title: Cathepsin B promotes the progression of pancreatic ductal adenocarcinoma in mice.
abstract: 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.
authors.affiliation: Li Ka Shing Centre, Cancer Research UK Cambridge Research Institute, Cambridge, UK.
authors.forename: Aarthi
authors.initials: A
authors.lastname: Gopinathan
authors.forename: Gina M
authors.initials: GM
authors.lastname: Denicola
authors.forename: Kristopher K
authors.initials: KK
authors.lastname: Frese
authors.forename: Natalie
authors.initials: N
authors.lastname: Cook
authors.forename: Florian A
authors.initials: FA
authors.lastname: Karreth
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinheckel
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000503:physiopathology*; D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000503:physiopathology*; D002401:Cathepsin B / Q000235:genetics / Q000502:physiology*; D056668:Cathepsin L / Q000502:physiology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000503:physiopathology*
chemical_list: D002401:Cathepsin B; D056668:Cathepsin L