Vascular integrins in tumor angiogenesis: mediators and therapeutic targets.
The notion that tumor angiogenesis may have therapeutic implications in the control of tumor growth was introduced by Dr. Judah Folkman in 1971. The approval of Avastin in 2004 as the first antiangiogenic systemic drug to treat cancer patients came as a validation of this visionary concept and opened new perspectives to the treatment of cancer. In addition, this success boosted the field to the quest for new therapeutic targets and antiangiogenic drugs. Preclinical and clinical evidence indicate that vascular integrins may be valid therapeutic targets. In preclinical studies, pharmacological inhibition of integrin function efficiently suppressed angiogenesis and inhibited tumor progression. alphaVbeta3 and alphaVbeta5 were the first vascular integrins targeted to suppress tumor angiogenesis. Subsequent experiments revealed that at least four additional integrins (i.e., alpha1beta1, alpha2beta1, alpha5beta1, and alpha6beta4) might be potential therapeutic targets. In clinical studies low-molecular-weight integrin inhibitors and anti-integrin function-blocking antibodies demonstrated low toxicity and good tolerability and are now being tested in combination with radiotherapy and chemotherapy for anticancer activity in patients. In this article the authors review the role of integrins in angiogenesis, present recent development in the use of alphaVbeta3 and alpha5beta1 integrin antagonists as potential therapeutics in cancer, and discuss future perspectives.
Alghisi
Gian Carlo
GC
Centre Pluridisciplinaire d'Oncologie (CePO), Faculty of Biology and Medicine, University of Lausanne, Switzerland.
Rüegg
Curzio
C
D000818:Animals; D002986:Clinical Trials as Topic; D042783:Endothelial Cells / Q000473:pathology; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009369:Neoplasms / Q000098:blood supply* / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000628:therapy
D016023:Integrins