TIMP-1 overexpression in pancreatic cancer attenuates tumor growth, decreases implantation and metastasis, and inhibits angiogenesis

J Surg Res. 2002 Jan;102(1):39-44. doi: 10.1006/jsre.2001.6318.

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.

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Division
  • Gene Expression*
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Liver Neoplasms / prevention & control
  • Liver Neoplasms / secondary
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis / prevention & control*
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / prevention & control*
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology*
  • RNA, Messenger / analysis
  • Tissue Inhibitor of Metalloproteinase-1 / analysis
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*
  • Tissue Inhibitor of Metalloproteinase-1 / physiology
  • Transfection
  • Tumor Cells, Cultured

Substances

  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1