Integrin signalling during tumour progression

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Abstract
Dysregulated combined signalling between integrins and receptor tyrosine kinases (RTKs) promotes the disruption of adherens junctions at the onset of carcinoma invasion. Src-family kinases (SFKs) induce the expression of SNAIL/SLUG transcription factors, which repress transcription of the E-cadherin gene, and also promote — presumably through Hakai — endocytosis of E-cadherin protein. Integrin-linked kinase also promotes transcriptional repression of E-cadherin. The integrins cooperate with RTKs to activate pro-migratory signalling pathways. Whereas focal adhesion kinase (FAK) signalling to Src induces the disassembly of focal adhesions at the rear of the cell, Rho-family GTPases coordinate the changes in the actin cytoskeleton that are necessary to anchor the leading edge of the cell to the matrix and propel the cell forward. The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK) and Jun amino-terminal kinase (JNK) contribute to cell migration by phosphorylating various cytoskeletal signalling molecules and by promoting AP-1-dependent transcription. The integrins facilitate matrix remodelling and the invasion of tumour cells through the recruitment of matrix-degrading proteases. Tumour cells tend to upregulate or to maintain the expression of integrins that cooperate with RTKs to promote tumour progression, whereas they tend to lose the expression of integrins that exert the opposite effect. Integrins have both adhesive and signalling roles during tumour angiogenesis. Various integrin–RTK pairs are likely to control angiogenesis — this will depend on the angiogenic stimulus, the tissue and the stage of angiogenesis. Integrins are targeted by activators as well as by inhibitors of angiogenesis. Joint integrin–RTK signalling controls the invasion of endothelial cells during angiogenesis, which implies that the invasion of tumour cells and tumour angiogenesis might be regulated by similar signalling mechanisms. Integrins mediate the formation of microemboli, which are composed of tumour cells, platelets and leukocytes. They also facilitate the adhesion of tumour cells to the endothelium, which therefore promotes their docking and extravasation at a metastatic site. Although cancer cells do not rely heavily on adhesion to the matrix for their survival and proliferation, dysregulated integrin–RTK signalling enhances the survival of cancer cells and the growth of primary tumours.