Vascular endothelial growth factor (VEGF) is important in tumour angiogenesis, but whether it is essential that cancer cells themselves express VEGF is unclear. A recent paper in The EMBO Journal shows that tumours can recruit stromal cells to carry out this function.

Jianying Dong, Napoleone Ferrara and colleagues generated Vegf-null mouse embryonic fibroblasts (MEFs), which were immortalized and then transformed with oncogenic Ras. These cells formed tumours on injection into mice, which were about half the size of those formed by a parental VEGF-expressing cell line that was similarly immortalized and transformed. The Vegf-null tumours successfully induced angiogenesis, with only a slight decrease in vessel density compared with tumours formed by parental cells.

Although these tumours do not express VEGF themselves, VEGF mRNA and protein were present in the tumours, although at markedly lower levels than in those formed by the parental cell line. Could stromal cells recruited to these tumours be the source of VEGF expression? This was confirmed by in situ hybridization using a probe specific for the exon of the Vegf gene that was deleted in the Vegf-null MEFs, showing that the transcript co-localized with tumour-associated stromal cells.

The authors used an anti-VEGF antibody to test whether the small amounts of VEGF produced by recruited stromal cells were responsible for angiogenesis and tumour growth in the Vegf-null tumours. Treatment with the antibody resulted in a decrease in tumour mass of up to 62%, indicating that the stroma-derived VEGF does indeed have an important role.

How do tumours recruit VEGF-expressing stromal cells? Fibroblasts are an important component of the tumour-associated stroma and are known to express VEGF. The authors showed that conditioned medium obtained from Vegf-null tumour cells stimulated migration and proliferation of a fibroblast cell line in vitro. Fractionation of the medium revealed a peak of activity corresponding to PDGFA — a member of the platelet-derived growth factor family. Consistent with a role of this protein in fibroblast recruitment, Pdgfa expression was seen throughout Vegf-null tumours, whereas expression of the mRNA encoding its receptor — PDGFRα — was localized to stromal cells. In addition, a soluble form of PDGFRα inhibited tumour growth by 50%, confirming an important role for signalling through this receptor.

These results have important implications for anticancer treatments that inhibit angiogenesis. The fact that tumour cells can recruit VEGF-expressing fibroblasts, as well as producing VEGF themselves, indicates that the signalling pathways involved in both of these mechanisms might need to be blocked to completely inhibit angiogenesis and tumour growth.