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.
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.
Department of Pathology, University of Oulu, Finland.
M
M
Määttä
Y
Y
Soini
A
A
Liakka
H
H
Autio-Harmainen
D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000293:Adolescent; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002648:Child; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000235:genetics*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000032:analysis / Q000235:genetics*; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D015996:Survival Rate; D014158:Transcription, Genetic
D012333:RNA, Messenger; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9