The host vascular response to a tumor often dictates the growth rate of the primary tumor and the capacity of the tumor to invade. Inhibitors of angiogenesis are beginning to show promise in the clinic. In fact, bevacizumab, an antibody that targets vascular endothelial growth factor (VEGF) is clinically approved to treat wide range of cancers. However, the clinical utility of bevacizumab is only realized when it is given in combination with more traditional chemotherapeutic agents. For this reason, it has been hypothesized that bevacizumab and perhaps other inhibitors of VEGF or its receptors act to normalize the host vascular response to the tumor and thereby facilitate more perfusion and better drug delivery to the tumor. In fact, tumor-bearing animals or patients with cancer treated with inhibitors of the VEGF pathway develop blood vessels that have decreased leakiness and increased pericyte coverage. Accordingly, angiogenesis not only depends on endothelial cell (EC) invasion and proliferation, but also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by VEGF and platelet-derived growth factor (PDGF) through their cognate receptors on ECs and pericytes or vascular smooth muscle cells (VSMCs), respectively. PDGF induces neovascularization by priming VSMCs and pericytes to release proangiogenic mediators. Although VEGF directly stimulates EC proliferation and migration, its role in pericyte biology is less clear. Here, we define a role for VEGF as an inhibitor of neovascularization based on its capacity to disrupt percitye and VSMC function. Specifically, under conditions of PDGF-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGF-R2 suppresses PDGF-R-beta signaling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-R--beta and VEGF-R2. Inhibition of VEGF-R2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. In fact, genetic deletion of tumor cell VEGF disrupts PDGF-R-beta/VEGF-R2 complex formation and increases tumor vessel maturation. Finally, mice expressing a deletion of myeloid cell VEGF develop tumors with a more mature vasculature than their wild-type counterparts. To our surprise, these tumors lacking VEGF grow at a faster rate yet are more sensitive to the effects of standard chemotherapy. These findings underscore the importance of VSMCs and pericytes in neovascularization and reveal a dichotomous role for VEGF and VEGF-R2 signaling as both a promoter of EC function and a negative regulator of VSMCs and vessel maturation. These findings provide new insight into the mechanism by which inhibitors of the VEGF pathway influence tumor blood vessels and the tumor response to chemotherapeutic agents.1, 2
References
1. Greenberg J, Shields D, Barillas S, et al. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature, 2008, in press.
2. Stockmann C, Doedens A, Weidemann A, et al. Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis. Nature, 2008, in press.
