Basement Membrane Production by Hepatocytes in Chronic Liver Disease

Bianchi, Francesco; Biagini, G.; Ballardini, G.; Cenacchi, Giovanna; Faccani, A.; Pisi, E; R, Laschi; Liotta, Lance A.; Garbisa, Spiridione

doi:10.1002/hep.1840040612

Cited by 81 publications

(33 citation statements)

References 18 publications

(9 reference statements)

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“…HCC is known as an invasive cancer, with liver itself being the most frequent target of metastasis (36)(37)(38)(39). However, in HCC, tumor cells grow embedded in a microenvironment with a high content of ECM proteins, such as laminin, collagen, vitronectin and fibronectin, as a consequence of the development of cirrhosis (40). Therefore, crossing the ECM barriers by tumor cells is regarded to be particularly important for metastatic progression of HCC.…”

Section: Discussionmentioning

confidence: 99%

Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis

et al. 2008

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We searched for potential suppressors of tumor metastasis by identifying the genes that are frequently down-regulated in hepatocellular carcinomas (HCC) while being negatively correlated with clinical parameters relevant to tumor metastasis, and we report here on the identification of N-myc downstream regulated gene 2 (NDRG2) as a promising candidate. NDRG2 expression was significantly reduced in HCC compared with nontumor or normal liver tissues [87.5% (35 of 40) and 62% (62 of 100) at RNA and protein levels, respectively]. Reduction of NDRG2 expression was intimately associated with promoter hypermethylation because its promoter region was found to carry extensively methylated CpG sites in HCC cell lines and primary tumors. Immunohistochemical analysis of NDRG2 protein in 100 HCC patient tissues indicated that NDRG2 expression loss is significantly correlated with aggressive tumor behaviors such as late tumor-node-metastasis (TNM) stage (P = 0.012), differentiation grade (P = 0.024), portal vein thrombi (P = 0.011), infiltrative growth pattern (P = 0.015), nodal/distant metastasis (P = 0.027), and recurrent tumor (P = 0.021), as well as shorter patient survival rates. Ectopically expressed NDRG2 suppressed invasion and migration of a highly invasive cell line, SK-Hep-1, and experimental tumor metastasis in vivo, whereas small interfering RNA-mediated knockdown resulted in increased invasion and migration of a weakly invasive cell line, PLC/PRF/5. In addition, NDRG2 could antagonize transforming growth factor B1-mediated tumor cell invasion by specifically down-regulating the expression of matrix metalloproteinase 2 and laminin 332 pathway components, with concomitant suppression of Rho GTPase activity. These results suggest that NDRG2 can inhibit extracellular matrix-based, Rho-driven tumor cell invasion and migration and thereby play important roles in suppressing tumor metastasis in HCC.

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Section: Discussionmentioning

confidence: 99%

Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis

et al. 2008

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“…Small HCCs without a capsule are thought to grow by replacing the hepatocytes at the tumor boundary. 44,45 Therefore, the HCC SECs may be a remainder or descendants of the SECs from the nontumorous liver, at some SECs mimic capillary ECs in cirrhosis, 13,23,48 that is, capillarization of the sinusoids occurs. Hence, it may be reasonable to consider that preexisting SECs or their descendants are influenced by the tumor and show phenotypic changes, at least in the early stage of hepatocarcinogenesis.…”

Section: Laminin Was Found In the Subendothelium Of The Sinusoidsmentioning

confidence: 99%

Immunohistochemical studies on endothelial cell phenotype in hepatocellular carcinoma

et al. 1997

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and functionally from ordinary endothelia. 2,3 SECs play an To examine the phenotype of the sinusoidal endothelial important role in the receptor-mediated clearance of various cells (SECs) surrounding tumor cells and the process of capilmacromolecules from the blood, including small particulate larization in hepatocellular carcinoma (HCC), 51 primary substances. In chronic hepatitis and cirrhosis, SECs frequently undergo CD4, CD14, and/or CD32 were found on HCC SECs only in transformation into capillary ECs possessing a basement 12 well-differentiated primary HCCs showing a thin trabecumembrane and no fenestrae, i.e., capillarization, 13 and they lar or pseudoglandular tumor cell arrangement. These 12 tulose some of their phenotypic features (including FcR expresmors were smaller than those without CD4-, CD14-, and/or sion) regardless of whether sinusoidal capillarization oc-CD32-positive SECs (P õ .05). Among them, 7, 5, and 11 curs. 8,14 In hepatocellular carcinoma (HCC), the endothelia tumors were negative or only partially positive for laminin, of the sinusoids, i.e., the blood vessels surrounding tumor PAL-E Ag, and FVIIIRAg, respectively. Staining for laminin cells, is generally considered to resemble the capillary endoand PAL-E Ag showed an inverse relationship to the expresthelia, 15,16 but several studies have indicated that the sinusoision of CD4, CD14, and CD32 on HCC SECs and the tumor dal endothelia of early HCC contains Kupffer cell-like macdifferentiation. In conclusion, the phenotypes of the SECs in rophages, 17,18 and shows morphological characteristics early and well-differentiated HCC are thought to be similar intermediate between those of ordinary capillary endothelia to those of the SECs in normal liver. With progressing tumor and the sinusoidal endothelia in normal liver. 19,20 It seems dedifferentiation the HCC SECs lose the phenotypes peculiar that the phenotypes of the SECs in HCC (HCC SECs) graduto liver SECs and acquire the characteristics of capillary ECs, ally changes into that of capillary ECs with tumor progresthough both types of phenotypical change occur indepension. However, the change in the expression of the receptors dently of each other. (HEPATOLOGY 1997;26:407-415.) and adhesion molecules specifically detected on SECs are unclear. This is important for understanding not only the Hepatic sinusoidal endothelial cells (SECs) are unique biological nature of HCC SECs, which are major stromal cells endothelial cells (ECs), which possess fenestrae and no basesupporting HCC cells, but also the pathobiology of sinusoidal ment membrane, and reside together with tissue-fixed macrocapillarization. phages, i.e., Kupffer cells. 1 SECs differ both morphologicallyIn the present study, to analyze the relationship between the phenotypes of SECs and sinusoidal capillarization in

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“…Therefore, cell adhesion, migration, and proteolysis of extracellular matrix (ECM) proteins are regarded as important steps in the development of metastasis (Murphy and Gavrilovic, 1999). This seems to be particularly important in the liver, where HCC cells grow in trabecular structures that are surrounded by tissue with a high content of ECM proteins, such as laminin (Ln), Collagen (Coll), vitronectin, and fibronectin, a consequence of the development of cirrhosis (Bianchi et al, 1984). These histologic features suggest that contact between HCC cells and ECM proteins may be essential for tumor progression and metastasis.…”

mentioning

confidence: 99%

Human Hepatocellular Carcinoma (HCC) Cells Require Both α3β1 Integrin and Matrix Metalloproteinases Activity for Migration and Invasion

Giannelli

Bergamini

Fransvea

et al. 2001

Laboratory Investigation

133

134

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SUMMARY:Hepatocellular carcinoma (HCC) is the most frequent malignant tumor of the liver; prognosis depends on the tendency to metastasize. Cancer cell invasion is regulated by proteolytic remodeling of extracellular matrix components and by integrin expression. We have shown that matrix metalloproteinase-2 (MMP-2) and membrane-type-1 matrix metalloproteinase (MT1-MMP) cleave Laminin-5 (Ln-5), stimulating cell migration. Here we report that all HCC cells express MT1-MMP, migrate on Ln-1 and Collagen IV, whereas only HCC cells that express ␣3␤1 integrin secrete detectable levels of gelatinases, migrate on Ln-5, and invade through a reconstituted basement membrane (BM). Migration on Ln-5 is blocked by BB-94, an MMP inhibitor, and by MIG1, a monoclonal antibody that hinders migration on MMP-2-cleaved Ln-5. Invasion through a reconstituted BM is also inhibited by BB-94. HCC ␣3␤1-negative cells migrate on Ln-1 and Collagen IV, but not on Ln-5, and do not invade through a reconstituted BM, although they express MT1-MMP. Anti-␣3␤1 blocking antibodies inhibit gelatinase activation, cell motility, and cell invasion through Matrigel. In vivo, ␣3␤1 integrin and Ln-5 are expressed in HCC tissue but not in normal liver. In conclusion, our data suggest that both ␣3␤1 integrin and gelatinase activity are required for HCC migration and invasion. (Lab Invest 2001, 81:613-627).

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Basement Membrane Production by Hepatocytes in Chronic Liver Disease

Cited by 81 publications

References 18 publications

Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis

Functional and Clinical Evidence for NDRG2 as a Candidate Suppressor of Liver Cancer Metastasis

Immunohistochemical studies on endothelial cell phenotype in hepatocellular carcinoma

Human Hepatocellular Carcinoma (HCC) Cells Require Both α3β1 Integrin and Matrix Metalloproteinases Activity for Migration and Invasion

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