Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas
Howard C. Crawford, … , Lynn M. Matrisian, Steven D. Leach
Howard C. Crawford, … , Lynn M. Matrisian, Steven D. Leach
Published June 1, 2002
Citation Information: J Clin Invest. 2002;109(11):1437-1444. https://doi.org/10.1172/JCI15051.
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Matrix metalloproteinase-7 is expressed by pancreatic cancer precursors and regulates acinar-to-ductal metaplasia in exocrine pancreas

Abstract

In gastrointestinal epithelium, metaplastic conversion between predominant cell types is associated with an increased risk of neoplasia. However, the mechanisms regulating metaplastic transitions in adult epithelia are largely undefined. Here we show that matrix metalloproteinase-7 (MMP-7) is expressed not only in the majority of human pancreatic ductal adenocarcinoma specimens, but also in human pancreatic intraepithelial neoplasia and metaplastic duct lesions in human and mouse. In a mouse model of pancreatic acinar-to-ductal metaplasia, MMP-7 progressively accumulates during the metaplastic transition, resulting in a concomitant increase in solubilization of Fas ligand (FasL). Under identical conditions, mice either deficient in MMP-7 or carrying an inactive FasL gene are severely inhibited in development of progressive metaplasia and acinar cell apoptosis. Thus, MMP-7 and FasL influence the initiation and maintenance of metaplastic events in pancreatic epithelium, explaining the observed link between metaplasia and apoptosis in pancreas and other gastrointestinal tissues.

Authors

Howard C. Crawford, Charles R. Scoggins, M. Kay Washington, Lynn M. Matrisian, Steven D. Leach

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Inhibition of ductal metaplasia and acinar cell apoptosis in gld mice. (...
Inhibition of ductal metaplasia and acinar cell apoptosis in gld mice. (a) Hematoxylin and eosin staining of the pancreatic tail from a gld mouse 7 days after ductal ligation. Arrowhead indicates one of the rare metaplastic duct lesions found in these pancreata, within a region of fibrosis and inflammation. Bar, 100 μm. (b) Immunoreactivity for cleaved caspase-3 in gld pancreas 5 days after ductal ligation. Arrows indicate positively staining acinar cells. Bar, 50 μm. (c) Quantitation of percent apoptosis as indicated by staining for cleaved caspase-3, n = 5. *Significantly different from wild-type according to two-tailed unpaired Student t test (P = 0.026). (d) Immunohistochemistry for MMP-7 expression in gld pancreas 7 days after ductal ligation. Arrows indicate small intercalated ducts that stain positive for MMP-7 expression. Bar, 22 μm.