Cyclooxygenase-2 (COX-2) has a key role in the metabolism of arachidonic acid to essential prostaglandins. But the enzyme COX-2 is also overexpressed, and so implicated, in many types of cancer. Inhibiting the function of COX-2 by nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduces the risk of cancer development in humans and suppresses tumour growth in animal models.
Although the mechanism underlying how NSAIDS promote their anti-cancer effect remains to be elucidated, NSAIDs appear to suppress tumour angiogenesis. One important pathway that has been identified in tumour angiogenesis is mediated by the adhesion receptor integrin aVb3.
In new work published in September's Nature Medicine, Curzio R�egg and colleagues of the University of Lausanne, Switzerland, link the action of NSAIDs to the integrin aVb3 pathway. They show that NSAID inhibition of COX-2 in endothelial cells suppresses aVb3-dependent activation of the GTP phosphatases Cdc42 and Rac. This in turn results in inhibition of the spreading and migration of endothelial cells in vitro, and the suppression of angiogenesis induced by fibroblast growth factor-2 in vivo.
The results of R�egg and co-workers establish a direct link between COX-2, integrin aVb3 and Cdc42/Rac-dependent endothelial-cell migration. Moreover, they provide a basis from which to understand the anti-angiogenic activity of NSAIDs.
article NSAIDs inhibit aVb3 integrin-mediated and Cdc42/Rac-dependent endothelial-cell spreading, migration and angiogenesis OLIVIER DORMOND, ALESSANDRO FOLETTI, C�CILE PAROZ Nature Medicine 7, 1041�1047 (September 2001)