Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas

被引:187
作者
Théret, N
Musso, O
Turlin, B
Lotrian, D
Bioulac-Sage, P
Campion, JP
Boudjéma, K
Clément, B
机构
[1] Univ Rennes 1, INSERM, U456, Detoxicat & Tissue Repair Unit, F-35043 Rennes, France
[2] Hop Pontchaillou, Serv Anat Pathol B, Rennes, France
[3] Hop Pellegrin, Serv Anat Pathol, F-33076 Bordeaux, France
关键词
D O I
10.1053/jhep.2001.25758
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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-l (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 yl 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), MTI-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 gamma1 (R = .33, P < .05). Unlike collagen IV and laminin gamma1 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.
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页码:82 / 88
页数:7
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