In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis

Musso, Orlando; Théret, Nathalie; Campion, Jean‐Pierre; Turlin, Bruno; Milani, Stefano; Grappone, Cecilia; Clément, Bruno

doi:10.1016/s0168-8278(97)80425-4

Cited by 78 publications

(71 citation statements)

References 28 publications

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“…Clinical evidences show MMP2 activity was much higher in tumors arising in cirrhotic livers than in those arising in noncirrhotic livers (Théret et al, 2001). By in situ detection, the striking density of MMP2(þ)/TIMP2(þ)/antialphaSM(þ) stellate-shaped cells in the perisinusoidal space adjacent to liver tumors suggested that HSCs, upon differentiation to myofibroblasts, may contribute to the dissemination of liver metastases through the sinusoidal network (Musso, et al, 1997).…”

Section: Role Of Hsc In Hcc Developmentmentioning

confidence: 99%

Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

Wang

Cheng

Gao

et al. 2010

The Anatomical Record

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Almost 80% of hepatocellular carcinoma (HCC) cases are associated with chronic hepatitis and cirrhosis resulting from inflammation and fibrosis. A three-step process of ''inflammation-fibrosis-carcinoma'' is believed to be involved in hepatocarcinogenesis. The activation of hepatic stellate cells (HSCs) may serve as an important mediator in the process of inflammation-fibrosis-carcinoma axis, even in tumor metastasis. A remarkable knowledge of activated HSCs in the pathology of HCC development is mostly focused on the liver fibrosis. The molecular links that connects inflammation and cancer in the activation of HSC are not completely known. This highlights urgent need to increase our understanding of the cellular and molecular mechanisms, by which activation of HSCs is involved in the hepatic inflammation, carcinogenesis, and metastasis.

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Section: Role Of Hsc In Hcc Developmentmentioning

confidence: 99%

Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

Wang

Cheng

Gao

et al. 2010

The Anatomical Record

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“…These changes could occur in a variety of cellular genes leading to escape from normal cellular and environmental controls. So far, over 20 cellular genes down-or up-regulated or mutated in HCC such as ras (Ogata et al, 1991;Kim et al, 2001), c-myc, c-fos, and c-jun (Kawate et al, 1999;Yuen, et al, 2001), rho (Genda et al, 1999), TGFa (Chung et al, 2000), HGF and c-met (Ueki et al, 1997), c-erbB-2 (Collier et al, 1992), IGF-II (Takeda et al, 1996), u-PA (de Petro et al, 1998), MXR7 (Hsu et al, 1997), MDM2 (Endo et al, 2000), MAGE (Tahara et al, 1999), matrix metalloproteinase (Musso et al, 1997), Smads (Yakicier et al, 1999), p53 (Shimizu et al, 1999;Rashid et al, 1999), pRB Santoni-Rugiu et al, 1998), p16INK4 Liew et al, 1999), p21 WAF1/CIP1 , p27 Kip1 (Chen et al, 2000;Tannapfel et al, 2000), PTEN (Fujiwara et al, 2000;Yao et al, 1999), E-cadherin ), beta-catenin (de La Coste et al, 1998 and AXIN1 (Satoh et al, 2000) have been described in humans and mice. Many of them are involved in deregulation of intracellular signal transduction and cell cycle, leading eventually to an uncontrolled proliferation of cancerous cells.…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning and characterization of a novel gene which is highly expressed in hepatocellular carcinoma

et al. 2002

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To gain new insight into the molecular mechanism underlying the pathogenesis of human primary hepatocellular carcinoma (HCC), we searched for HCC-specific molecules through screening genes that are differentially expressed between cancerous and noncancerous counterparts of liver and identified a novel HCC-associated gene, HCCA1 encoding a *80 kDa cytoplasmic protein that contains several proline-rich motifs likely for SH3-binding. HCCA1 transcript, albeit present in some adult tissues, is up-regulated selectively in HCC but not in other tumor cells. High expression of HCCA1 occurs as a late event frequently (89.2%) in HCCs and correlated significantly with the degree of tumor progression. When treated with antisense oligonucleotides to HCCA1, HCCA1 expression in HCC cells (HuH-7) was effectively suppressed and cell growth was down-regulated in a time-and dose-dependent manner. Furthermore, HuH-7 cells harboring the HCCA1 antisense expression clone displayed a remarkably reduced efficiency in colony formation. Together, these data strongly suggest that HCCA1 is a positive effector in cell proliferation and contributes to HCC carcinogenesis and progression. We believe that this protein will serve as a novel useful marker for HCC and is a potential target for pharmaceutical intervention of this malignant disease.

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“…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, hepatic stellate cells (HSC) play a central role in both synthesis and degradation of ECM components; on fibrogenic stimuli, HSC proliferate, become activated, secrete abundant extracellular matrix proteins, including collagen I, 13 and express MMP2 [14][15][16] at high levels. We have recently shown that extracellular matrix deposition induces activation of the pro-MMP2, secreted by human activated hepatic stellate cell cultures, 15 this process being related to collagen I.…”

mentioning

confidence: 99%

“…Specificity of all probes was previously shown by northern blot analyses. 12,[15][16][17] The optimization parameters of mRNA detection, to ensure analyses within the linear range, included cDNA probe concentration and specific activity, stringency washings, exposure time, film processing, and image analysis. Results were expressed as relative mRNA amounts, normalized for differences in RNA loading by comparison with the signal obtained for 18S rRNA.…”

mentioning

confidence: 99%

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

Théret¹

2001

Hepatology

183

128

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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...

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In situ detection of matrix metalloproteinase-2 (MMP2) and the metalloproteinase inhibitor TIMP2 transcripts in human primary hepatocellular carcinoma and in liver metastasis

Cited by 78 publications

References 28 publications

Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

Molecular cloning and characterization of a novel gene which is highly expressed in hepatocellular carcinoma

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

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