Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas
Article first published online: 30 DEC 2003
Copyright © 2001 American Association for the Study of Liver Diseases
Volume 34, Issue 1, pages 82–88, July 2001
How to Cite
Théret, N., Musso, O., Turlin, B., Lotrian, D., Bioulac-Sage, P., Campion, J.-P., Boudjéma, K. and Clément, B. (2001), Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas. Hepatology, 34: 82–88. doi: 10.1053/jhep.2001.25758
- Issue published online: 30 DEC 2003
- Article first published online: 30 DEC 2003
- Manuscript Accepted: 5 APR 2001
- Manuscript Received: 26 SEP 2000
- Institut National de la Santé et de la Recherche Médicale, the Secrétariat d'Etat à la Santé (programme PHRC 1997, DRC Bretagne) and the Association pour la Recherche contre le Cancer (Paris, France).
Matrix metalloproteinase-2 (MMP2) is a key enzyme in the process of extracellular matrix remodeling involved in tumor invasion and metastasis. The activation of MMP2 involves interplay with the membrane type-matrix metalloproteinase-1 (MT1-MMP) and the tissue inhibitor of metalloproteinase-2 (TIMP2). In vitro, activated hepatic stellate cells are a main source of MMP2 and collagen I induces MMP2 activation. The steady-state mRNA levels of MMP2, MT1-MMP, TIMP2, collagen I, collagen IV, and laminin γ1 were compared with MMP2 activity in 55 hepatocellular carcinomas, 47 matching nontumor biopsies and 19 histologically normal livers. In hepatocellular carcinomas, increased collagen I mRNA levels were strongly associated with those of MMP2 (Spearman R = .74, P < .001), MT1-MMP (R = .65, P < .001) and TIMP2 (R = 0.61, P < .001). MMP2 activity was correlated with the mRNA expression of collagen I (R = .45 P < .01), collagen IV (R = .40, P < .01) and laminin γ1 (R = .33, P < .05). Unlike collagen IV and laminin γ1 mRNAs, MMP2, MT1-MMP, TIMP2, collagen I mRNA levels were increased in nonencapsulated compared with encapsulated tumors (P < .05). In addition, MMP2 activity was fourfold higher (P < .01) in tumors arising in cirrhotic livers than in those arising in noncirrhotic livers. Moreover, tumor recurrence was associated with 4.6- and 2.8-fold (P < .05) higher collagen I and MMP2 mRNA levels, respectively, in hepatocellular carcinomas arising in cirrhotic livers. Thus, a high extracellular matrix remodeling favors tumor progression in hepatocellular carcinomas.