Origin of hepatocellular carcinoma: Role of stem cells

Wu, Xiaoqing; Chen, Dan

doi:10.1111/j.1440-1746.2006.04485.x

Cited by 58 publications

(42 citation statements)

References 95 publications

(178 reference statements)

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“…We thus found that the increase in liver size induced by exposure to DDC was also enhanced in these animals compared with that in control mice. Finally, WW45 Liv-cKO mice developed tumors with a mixed (HCC/CC) phenotype, with such tumors being thought to originate from transformed oval cells (13,14,16). These tumors are thus distinct from the HCC, originating from aberrant proliferation of hepatocytes, that was observed in the MST1/2 conditional knockout mice (38).…”

Section: Discussionmentioning

confidence: 99%

“…However, some primary hepatomas exhibit an intermediate or combined (HCC/CC) phenotype and are thought to be derived from transformed progenitor (oval) cells or by dedifferentiation of mature cells (10)(11)(12)(13)(14)(15)(16). Oval cells are thought to be bipotential progenitor cells that can differentiate into either hepatocytes or ductal cholangiocytes but do so only if proliferation of hepatocytes is inhibited (17)(18)(19).…”

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confidence: 99%

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The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis

Lee

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

434

405

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Loss of Hippo signaling in Drosophila leads to tissue overgrowth as a result of increased cell proliferation and decreased cell death. YAP (a homolog of Drosophila Yorkie and target of the Hippo pathway) was recently implicated in control of organ size, epithelial tissue development, and tumorigenesis in mammals. However, the role of the mammalian Hippo pathway in such regulation has remained unclear. We now show that mice with liver-specific ablation of WW45 (a homolog of Drosophila Salvador and adaptor for the Hippo kinase) manifest increased liver size and expansion of hepatic progenitor cells (oval cells) and eventually develop hepatomas. Moreover, ablation of WW45 increased the abundance of YAP and induced its localization to the nucleus in oval cells, likely accounting for their increased proliferative capacity, but not in hepatocytes. Liver tumors that developed in mice heterozygous for WW45 deletion or with liver-specific WW45 ablation showed a mixed pathology combining characteristics of hepatocellular carcinoma and cholangiocarcinoma and seemed to originate from oval cells. Together, our results suggest that the mammalian Hippo-Salvador pathway restricts the proliferation of hepatic oval cells and thereby controls liver size and prevents the development of oval cellderived tumors.T he mammalian Hippo signaling pathway has been implicated in regulation of contact inhibition, organ size, and tumorigenesis (1-4). Such regulation is thought to be mediated by control of the expression level or localization of YAP, a major target of the Hippo pathway. YAP is overexpressed in certain mammalian cancers, and YAP transgenic mice show increased liver size and intestinal dysplasia and eventually develop liver tumors. The role of YAP in control of organ size and tumorigenesis prompted us to examine whether upstream components of the Hippo pathway indeed function to regulate YAP in this context. However, embryonic mortality (WW45 −/− , LATS2 −/− , MST1 −/− MST2 −/− , or YAP −/− ) or the absence of any overt enlargement of specific organs (LATS1 −/− ) in mice lacking such components has hampered this investigation (5-9). The generation of conditional knockout mice would thus seem to be warranted for investigation of the role of the mammalian Hippo pathway in the control of liver size and tumorigenesis.Primary liver tumors have been categorized into two major types: hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), which originate from hepatocytes and cholangiocytes, respectively. However, some primary hepatomas exhibit an intermediate or combined (HCC/CC) phenotype and are thought to be derived from transformed progenitor (oval) cells or by dedifferentiation of mature cells (10-16). Oval cells are thought to be bipotential progenitor cells that can differentiate into either hepatocytes or ductal cholangiocytes but do so only if proliferation of hepatocytes is inhibited (17-19). However, the precise mechanism responsible for regulation of oval cell proliferation and how its deregulation contributes to tumor ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis

Lee

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

434

405

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“…Three levels of cells that can respond to liver tissue renewal or damage have been verified [8][9][10]. The first is mature liver cells, also called hepatocytes.…”

Section: Populations Of Liver Stem Cellsmentioning

confidence: 99%

Stem cell research in hepatocellular carcinoma

Sun¹,

Zuo²

2008

Front. Med. China

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The traditional view that adult human liver tumors, mainly hepatocellular carcinoma (HCC), arise from mature cell types has been challenged in recent decades. The results of several studies suggest that HCC can be derived from liver stem cells. There are four levels of cells in the liver stem cell lineage: hepatocytes, hepatic stem cells/oval cells, bone marrow stem cells and hepato-pancreas stem cells. However, whether HCC is resulted from the differentiation block of stem cells and, moreover, which liver stem cell lineage is the source cell of hepatocarcinogenesis remain controversial. In this review, we focus on the current status of liver stem cell research and their roles in carcinogenesis of HCC, in order to explore new approaches for stem cell therapy of HCC.

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“…Oval cells are the stem cells of liver (Bird et al, 2008;Strick-Marchand et al, 2008;Okabe et al, 2009;Shupe et al, 2009). Recently a great deal of research suggested a positive relationship between its proliferation and the incidence of hepaticarcinoma (Alison et al, 2005;Alison et al, 2006;Wu et al, 2006). Thy-1, as a marker protein of oval cells, has recently been suggested to play a role in potential liver cancer stem cells (Dahlke et al, 2003;Ceafalan et al, 2005;Masson et al, 2006;Xu et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of Thy-1 Promotes Invasion and Metastasis of Hepatocarcinomas

Cheng

Jiang²,

Li³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Increasing evidence has revealed that thy-1 was a potential stem cell marker of liver cancer, but no data have been shown on how thy-1 regulates the pathophysiology of liver cancer, such as proliferation, apoptosis, invasion and migration. We previously demonstrated that thy-1 was expressed in about 1% of hepg2 cells, thy-1+ hepg2 cells, but not thy-1-, demonstrating high tumorigenesis on inoculation 0.5x10 5 cells per BACA/LA mouse after 2 months. In the present study, our results showed that higher expression of thy-1 occurs in 72% (36/50 cases) of neoplastic hepatic tissues as compared to 40% (20/50 cases) of control tissues, and the expression of thy-1 is higher in poorly differentiated liver tumors than in the well-differentiated ones. In addition, thy-1 expression was detected in 85% of blood samples from liver cancer patients, but none in normal subjects or patients with cirrhosis or hepatitis. There was a significant negative correlation between thy-1expression and E-cadherin expression (a marker of invasion and migraton), but not between thy-1 expression and AFP expression in all the liver cancer and blood samples. We further investigated the relationship between thy-1 and E-cadherin in liver cancer hepg2 cell line which was transfected with pReceiver-M29/thy-1 eukaryotic expression vector followed by aspirin treatment. Lower expression of E-cadherin but higher expressions of thy-1 were detected in hepg2 cells transfected with pReceiver-M29/thy-1. Taken together, our study suggested that thy-1 probably regulates liver cancer invasion and migration.

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Origin of hepatocellular carcinoma: Role of stem cells

Cited by 58 publications

References 95 publications

The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis

The Hippo–Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis

Stem cell research in hepatocellular carcinoma

Up-regulation of Thy-1 Promotes Invasion and Metastasis of Hepatocarcinomas

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