Integrins in angiogenesis and lymphangiogenesis

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Abstract
Angiogenesis and lymphangiogenesis have important roles in cancer progression: angiogenesis, the growth of new blood vessels, promotes tumour growth and tumour metastasis, and lymphangiogenesis, the growth of new lymphatic vessels, promotes tumour metastasis. Angiogenesis and lymphangiogenesis are regulated by integrins, which are members of a family of cell surface adhesion receptors. The integrin family is an extensive group of structurally related receptors for extracellular matrix proteins and immunoglobulin superfamily molecules. Integrin ligation promotes intracellular signal transduction, cell migration and survival in angiogenesis and lymphangiogenesis. A number of endothelial cell integrins regulate angiogenesis in diverse manners, including integrins α1β1, α2β1, α4β1, α5β1, α9β1 and α6β4. αv integrins are also important in angiogenesis, although the exact nature of these roles is hotly disputed. Expression and function analysis of αv integrins in wild-type animals using integrin antagonists as well as analysis of knock-in mutant mice indicate that αv integrins promote angiogenesis, whereas genetic deletion studies suggest that αv integrins are not required for angiogenesis. Although less is known about the integrins that regulate lymphangiogenesis, integrin α9 is required for normal developmental lymphangiogenesis. Integrins α4β1, α2β1 and α1β1 have also been implicated in the regulation of tumour lymphangiogenesis. Integrins on bone marrow-derived myeloid cells can also promote angiogenesis. Circulating bone marrow-derived cells migrate into tumours in response to tumour-secreted chemokines and cytokines and integrins α4β1 and αMβ2 (CD11b) have key roles in this process, indirectly influencing tumour angiogenesis. Antagonists of several integrins, including αvβ3, αvβ5 and α5β1, are currently under investigation as clinical agents to suppress tumour angiogenesis and growth either alone or in combination with current cancer therapeutics.