Several studies have reported that integrin inhibitors prevent tumour growth and angiogenesis, but a new report in Nature Medicine finds that tumour growth is actually enhanced in mice lacking 3 and 5 integrins.
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 3 and 5 integrins.
Integrins are a family of heterodimeric transmembrane receptors that consist of an and subunit that each recognize a unique set of ECM ligands. Blockade of v3 or v5 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 v, 3 or 5 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 3-deficient and 3/5 double knockout mice. Furthermore, tumours grow faster in the knockout mice. So the authors conclude that neither 3 nor 5 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 v3 and v5 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 3-null endothelial cells with the gene encoding 3 integrin reduced the expression of VEGFR-2 to wild-type levels, indicating that 3 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 v3 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.
Kristine Novak
References
ORIGINAL RESEARCH PAPER Reynolds, A. et al. Enhanced pathological angiogenesis in mice lacking 3 integrin or 3 and 5 integrins. Nature Medicine8, 27–34 (2002) | Article | PubMed |
FURTHER READING Eliceiri, B. P. & Cheresh, D. A. The role of v integrins during angiogenesis: insights into potential mechanisms of action and clinical development. J. Clin. Invest. 103, 1227–1230 (1999) | PubMed |
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