Integrin αvβ6 sets the stage for colorectal cancer metastasis.
The β6 subunit of the αvβ6 integrin heterodimer has long been an enigma in cancer biology though recent research has provided many new insights into its biology. Collectively, these findings include discovery of the transcriptional, translational and cell biological mechanisms by which β6 acts, the identification of the cellular influences β6 exerts upon the cell proteome, the characterisation of multiple β6-centric pro-metastatic signalling systems and the search for pharmacological therapies (industry and academia) targeted against β6. Once expressional restriction is overcome in early colorectal cancer (CRC), epithelial cell surface restricted αvβ6 can physically interact with, and activate, known oncoproteins, and has the potential to enable the cross-talk through non-canonical signal transduction pathways, resulting in the adoption of an invasive/metastatic phenotype. This recent research has identified numerous interconnections and potential feedback loops, highlighting the fact that the expression of the β6 subunit may initiate a cascade of downstream effects on the CRC cell rather than acting through a single mechanism. We here review these recent studies and postulate that the existence of a cell surface uPAR/αvβ6/TGFβ "metastasome" interactome in/on a proportion of colorectal cancer cells, where β6 expression sequesters and activates multiple systems at the invasive front of tumour lesions, promoting cancer metastasis and hence explaining why β6 has been correlated with reduced patient survival in CRC.
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, F10A Building, 2 Technology Place, Sydney, NSW, 2109, Australia.
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Cantor
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, F10A Building, 2 Technology Place, Sydney, NSW, 2109, Australia.
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Cheruku
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, 5800, Australia.
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Nice
Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, F10A Building, 2 Technology Place, Sydney, NSW, 2109, Australia. mark.baker@mq.edu.au.
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Baker
D000951:Antigens, Neoplasm / Q000378:metabolism*; D002465:Cell Movement; D054377:Chemokine CXCL12 / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000473:pathology*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D000951:Antigens, Neoplasm; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D039561:Eukaryotic Initiation Factor-4E; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D014568:Urokinase-Type Plasminogen Activator
Colorectal cancer; Metastatic transformation; β6 integrin