The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy

Reader, C. S. et al. (2019) The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy. Journal of Pathology, 249(3), pp. 332-342. (doi: 10.1002/path.5320) (PMID:31259422) (PMCID:PMC6852434)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a five‐year survival rate of <4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed high levels of β6 mRNA correlated strongly with significantly poorer survival (n=491 cases, p= 3.17x10‐8). In two separate cohorts we showed that over 80% of PDAC expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration and invasion. Treatment of both αvβ6‐positive human PDAC xenografts and transgenic mice bearing αvβ6‐positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p<0.0001) and increased survival (Log‐rank test, p<0.05). Antibody therapy was associated with suppression of both tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated Caspase 3) and suppression of the pro‐tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA‐positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy.

• Item Type: Articles
• Additional Information: CR and SV were funded by Howard Kerr PhD Fellowships provided by the Pancreatic Cancer Research Fund. CWS received a Wellcome Trust Research Training Fellowship. We thank the CRUK Core Facilities at Barts Cancer Institute, London (Core Award C16420/A18066), and the CRUK Histology services at The Beatson Institute, Glasgow.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Nigel and Biankin, Professor Andrew and Bailey, Dr Peter and Evans, Professor Jeff and Steele, Dr Colin and Morton, Professor Jen and Chang, Professor David and Sansom, Professor Owen
• Authors: Reader, C. S., Vallath, S., Steele, C. W., Haider, S., Brentnall, A., Desai, A., Moore, K. M., Jamieson, N. B., Chang, D., Bailey, P., Scarpa, A., Lawlor, R., Chelala, C., Keyse, S. M., Biankin, A., Morton, J. P., Evans, T.R. J., Barry, S. T., Sansom, O. J., Kocher, H. M., and Marshall, J. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Journal of Pathology
• Publisher: Wiley
• ISSN: 0022-3417
• ISSN (Online): 1096-9896
• Published Online: 01 July 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Journal of Pathology 249(3):332-342
• Publisher Policy: Reproduced under a Creative Commons license