Adhesion molecules such as integrins allow cells to transmit signals from the extracellular matrix (ECM), and have been implicated in tumour growth and angiogenesis. Several studies have reported that integrin inhibitors prevent tumour growth and angiogenesis in mice, and one inhibitor — vitaxin — is now being tested in cancer clinical trials. But a surprising article in the January issue of Nature Medicine reports a contradictory finding — that tumour growth is actually enhanced in mice lacking β3 and β5 integrins.

Integrins are a family of heterodimeric transmembrane receptors that consist of an α and β subunit that each recognize a unique set of ECM ligands. Blockade of αvβ3 or αvβ5 integrins with monoclonal antibodies or small-molecule inhibitors prevent tumour growth and angiogenesis in animal models. Conversely, previous knockout studies have reported that mice lacking αv, β3 or β5 integrins undergo normal developmental angiogenesis. The Nature Medicine study by Reynolds et al. adds to these results, showing that tumour-induced angiogenesis also occurs, and is actually enhanced, in β3-deficient and β3/β5 double knockout mice. Furthermore, tumours grow faster in the knockout mice. So the authors conclude that neither β3 nor β5 integrins are essential for neovascular formation.

But what could explain the differences between blocking agents and knockout models? One possibility is that in the knockout mice, other adhesion proteins are overexpressed in compensation. Reynolds et al. did not detect increased levels or activities of other integrins, although upregulation of other adhesion proteins could not be ruled out. A second possibility is that the integrin antagonists could indirectly inhibit the function of other integrins or other cell-surface molecules. A third possibility is that the integrin-null mice undergo an abnormal mechanism of angiogenesis.

The authors conclude, however, that rather than being required for angiogenesis, integrins αvβ3 and αvβ5 might normally function to limit it. They observed that expression of the vascular endothelial growth factor receptor-2 (VEGFR-2) was increased in endothelial cells of integrin knockout mice, which could promote angiogenesis. Transfection of β3-null endothelial cells with the gene encoding β3 integrin reduced the expression of VEGFR-2 to wild-type levels, indicating that β3 integrin signalling downregulates VEGFR-2 expression. Reynolds et al. propose that integrin inhibitors might dysrgulate this pathway, although they don't explain how. Although the authors do not dispute the efficacy of αvβ3 antagonists in preventing angiogenesis or their potential as anticancer drugs, they state that a more thorough understanding of the mechanisms of action of these inhibitors and the roles of integrins in angiogenesis is required.