title: TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) are involved in pancreatic cancer progression. This study was undertaken to determine the effects of overexpression of a natural tissue inhibitor of MMP (TIMP-1) on pancreatic cancer cell growth, metastasis, and angiogenesis.
  
  
  METHODS
  A poorly differentiated human pancreatic cancer cell line (PANC-1) underwent gene transfection to overexpress TIMP-1 (CD-1 cells). One million PANC-1 or CD-1 cells were injected into 40 nude mice subcutaneously (N = 20) or orthotopically (N = 20). Mice were sacrificed at 120 days. TIMP-1 overexpression by CD-1 cells was confirmed prior to injection and after necropsy. Immunohistochemical staining was undertaken after necropsy to evaluate tumors for TIMP-1, MMP-2, apoptosis (TUNEL), and angiogenesis (CD-31).
  
  
  RESULTS
  Tumors of CD-1 cells were less likely to implant (35% vs 70%, P = 0.05) and grew to smaller size (0.5 g +/- 0.03 vs 1.5 g +/- 0.20, P < 0.001) than tumors of PANC-1 cells. As well, subcutaneous CD-1 tumors appeared later than PANC-1 tumors (45 days +/- 2.0 vs 27 days +/- 2.2, P < 0.001). Orthotopic CD-1 tumors metastasized less often than PANC-1 tumors (20% vs 60%, P < 0.05). MMP-2 expression was similar in PANC-1 and CD-1 tumors, while CD-1 tumors showed increased TIMP-1 expression, increased apoptosis, and decreased angiogenesis relative to PANC-1 tumors.
  
  
  CONCLUSIONS
  TIMP-1 overexpression reduces pancreatic cancer cell implantation, growth, metastasis, and angiogenesis, while increasing tumor apoptosis, all without altering MMP-2 production. This study demonstrates the potential role of TIMP-1 as a target in gene therapy for pancreatic cancer.
authors.affiliation: Department of Surgery, University of South Florida, Tampa, Florida 33601, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Bloomston
authors.forename: Alexis
authors.initials: A
authors.lastname: Shafii
authors.forename: Emmanuel E
authors.initials: EE
authors.lastname: Zervos
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Rosemurgy
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1