• Major finding: The TSC2–mTOR pathway regulates the differentiation of monocytes into TAMs.

  • Concept: Inhibition of mTOR causes a reduction in TAM-induced tumor angiogenesis.

  • Impact: mTOR pathway inhibitors may prevent tumor growth via immune system modulation.

Macrophages are phagocytic immune cells that play important roles in tumor growth. Classic M1 macrophages display antitumor effects, and M2 macrophages, known as tumor-associated macrophages (TAM), have been shown to support tumor invasion via the promotion of angiogenesis. Although the behavior of macrophages is determined by their differentiation into one of these two polarized phenotypes, the molecular mechanisms that regulate this development remain unclear. In a recent article, Chen and colleagues demonstrate that the mTOR pathway, which is involved in the regulation of cell growth, plays a critical role in the differentiation of monocytes into TAMs and is required for TAM-mediated angiogenesis. The authors found that when peripheral monocytes were stimulated in the presence of the mTOR inhibitor rapamycin, they developed into M1 macrophages that did not promote angiogenesis. However, peripheral monocytes that overexpressed mTOR, secondary to knockdown of the upstream negative regulator tuberous sclerosis complex 2 (TSC2), differentiated into proangiogenic TAMs. These findings were confirmed in vivo when monocytes expressing differing levels of TSC2 were reintroduced into tumor-bearing mice. Tumor growth and angiogenesis were reduced in the presence of rapamycin or when TSC2 was overexpressed but were increased in the absence of TSC2. In addition, the transcription factor STAT3 was identified as the downstream target of mTOR that mediates TAM-dependent tumor angiogenesis in vivo. These studies establish an essential role for the TSC2–mTOR pathway in the differentiation of proangiogenic TAMs. Inhibition of mTOR in monocytes therefore may represent an antitumor therapeutic strategy.

Chen W, Ma T, Shen X, Xia X, Xu G, Bai X, et al. Macrophage-induced tumor angiogenesis is regulated by the TSC2-mTOR pathway. Cancer Res 2012 Jan 27. [Epub ahead of print].

Note:Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at www.AACR.org/CDnews.