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

J Pathol. 2019 Nov;249(3):332-342. doi: 10.1002/path.5320. Epub 2019 Jul 30.


Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 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 that high levels of β6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10-8 ). In two separate cohorts, we showed that over 80% of PDACs 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 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. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Keywords: 264RAD; PDAC; cancer; integrin; mouse model; pancreas; transgenic; αvβ6.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Antigens, Neoplasm / metabolism*
  • Antineoplastic Agents, Immunological / pharmacology
  • Apoptosis
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / secondary
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Dual Specificity Phosphatase 6 / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, ras
  • Humans
  • Integrases / genetics
  • Integrins / antagonists & inhibitors
  • Integrins / genetics
  • Integrins / metabolism*
  • Italy
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasm Invasiveness
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Signal Transduction
  • Tumor Burden
  • Tumor Microenvironment
  • United Kingdom
  • Xenograft Model Antitumor Assays


  • Antigens, Neoplasm
  • Antineoplastic Agents, Immunological
  • Integrins
  • integrin alphavbeta6
  • Cre recombinase
  • Integrases
  • Dual Specificity Phosphatase 6
  • Dusp6 protein, mouse