Macrophage-Induced Tumor Angiogenesis Is Regulated by the TSC2―mTOR Pathway

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-03, Vol.72 (6), p.1363-1372
• Main Authors: WEI CHEN, TAO MA, SHEN, Xu-Ning, XIA, Xue-Feng, XU, Guo-Dong, BAI, Xue-Li, LIANG, Ting-Bo
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Cancer; Cell Differentiation - drug effects; Cell Line, Tumor; Differentiation; Endothelial cells; Human Umbilical Vein Endothelial Cells; Humans; Interleukin 10; Interleukin 12; Interleukin-10 - metabolism; Interleukin-12 - secretion; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - physiology; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophages; Macrophages - drug effects; Macrophages - physiology; Male; Medical sciences; Mice; Mice, Nude; Monocytes; Neovascularization, Pathologic - metabolism; Pharmacology. Drug treatments; Rapamycin; Repressors; RNA; Sirolimus - pharmacology; STAT3 Transcription Factor - physiology; TOR protein; TOR Serine-Threonine Kinases - metabolism; tuberous sclerosis; Tuberous sclerosis 2 protein; Tumor Suppressor Proteins - metabolism; Tumors; umbilical vein; Xenografts
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-2684

Tumor-associated macrophages (TAM) have multifaceted roles in tumor development but they have been associated particularly closely with tumor angiogenesis. However, although the accumulation of TAM (M2 phenotype) promotes tumor angiogenesis, the mechanism through which monocytes differentiate to generate TAM is unclear. Here, we report that the mTOR pathway is a critical element in the regulation of monocyte differentiation to TAM. In human peripheral monocytes stimulated by lipopolysaccharide, mTOR was inhibited by rapamycin or activated by RNA interference-mediated knockdown of the mTOR repressor tuberous sclerosis complex 2 (TSC2). Rapamycin caused the monocytes to differentiate into M1 macrophages releasing more interleukin (IL)-12 and less IL-10, whereas TSC2 knockdown caused the monocytes to differentiate into M2 macrophages releasing less IL-12 and more IL-10. In parallel fashion, angiogenic properties were promoted or reduced in human umbilical vein endothelial cells cocultured 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. Finally, in vivo depletion of macrophages was sufficient to block the antiangiogenic effects of rapamycin on tumors. Our results define the TSC2-mTOR pathway as a key determinant in the differentiation of monocytes into M2 phenotype TAM that promote angiogenesis.