Journal
GUT
Volume 61, Issue 6, Pages 877-884Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2011-300850
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Funding
- histology core and biological resources unit at the CRI
- Lustgarten Foundation
- University of Cambridge
- Cancer Research UK
- Li Ka Shing Foundation
- Hutchison Whampoa Limited
- National Institute for Health Research Cambridge Biomedical Research Centre
- NIH [CA101973, CA111294, CA084291, CA105490]
- European Commission [256974, 201279]
- Deutsche Krebshilfe/Dr Mildred-Scheel-Stiftung [109102]
- Deutsche Forschungsgemeinschaft [MA 4115/1-2/3, SFB 850]
- European Union (EU) [EU-FP7-REGPOT-2010-1]
- Excellence Initiative of the German Federal and State Governments [EXC 294]
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Objective The lysosomal protease cathepsin B is upregulated in human pancreatic ductal adenocarcinoma (PDA) and represents a potential therapeutic target. Loss of cathepsin B delays tumour progression in mouse models of islet, mammary and intestinal carcinoma and decreases invasion and metastasis. This study examines the role of cathepsin B in the initiation, progression and metastasis of PDA. Methods Cathepsin B germline knockout mice were crossed with animals expressing an endogenous Kras(G12D) allele in the pancreas, and mice were aged to evaluate the role of cathepsin B in pancreatic intraepithelial neoplasia (PanIN). A survival study was also performed with mice carrying an additional heterozygous conditional Trp53(R172H) allele. Cell lines derived from tumours were used to investigate the role of cathepsin B in vitro, and subcutaneous allografts investigated the cell autonomous and non-cell autonomous roles of cathepsin B in pancreatic cancer. Results Constitutive cathepsin B loss resulted in delayed progression of both PanIN and PDA and a significant survival advantage in mice. Cathepsin B-deficient PDA cells and PanIN showed decreased proliferation and mitogen-activated protein (MAP) kinase signalling. The reconstitution of deficient cells with cathepsin B reversed these findings, which correlated with decreased levels of the active forms of the related protease cathepsin L. Conversely, acute ablation of cathepsin L activated the MAP kinase cascade in PDA cells. Conclusions These results confirm that cathepsin B plays an important cell autonomous role in the progression of PDA and suggest that the regulation of cathepsin L by cathepsin B may be a means of stimulating cell proliferation in neoplasia.
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