿瘤微环境
生物
新生血管
肿瘤进展
细胞生物学
厌氧糖酵解
化学
癌症
新陈代谢
内科学
内分泌学
医学
信号转导
生物化学
体外
肿瘤细胞
氧气
有机化学
基因
作者
Mathias Wenes,Min Shang,Mario Di Matteo,Jermaine Goveia,Rosa Martín‐Pérez,Jens Serneels,Hans Prenen,Bart Ghesquière,Peter Carmeliet,Massimiliano Mazzone
标识
DOI:10.1016/j.cmet.2016.09.008
摘要
Hypoxic tumor-associated macrophages (TAMs) acquire angiogenic and immunosuppressive properties. Yet it remains unknown if metabolic changes influence these functions. Here, we argue that hypoxic TAMs strongly upregulate the expression of REDD1, a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis in TAMs and curtails their excessive angiogenic response, with consequent formation of abnormal blood vessels. Accordingly, REDD1 deficiency in TAMs leads to the formation of smoothly aligned, pericyte-covered, functional vessels, which prevents vessel leakiness, hypoxia, and metastases. Mechanistically, highly glycolytic REDD1-deficient TAMs outcompete endothelial cells for glucose usage that thwarts vascular hyperactivation and promotes the formation of quiescent vascular junctions. Tuning down glycolysis in REDD1 knockout TAMs re-establishes abnormal angiogenesis and metastases. On this basis, we prove that the anti-tumor effect of mTOR inhibitors is partly countered by the deleterious outcome of these drugs on TAMs. Our data provide a functional link between TAM metabolism and tumor angiogenesis.
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