Angiogenesis — the migration, proliferation and incorporation of endothelial cells into new blood vessels — is required for normal embryonic development, but also for tumour growth. Although a variety of growth factors have been identified that promote angiogenesis, little is known about the origin of the cells that contribute to tumour-associated vessels. In the November issue of Nature Medicine, Lyden et al. report that bone-marrow-derived cells are recruited by vascular endothelial growth factor (VEGF) to the newly forming vasculature.

To identify the cells that contribute to tumour angiogenesis, the authors studied Id-mutant mice, which do not undergo postnatal angiogenesis. The Id proteins are a family of four related transcriptional repressors that control differentiation and cell-cycle progression. Although mice with reduced Id gene dosages ( Id1 +/−/ Id3 −/−) undergo normal development, they cannot support neo-angiogenesis. Tumours, therefore, do not grow well in these mice.

Bone-marrow-derived endothelial-like cells have been shown to contribute to angiogenesis in ischaemic limbs, so the authors asked whether these cells could also contribute to tumour angiogenesis. They found that transplantation of wild-type bone marrow into Id1+/−/Id3−/−mice restored tumour neoangiogenesis and growth. Conversely, Id1+/−/Id3−/− bone marrow engrafted into wild-type animals reduced tumour growth. This indicated that bone-marrow-derived cells could promote formation of new blood vessels by tumours.

But what specific cells in the bone marrow contribute to neo-angiogenesis? Lyden et al. tracked the transplanted bone marrow cells by labelling them with β-galactosidase. A few days after engraftment, a subpopulation of bone marrow cells, identified by their surface markers as circulating endothelial precursor cells (CEPs), became extensively incorporated into the lining of tumour blood vessels. These cells expressed one of the VEGF receptors, VEGFR2. Furthermore, myeloid precursors that expressed a different VEGF receptor, VEGFR1, contributed to formation of the blood vessel walls as well.

So, does VEGF signalling induce bone marrow cells to contribute to tumour angiogenesis? Increasing VEGF levels in the blood of wild-type mice induced co-mobilization of bone-marrow-derived VEGFR2+ CEPs and VEGFR1+ haematopoietic cells to the peripheral circulation. Administration of antibodies against VEGFR2 prevented CEP mobilization and subsequent angiogenesis in wild-type mice. Finally, administration of antibodies against both VEGFR1 and VEGFR2 was more effective than either antibody itself in blocking tumour formation, indicating that both cell types contribute to tumour angiogenesis.

Increasing the plasma concentration of VEGF also upregulated Id1 and Id3 expression in bone marrow cells of wild-type mice. Are Id1 and Id3 required for VEGF signalling? Apparently so, as in Id-mutant bone-marrow cultures, VEGFR2+ CEPs and VEGFR1+ myeloid precursors failed to expand after VEGF treatment. Furthermore, increasing plasma VEGF levels in Id-mutant mice failed to recruit bone-marrow-derived precursor cells to the peripheral circulation.

Tumour cells produce VEGF, and these findings indicate that one of the functions of this growth factor is to signal bone marrow VEGFR2+ CEPs and VEGFR1+ myeloid progenitors through Id1 and Id3, to move into the peripheral circulation and contribute to new blood vessels. Therapeutics designed to target these blood vessel precursors and their signalling molecules might be one way to slow tumour growth.