Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?

Sell, Stewart

doi:10.1289/ehp.93101s515

Cited by 189 publications

(82 citation statements)

References 67 publications

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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: 94%

“…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.

429

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: 94%

mentioning

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.

429

405

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“…A probable origin of HCC from oval cells is suggested by the fact that if oval cell expansion is blocked in the CDE diet mouse model by targeting c-Kit with imatinib mesylate, then tumour formation is reduced [146]. If tumours do arise from oval/HPCs, then this would suggest a block in oval cell differentiation, a process termed 'stem cell maturation arrest' [147,148]. This hypothesis is supported by the fact that HCCs induced by a CDE diet exhibit a range of neoplastic phenotypes recapitulating stages in normal development, suggesting transitional states between bipotent oval cells and hepatocytes [149].…”

Section: Mr Alison Et Almentioning

confidence: 99%

Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Alison

Islam

Lim

2008

The Journal of Pathology

198

149

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The worldwide shortage of donor livers to transplant end stage liver disease patients has prompted the search for alternative cell therapies for intractable liver diseases, such as acute liver failure, cirrhosis and hepatocellular carcinoma (HCC). Under normal circumstances the liver undergoes a low rate of hepatocyte 'wear and tear' renewal, but can mount a brisk regenerative response to the acute loss of two-thirds or more of the parenchymal mass. A body of evidence favours placement of a stem cell niche in the periportal regions, although the identity of such stem cells in rodents and man is far from clear. In animal models of liver disease, adopting strategies to provide a selective advantage for transplanted hepatocytes has proved highly effective in repopulating recipient livers, but the poor success of today's hepatocyte transplants can be attributed to the lack of a clinically applicable procedure to force a similar repopulation of the human liver. The activation of bipotential hepatic progenitor cells (HPCs) is clearly vital for survival in many cases of acute liver failure, and the signals that promote such reactions are being elucidated. Bone marrow cells (BMCs) make, at best, a trivial contribution to hepatocyte replacement after damage, but other BMCs contribute to the hepatic collagen-producing cell population, resulting in fibrotic disease; paradoxically, BMC transplantation may help alleviate established fibrotic disease. HCC may have its origins in either hepatocytes or HPCs, and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells.

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“…4 Early models of chemical hepatocarcinogenesis in rats favored the hypothesis that HCC results from the proliferation of initiated hepatocytes, leading to sequential development of enzyme-altered foci, preneoplastic nodules, and persistent nodules that eventually lead to HCC. 1,5 However, exposure to most carcinogens also results in the proliferation of small, undifferentiated epithelial cells called oval cells.…”

Section: Evelopment Of Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Demonstration of direct lineage between hepatocytes and hepatocellular carcinoma in diethylnitrosamine-treated rats

2002

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Cellular origin of cancer: dedifferentiation or stem cell maturation arrest?

Cited by 189 publications

References 67 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 cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly

Demonstration of direct lineage between hepatocytes and hepatocellular carcinoma in diethylnitrosamine-treated rats

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