Janes, Sam M.; (2003) Integrin regulated differentiation and apoptosis in normal keratinocytes and squamous cell carcinomas. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Integrins are cell surface receptors, consisting of a heterodimer of an α and β subunit. The extracellular domains confer binding specificity to ligands such as extracellular matrix proteins and cellular counter-receptors. The short intracellular portion is associated with molecules that are known to play a role in signal transduction; hence integrin ligation provides a mechanism by which cells can respond to their immediate environment and profoundly affect cell functions such as survival, proliferation and commitment to differentiation. Normal stratified epithelia express the αvβ5 integrin, but in squamous cell carcinomas (SCCs) there is a downregulation of αvβ5 and an upregulation of αvβ6. To investigate the significance of this change we studied a human SCC cell line, H357, that lacks av integrins. Transduction of H357 cells with an αv expressing retrovirus resulted in cell surface expression of αvβ5. Unlike the parental cells αvβ5 expressing cells underwent suspension-induced apoptosis (anoikis), which could be inhibited by αvβ5 ligation. Introduction of the β6 subunit resulted in replacement of the αvβ5 with αvβ6 and suppressed anoikis. Cells that were resistant to anoikis activated PI3-kinase signalling in suspension, as measured by PKB/Akt phosphorylation, whereas αvβ5 expressing cells did not. Anoikis could be induced in parent and αvβ6 cells by inhibition of PI3-kinase. Conversely, activation of Akt in αvβ5 expressing cells suppressed anoikis. Anoikis required the cytoplasmic domain of β5 and was independent of the death receptor pathway. These results suggest that downregulation of αvβ5 and upregulation of αvβ6 may protect SCCs from anoikis by activating a PI3-kinase survival signal. Normal primary kertinocytes differentiate rather than apoptose when placed in suspension. It appears that caspases are also activated within 2 hours of the onset of epidermal cell differentiation and that caspase activation and differentiation are inhibited by a PI3-kinase inhibitor while an active Akt construct drives differentiation.

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