Use of IHC and newly designed matriptase inhibitors to elucidate the role of matriptase in pancreatic ductal adenocarcinoma.
Matriptase, also known as MT-SP1, is a type II transmembrane serine protease strongly implicated in both the development and progression of a variety of epithelial cancers. Evidence comes from studies of its expression in human cancers and from mouse models of spontaneous cancer. Matriptase is considered to be a major activator of two key stimulators of invasive growth, namely hepatocyte growth factor/scatter factor and urokinase-type plasminogen activator. The aim of this study was to examine the role of matriptase in pancreatic ductal adenocarcinoma by expression analysis and functional assays in vitro. Immunohistochemical analysis of matriptase performed on microtissue arrays and large samples of 55 pancreatic ductal adenocarcinomas and on 31 samples of normal pancreatic ducts revealed that although matriptase expression differed greatly in both malignant and normal ductal pancreatic tissue, matriptase scores were significantly (p=0.02) elevated in pancreatic ductal adenocarcinoma compared to normal pancreatic ducts. To evaluate the role of matriptase during development of pancreatic cancer, we studied the effects of newly designed matriptase inhibitors on the processing of the zymogen of urokinase-type plasminogen activator in the human adenocarcinoma cell lines AsPC-1 and BxPC-3. In both cell lines, at 1 microM, all matriptase inhibitors completely prevented zymogen activation. At lower inhibitor concentrations, the degree of inhibition of zymogen processing correlated with the affinities of the inhibitors towards matriptase indicating that this is a specific result of matriptase inhibition. Furthermore, matriptase inhibitors reduced the phosphorylation of the HGF receptor/cMet and the overall cellular invasiveness of the human pancreatic adenocarcinoma cell line AsPC-1. Our findings demonstrate for the first time that matriptase may be involved in the progression of pancreatic ductal adenocarcinoma and that matriptase inhibition may contribute to preventing the progression of this devastating disease.
Uhland
Kerstin
K
The Medicines Company (Leipzig) GmbH, D-04103 Leipzig, Germany.
Siphos
Bence
B
Arkona
Christoph
C
Schuster
Maj
M
Petri
Bernhard
B
Steinmetzer
Peter
P
Mueller
Friedemann
F
Schweinitz
Andrea
A
Steinmetzer
Torsten
T
Van De Locht
Andreas
A
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D010183:Pancreatic Ducts / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D012697:Serine Endopeptidases / Q000032:analysis / Q000502:physiology*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D015842:Serine Proteinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D012697:Serine Endopeptidases; C485595:matriptase