Morphological study of vascular dissemination in a metastatic hepatocellular carcinoma model in the monkey

Lindsay, Carol K.; Sinha, C. C.; Thorgeirsson, Unnur P.

doi:10.1002/hep.510260519

Cited by 14 publications

(11 citation statements)

References 22 publications

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“…Tumor thrombi in the portal or hepatic veins (venous metastases) represent metastatic HCC cells that have acquired molecular changes that enable them to detach from the primary tumor mass, invade the blood vessel, and survive in the circulatory system. 34, 35 In this study, we performed a global expression analysis to investigate the miRNA expression changes in HCC metastasis formation by examining a series of clinical specimens consisting of 20 sets of paired nontumorous livers, primary HCCs, and venous metastases. By way of unsupervised clustering analysis, we found that the global miRNA expression profiles between tumor and nontumorous liver samples are substantially different.…”

Section: Discussionmentioning

confidence: 99%

Sequential alterations of microrna expression in hepatocellular carcinoma development and venous metastasis

Wong

Lee

et al. 2012

Hepatology

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Hepatocellular carcinoma (HCC) is a prevalent cancer with an extremely high mortality rate attributed to HCC metastasis, which is the major cause of tumor recurrence and organ failure. Presence of tumor thrombi in the portal veins (venous metastases) is a clinicopathological feature of metastatic HCCs. In this study, we analyzed the microRNA (miRNA) expression profiles of nontumorous livers, primary HCCs, and venous metastases in the same livers from 20 HCC patients by way of TaqMan low-density array (TLDA) and identified the precise alterations of miRNA expression from nontumorous livers to primary HCCs and venous metastases globally. By unsupervised clustering analysis, nontumorous livers were distinctly segregated from primary HCCs and venous metastases, whereas no discernible difference in the expression pattern could be found between primary HCCs and venous metastases. However, a marked global reduction of miRNA expression levels was detected in venous metastases, as compared with primary HCCs. These data suggest that miRNA deregulation is an early event in liver carcinogenesis and the later global miRNA down-regulation aggravates the preexisting miRNA deregulation to further promote HCC metastasis. Conclusion: Our study has enriched the current understanding of the deregulation of miRNAs in HCC progression and highlighted the sequential and distinctive alterations of miRNA expression in primary HCC and venous metastasis formation. (HEPATOLOGY 2012;55:1453-1461 H epatocellular carcinoma (HCC), the most common primary liver cancer, is an extremely lethal disease that causes about 700,000 deaths worldwide annually.1 The high mortality rate of HCC is mainly related to intra-and extrahepatic metastasis leading to liver and extrahepatic organ failures. Although tumor resection or liver transplantation is the most efficient treatment option for HCC patients, the majority of patients are unsuitable for the operation because either metastasis has already occurred at the time of diagnosis or patients have poor liver function. Furthermore, HCC is highly recurrent and intra-hepatic metastasis is the major cause of tumor relapse after resection.2 Therefore, metastasis remains a major obstacle to HCC treatment. Understanding of the mechanisms underlying metastasis is important to the development of better diagnostic platforms and therapeutic options for HCC patients. Metastasis is a complicated disease which involves multiple steps: invasion out of the primary tumor site, intravasation, survival in the circulatory system, extravasation, and colonization at secondary site. Cancer cells that are able to accomplish these steps have higher metastatic capability due to accumulation of genetic and epigenetic alterations including microRNA (miRNA) 4 It is estimated that miRNAs regulate the expression of one-third of human genes, thereby directing a wide repertoire of biological mechanisms in cells.5 Accumulating evidence has demonstrated that miRNAs contribute to aberrant gene expression in cancer initiation and progressio...

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Section: Discussionmentioning

confidence: 99%

Sequential alterations of microrna expression in hepatocellular carcinoma development and venous metastasis

Wong

Lee

et al. 2012

Hepatology

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“…However, since it appears difficult to distinguish a small number of human HCC cells in mouse liver, they did not demonstrate how early intrahepatic invasion and metastasis of HCC occurs. Lindsay et al (1997) have shown morphological evidence of intravascular tumor growth after tumor invasion and spread through the intrahepatic portal venous system, using a monkey HCC model without cirrhosis induced by a chemical carcinogen. We have shown that HCC cells preferentially migrated to and invaded Zone 1 but not Zone 3 of normal liver, when murine HCC cells labeled with DiI were implanted orthotopically into syngeneic mice (Kuriyama et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular carcinoma in an orthotopic mouse model metastasizes intrahepatically in cirrhotic but not in normal liver

et al. 1999

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Prognosis of hepatocellular carcinoma (HCC) still remains poor mainly because of intrahepatic metastasis. In the majority of cases, HCC is found in conjunction with liver cirrhosis. It is, therefore, of great importance to investigate the invasive and metastatic behavior of HCC in cirrhotic liver. To examine this, a liver cirrhosis model was produced by injecting thioacetamide i.p. into mice. Murine HCC cells were labeled with the fluorescent carbocyanine dye, DiI, and implanted directly under the capsule of cirrhotic and normal livers of syngeneic mice. DiI‐labeled HCC cells in the liver were observed under fluorescent and confocal microscopy. Histological analysis of cirrhotic and normal livers revealed that implanted HCC cells migrated to and invaded the adjacent periportal regions, but not the adjacent centrolobular areas. This characteristic behavior of HCC was more evident in cirrhotic liver than in normal liver. Furthermore, intrahepatic metastasis to unimplanted hepatic lobes was observed in cirrhotic liver as early as 7 days after implantation, while it was not detected in normal liver even 4 weeks later. Thus, an orthotopic animal model for HCC with cirrhosis described here may be suitable for investigating the invasive and metastatic behavior of HCC. Importantly, labeling tumor cells with a fluorescent dye before orthotopic implantation may be a convenient and useful method to investigate the invasive and metastatic behavior of various types of cancer. Int. J. Cancer 80:471–476, 1999. © 1999 Wiley‐Liss, Inc.

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“…4 CD31 was also shown to be a sensitive marker in EC. 48 Among these markers, it has been reported that CD34 expression may be decreased by VEGF. 49 We thus used CD31 expression in the current study.…”

Section: Neovascularisationmentioning

confidence: 99%

Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis

Yoshiji

Kuriyama²,

Yoshii³

et al. 2003

Gut

271

228

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Background: It has been shown that expression of the potent angiogenic factor, vascular endothelial growth factor (VEGF), and its receptors, flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), increased during the development of liver fibrosis. Aims: To elucidate the in vivo role of interaction between VEGF and its receptors in liver fibrogenesis. Methods: A model of CCl 4 induced hepatic fibrosis was used to assess the role of VEGFR-1 and VEGFR-2 by means of specific neutralising monoclonal antibodies (R-1mAb and R-2mAb, respectively). R-1mAb and R-2mAb were administered after two weeks of treatment with CCl 4 , and indices of fibrosis were assessed at eight weeks. Results: Hepatic VEGF mRNA expression significantly increased during the development of liver fibrosis. Both R-1mAb and R-2mAb treatments significantly attenuated the development of fibrosis associated with suppression of neovascularisation in the liver. Hepatic hydroxyproline and serum fibrosis markers were also suppressed. Furthermore, the number of α-smooth muscle actin positive cells and α1(I)-procollagen mRNA expression were significantly suppressed by R-1mAb and R-2mAb treatment. The inhibitory effect of R-2mAb was more potent than that of R-1mAb, and combination treatment with both mAbs almost completely attenuated fibrosis development. Our in vitro study showed that VEGF treatment significantly stimulated proliferation of both activated hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC). VEGF also significantly increased α1(I)-procollagen mRNA expression in activated HSC. Conclusions: These results suggest that the interaction of VEGF and its receptor, which reflected the combined effects of both on HSC and SEC, was a prerequisite for liver fibrosis development.

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Morphological study of vascular dissemination in a metastatic hepatocellular carcinoma model in the monkey

Cited by 14 publications

References 22 publications

Sequential alterations of microrna expression in hepatocellular carcinoma development and venous metastasis

Sequential alterations of microrna expression in hepatocellular carcinoma development and venous metastasis

Hepatocellular carcinoma in an orthotopic mouse model metastasizes intrahepatically in cirrhotic but not in normal liver

Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis

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