Randall Johnson and colleagues examined the role of myeloid cell-derived VEGFA in angiogenesis and tumour progression by using the Cre–Lox system to specifically delete Vegfa in mouse myeloid cells. When these mice were crossed to MMTV–PyMT mice (which develop mammary tumours), the authors found an increase in total tumour mass and more tumours that had progressed to malignancy in the mice lacking myeloid VEGFA (referred to as mutant mice). Analysis of the tumour vasculature in these animals indicated that deletion of myeloid VEGFA resulted in decreased vascular density, shorter and less tortuous vessels, and increased pericyte coverage — that is, these vessels were normalized. Although overall levels of VEGFA protein were the same in tumours from Vegfa wild-type or mutant mice, phosphorylation of VEGF receptor 2 (VEGFR2) was reduced in mutant mice, indicating that other sources of VEGFA cannot compensate for myeloid cell-derived VEGFA. The authors found similar results using isografts of Lewis lung carcinoma (LLC) or fibrosarcoma cells in Vegfa mutant and wild-type mice. Interestingly, LLC tumours in mice lacking myeloid cell-derived VEGFA were more susceptible to chemotherapy with either cyclophosphamide or cisplatin, which may partially explain the efficacy of anti-VEGF therapy in combination with chemotherapy (and the lack of single-agent efficacy of these agents) in some cancers.
In a related paper, David Cheresh and colleagues investigated a possible synergistic role in angiogenesis between VEGFA, which activates endothelial cells, and platelet-derived growth factor (PDGF), which activates vascular smooth muscle cells (VSMCs). VEGFA or PDGF induced neovascularization in mouse and chorioallantoic membrane models but, surprisingly, the combination of the two factors suppressed angiogenesis completely. The reduced neovascularization appeared to be a result of reduced VSMC activation and reduced pericyte coverage of vessels leading to vessel destabilization. The antagonistic relationship of these growth factors did not result from competition for receptor binding but from reduction of PDGF-mediated phosphorylation of PDGF receptor-β (PDGFRβ) on VSMCs in the presence of VEGFA. Co-immunoprecipitation studies and proximity ligation assays showed that this cross-talk was a result of the formation of VEGFR2–PDGFRβ complexes in VSMCs, which was blocked by VEGFR2 inhibition. To evaluate the interplay of these two pathways in tumour vasculature, the authors examined mouse fibrosarcomas that were either wild-type or null for VEGFA. Perivascular cells from tumours lacking VEGFA did not form VEGFR2–PDGFRβ complexes, and these tumours had more mature blood vessels with more pericyte coverage.
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