Journal
LABORATORY INVESTIGATION
Volume 95, Issue 9, Pages 976-986Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.2015.82
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Funding
- National Institutes of Health [T32 CA160003, R01 CA109136]
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Integrin alpha 6 beta 4 is a cellular adhesion molecule that binds to laminins in the extracellular matrix and nucleates the formation of hemidesmosomes. During carcinoma progression, integrin alpha 6 beta 4 is released from hemidesmosomes, where it can then signal to facilitate multiple aspects of tumor progression including sustaining proliferative signaling, tumor invasion and metastasis, evasion of apoptosis, and stimulation of angiogenesis. The integrin achieves these ends by cooperating with growth factor receptors including EGFR, ErbB-2, and c-Met to amplify downstream pathways such as PI3K, AKT, MAPK, and the Rho family small GTPases. Furthermore, it dramatically alters the transcriptome toward a more invasive phenotype by controlling promoter DNA demethylation of invasion and metastasis-associated proteins, such as S100A4 and autotaxin, and upregulates and activates key tumor-promoting transcription factors such as the NFATs and NF-kappa B. Expression of integrin alpha 6 beta 4 has been studied in many human malignancies where its overexpression is associated with aggressive behavior and a poor prognosis. This review provides an assessment of integrin alpha 6 beta 4 expression patterns and their prognostic significance in human malignancies, and describes key signaling functions of integrin alpha 6 beta 4 that contribute to tumor progression.
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