Differential expression of matrix metalloproteinase (MMP)-2, MMP-9, and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma: implications for tumor progression and clinical prognosis

Clin Cancer Res. 2000 Jul;6(7):2726-34.

Abstract

In the present study, we used in situ hybridization to study 36 primary hepatocellular carcinomas (HCCs) and 35 pancreatic adenocarcinomas to analyze the expressions of membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-2, and MMP-9 mRNAs. In HCCs, MT1-MMP mRNA was mainly expressed by cancer cells and to a lesser extent by stromal cells. MMP-2 mRNA was expressed predominantly by cells of tumor stroma, whereas MMP-9 mRNA was seen mainly in neoplastic epithelial cells. In pancreatic adenocarcinomas, MT1-MMP and MMP-9 mRNA were seen at moderate levels both in cancer and in stromal cells, whereas MMP-2 mRNA was predominantly expressed by the tumor stroma. Antigens of MMP-2, MMP-9, and MT1-MMP immunolocalized to the neoplastic epithelium and to the stromal cells in both tumor types. In gelatin zymography, increased amounts of latent and active MMP-2 were found in tumor samples of HCC as compared with adjacent nontumorous liver tissue. On the other hand, the latent form of MMP-9 was found in almost equal amounts both in tumor and normal liver samples, but its active form was present only in HCC. Expression of MT1-MMP mRNA had a tendency to be associated with a lower degree of differentiation in HCC, but such association was not noticed in pancreatic tumors. Correlation to the clinical data showed that MT1-MMP expression had a strong statistical association with a poor outcome of patients (P < 0.01). A similar tendency was also observed in pancreatic adenocarcinomas, but the association did not reach statistical significance. MMP-2 and MMP-9 mRNA expression did not have significant correlation with prognosis. The results of this study support the previous suggestions of the importance of MT1-MMP for malignant growth and indicate that increased MT1-MMP mRNA expression by tumor cells in HCCs and pancreatic adenocarcinomas may have prognostic significance.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / enzymology
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / mortality
  • Adenocarcinoma / pathology
  • Adolescent
  • Aged
  • Aged, 80 and over
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Child
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Humans
  • Immunohistochemistry
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Male
  • Matrix Metalloproteinase 2 / analysis
  • Matrix Metalloproteinase 2 / genetics*
  • Matrix Metalloproteinase 9 / analysis
  • Matrix Metalloproteinase 9 / genetics*
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases / analysis
  • Metalloendopeptidases / genetics*
  • Middle Aged
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • RNA, Messenger / genetics
  • Stromal Cells / enzymology
  • Stromal Cells / pathology
  • Survival Rate
  • Transcription, Genetic

Substances

  • RNA, Messenger
  • Matrix Metalloproteinases, Membrane-Associated
  • Metalloendopeptidases
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9