Increased Extracellular Matrix Remodeling Is Associated With Tumor Progression in Human Hepatocellular Carcinomas

Abstract

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 ␥1 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 ␥1 (R ‫؍‬ .33, P < .05). Unlike collagen IV and laminin ␥1 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. (HEPATOLOGY 2001;34:82-88.)Tumor progression depends on the interplay between transformed cells and their micro-environment, particularly the surrounding extracellular matrix (ECM). 1 The balance between synthesis and degradation of ECM components is indeed a key modulator of tumor growth and metastasis. Among the proteases involved in the turnover of ECM, matrix metalloproteinase 2 (MMP2), the type IV collagenase/gelatinase, was shown to specifically act in the process of basementmembrane remodeling related to tumor progression. 2 MMP2 is secreted as a proenzyme and the critical step of MMP2 activation occurs at the cell surface through the formation of a molecular complex involving MMP2, the membrane-type matrix metalloproteinase MT1-MMP 3 and the tissue inhibitor of MMP2, TIMP2, which promotes the binding of MT1-MMP to MMP2. 4 Thus, TIMP2 plays a dual role by acting at a high concentration as a specific inhibitor of MMP2 activation and at a low concentration as a trigger of MMP2 and MT1-MMP clustering. 5 In human livers, fibrogenesis underlies the development of HCC in at least 90% of cases and HCC is an ominous complication of cirrhosis in 30% of the patients. 6,7 However, direct relationships between fibrosis and the progression of HCC were not shown, so far. Increased expression of MMP2, tissue inhibitors of metalloproteinase (TIMP1 and TIMP2), and MT1-MMP by nonparenchymal cells were reported in fibrosis 8-9 and in HCC. [10][11][12] Indeed, hep...

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

“…Changes in the ECM composition of the liver, including increased deposition of collagen IV a1 and a2 in the space of Disse, are also characteristic of other pathological conditions of the liver such as cirrhosis (Neubauer et al, 2001;Yang et al, 2003;Zeisberg et al, 2006) and are the hallmark of the tissue-repair response of this organ. Tumor cell entry into the liver may trigger this repair process through localized tissue injury and these changes to the tumor microenvironment may, in turn, provide additional scaffolding for tumor cell adhesion and migration (Malinda and Kleinman, 1996;Habeck, 2001) and cues for cell proliferation in the otherwise tightly controlled, nonpermissive microenvironment of the liver (Bissell, 2001;Theret et al, 2001).…”

Emerging roles of ADAM and ADAMTS metalloproteinases in cancer

“…Upon the occurrence of liver injury, activated hepatic stellate cells (HSC) contribute to the inflammatory response by secretion of MMPs resulting in ECM remodelling and increased matrix deposition [135]. ADAMs are also implicated in hepatocellular carcinoma development [136].…”

18β‐glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell‐mediated immunosuppression in mice

“…It has been reported that MMP2 activity on the cell surface might facilitate HCC invasion and progression. 40,41 All these results together demonstrate that GA effectively inhibits HCC invasion in vitro and metastasis in vivo.…”