title: Tissue Inhibitor of Metalloproteinase-1 Is Confined to Tumor-Associated Myofibroblasts and Is Increased With Progression in Gastric Adenocarcinoma.
abstract: The tissue inhibitor of metalloproteinase-1 (TIMP-1) inhibits the extracellular matrix-degrading activity of several matrix metalloproteinases, thereby regulating cancer cell invasion and metastasis. Studies describing the expression pattern and cellular localization of TIMP-1 in gastric cancer are, however, highly discordant. We addressed these inconsistencies by performing immunohistochemistry and in situ hybridization analyses in a set of 49 gastric cancer lesions to reexamine the TIMP-1 localization. In addition, we correlated these findings to clinicopathological parameters. We show that strong expression of TIMP-1 protein and mRNA was observed in a subpopulation of stromal fibroblast-like cells at the periphery of the cancer lesions. In a few cases, a small fraction of cancer cells showed weak expression of TIMP-1 protein and mRNA. The stromal TIMP-1-expressing cells were mainly tumor-associated myofibroblasts. In the normal-appearing mucosa, scattered TIMP-1 protein was only found in chromogranin A positive cells. TIMP-1-positive myofibroblasts at the invasive front of the tumors were more frequently seen in intestinal than in diffuse histological subtype cases (p=0.009). A significant trend to a higher number of cases showing TIMP-1 staining in myofibroblasts with increasing tumor, node, metastasis (TNM) stage was also revealed (p=0.041). In conclusion, tumor-associated myofibroblasts are the main source of increased TIMP-1 expression in gastric cancer.
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)|Center for Research in Microscopic Structures (CIEMIC) and Cancer Research Program, Health Research Institute (INISA), University of Costa Rica, San José, Costa Rica (WA-A)
authors.forename: Warner
authors.initials: W
authors.lastname: Alpízar-Alpízar
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)|Department of Clinical Medicine, The Gade Laboratory for Pathology, University of Bergen, Bergen, Norway (ODL)|Departments of Pathology, Haukeland University Hospital, Bergen, Norway (ODL)
authors.forename: Ole Didrik
authors.initials: OD
authors.lastname: Laerum
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)
authors.forename: Ib J
authors.initials: IJ
authors.lastname: Christensen
authors.affiliation: Department of Surgical Sciences, University of Bergen, Bergen, Norway (KO)|Surgery, Haukeland University Hospital, Bergen, Norway (KO, AS)
authors.forename: Kjell
authors.initials: K
authors.lastname: Ovrebo
authors.affiliation: Department of Clinical Medicine, University of Bergen, Bergen, Norway (AS)|Surgery, Haukeland University Hospital, Bergen, Norway (KO, AS)
authors.forename: Arne
authors.initials: A
authors.lastname: Skarstein
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)
authors.forename: Gunilla
authors.initials: G
authors.lastname: Høyer-Hansen
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)
authors.forename: Michael
authors.initials: M
authors.lastname: Ploug
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Denmark (WA-A, ODL, IJC, GH-H, MP, MI)
authors.forename: Martin
authors.initials: M
authors.lastname: Illemann
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D016022:Case-Control Studies; D018450:Disease Progression; D006801:Humans; D058628:Myofibroblasts / Q000201:enzymology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1
keywords: TIMP-1; gastric cancer; immunohistochemistry; in situ hybridization; invasion; myofibroblasts; neuroendocrine cells