The SDF‐1/CXCR4 axis utilizes mTOR signal transduction to promote angiogenesis (278.8)

Abstract

Pathological angiogenesis, which occurs during chronic inflammation or tumor growth, results when positive and negative angiogenic regulators are disrupted. The chemokine stromal‐cell derived factor‐1 (SDF‐1) and its receptor CXCR4 promote endothelial cell (EC) migration and tube formation. PI3K is a key downstream regulator of CXCR4‐mediated chemotaxis and mammalian target of rapamycin (mTOR) is at the center of PI3K‐mediated signal transduction. We have hypothesized that the SDF‐1/CXCR4/mTOR signaling axis contributes to the molecular mechanism of angiogenesis. This study illustrates that SDF‐1 stimulation activates mTOR signal transduction in EC grown in monolayer cell culture. The pharmacological inhibition of CXCR4 or mTOR blocks sprouting in an in vitro 3D angiogenesis model, and also abolishes EC migration in a 3D angiogenic invasion assay. Specific inhibition of mTOR complex 1 or mTOR complex 2 (mTORC2) reveals that SDF‐1‐induced angiogenesis occurs via mTORC2 signal transduction. An analysis of targets downstream of mTOR indicates that 6‐phosphofructo‐2‐kinase (PFKFB3), which is a key regulator of glycolysis, is downregulated in EC in which mTORC2 is inhibited. Taken together these data indicate that the SDF‐1/CXCR4 axis activates angiogenesis by utilizing an mTORC2 signal transduction pathway. In addition, these data present a potential link between mTORC2, metabolism and angiogenesis, which deserves further exploration.Grant Funding Source: The project described was supported by Grant Number T32CA009054 from the National Cancer Institute.