Association of E-cadherin, matrix metalloproteinases, and tissue inhibitors of metalloproteinases with the progression and metastasis of hepatocellular carcinoma.
Molecular markers can provide additional information to traditional histomorphological evaluation for the assessment of tumor progression and predicting the likelihood of invasion and metastasis in various types of malignancies. We studied the association of E-cadherin, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinase with the progression and metastasis of hepatocellular carcinoma. Tissue microarray including six normal livers, 14 cirrhotic livers, 39 macroregenerative nodules, 16 dysplastic nodules, 22 grade I hepatocellular carcinomas, 43 grade II hepatocellular carcinomas, seven grade III hepatocellular carcinomas, and 10 metastatic hepatocellular carcinomas were stained immunohistochemically with antibodies against MMPs -1, -2, -3, -7, -9, tissue inhibitors of metalloproteinase-1, -2, -3, and E-cadherin. The intensities of staining were scored manually by two pathologists and verified by the Chromavision Automated Cellular Imaging System. Compared with normal liver, cirrhotic liver had significantly lower E-cadherin and tissue inhibitors of metalloproteinase-1 but higher MMP-1 and -7, which suggest a more favorable environment for tumor invasion and metastasis. Grade I and grade II hepatocellular carcinomas demonstrated high E-cadherin and decreased MMP-3 and -9, which may explain the rarity of extrahepatic metastasis in low-grade hepatocellular carcinomas despite the high circulatory volume of the liver. The histological progression from dysplastic nodule to well-differentiated hepatocellular carcinoma and to less differentiated tumors was associated with a gradual decrease in tissue expression of E-cadherin, tissue inhibitors of metalloproteinase-2 and -3. Metastatic hepatocellular carcinomas showed significantly lower level of tissue inhibitors of metalloproteinase-1, -2, -3 but higher level of MMP-7. These data suggest that tissue expression of E-cadherin, certain MMPs, and tissue inhibitors of metalloproteinases could be useful markers to predict the progression and metastasis of hepatocellular carcinoma.
Gao
Zu-hua
ZH
Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, AB, Canada. zu-hua.gao@cls.ab.ca
Tretiakova
Maria S
MS
Liu
Wen-hua
WH
Gong
Can
C
Farris
Peter D
PD
Hart
John
J
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000032:analysis*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000032:analysis; D019278:Matrix Metalloproteinase 3 / Q000032:analysis; D020783:Matrix Metalloproteinase 7 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000032:analysis*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis*
D015820:Cadherins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1