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

Bralet, Marie‐Pierre; Pichard, Virginie; Ferry, Nicolas

doi:10.1053/jhep.2002.35540

Cited by 68 publications

(47 citation statements)

References 26 publications

(33 reference statements)

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“…There are two major nonexclusive hypotheses of the cellular origin of cancer: from stem cells due to maturation arrest or from dedifferentiation of mature cells. Debate has centered on whether hepatocytes are responsible for HCCs through dedifferentiation, or whether oval cells are the prime target for malignant changes after a differential "block" [3,5] . Oval cells are possibly involved in hepatocarcinogenesis based on the followings: (1) massive existence of oval cells in an animal rodent hepatocarcinogenic model [28] ; (2) development of HCC after transformation of oval cells [8] ; and (3) occurrence of mixed hepatocellular and cholangiocarcinomatous tumors (oval cell exhibits bipotential developmental ability) [29] .…”

Section: Discussionmentioning

confidence: 99%

“…Thereafter, DEN (Sigma) was continuously administered for 12 wk through drinking water at a final concentration of 100 μg/L to induce hepatocarcinogenesis [3] .…”

Section: Diethylnitrosamine(den)-induced Hepatocarcinogenesismentioning

confidence: 99%

“…Hepatitis B or C virus can induce chronic hepatitis and potentially result in liver cirrhosis and HCC, and these viral infections are frequently seen among HCC patients [2] . However, there is no clear evidence as to which cell is directly involved in the development of HCCs [3][4][5] . Two cell lineages have been considered as candidates: the first is hepatic stem cell, and the second is mature hepatocyte.…”

Section: Introductionmentioning

confidence: 99%

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Transplanted bone marrow stromal cells are not cellular origin of hepatocellular carcinomas in a mouse model of carcinogenesis

Zheng¹,

Liu²

2008

WJG

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AIM:To investigate the malignant potential of hepatic stem cells derived from the bone marrow stromal cells (BMSCs) in a mouse model of chemical hepatocarcinogenesis. METHODS:BMSCs from male BALB/c mice were harvested and cultured, then transplanted into female syngenic BALB/ c mice via portal vein. Hepato-carcinogenesis was induced by 6 mo of treatment with diethylnitrosamine (DEN). Six months later, the liver was removed from each treated mouse and evaluated by immunohistochemistry and fluorescence in situ hybridization (FISH). RESULTS:Twenty-six percent of recipient mice survived and developed multiple hepatocellular carcinomas (HCCs). Immunohistochemically, HCC expressed placental form of glutathione-S-transferase (GST-P) and α-fetoprotein, but did not express cytokeratin 19. Y chromosome

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Section: Discussionmentioning

confidence: 99%

“…Thereafter, DEN (Sigma) was continuously administered for 12 wk through drinking water at a final concentration of 100 μg/L to induce hepatocarcinogenesis [3] .…”

Section: Diethylnitrosamine(den)-induced Hepatocarcinogenesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transplanted bone marrow stromal cells are not cellular origin of hepatocellular carcinomas in a mouse model of carcinogenesis

Zheng¹,

Liu²

2008

WJG

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“…To further examine the role of E-cadherin in hepatocarcinogenesis, we used diethylnitrosamine (DEN) to induce a hepatocyte-derived HCC [ 9 ]. CDH1 F/F mice and CDH1 Δ L mice were injected with 25 mg/kg DEN on postnatal day 14 [ 10 ].…”

Section: Loss Of E-cadherin Promotes Chemical-induced Hccmentioning

confidence: 99%

Roles of E-cadherin in Hepatocarcinogenesis

Maeda

Nakagawa

2015

Innovative Medicine

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Loss of E-cadherin function has been reported to be associated with progression and poor prognosis of liver cancer. However, the precise role of E-cadherin in liver cancer development has not been elucidated. Thus, we generated liver-specifi c E-cadherin ( Cdh1 ) knockout mice ( Cdh1 ∆ Liv ) by crossing Cdh1 fl ox/fl ox mice with albumin-Cre transgenic mice. Interestingly, Cdh1 ∆ Liv mice developed spontaneous infl ammation in the portal areas, and then developed periductal onion skin-like fi brosis, which resembled primary sclerosing cholangitis. Microarray analysis showed that expression of stem cell markers such as CD44 and Sox9, and infl ammatory cytokines such as IL-6 and TNF-α, are increased in Cdh1 ∆ Liv liver compared with Cdh1 fl ox/fl ox liver. To investigate the role of E-cadherin in the liver tumorigenesis, we crossed Cdh1 ∆ Liv mice with lox-stop-lox Kras G12D mice ( Kras + Cdh1 ∆ Liv ). Kras + Cdh1 ∆ Liv mice developed liver tumors at age 28 weeks (8/8, 100 %), whereas Kras + Cdh1 fl ox/+ mice did not develop any tumors. Histologically, these tumors were hepatocellular carcinomas with a small proportion of ductal lesions and strongly positive for progenitor cell markers such as CD44 and Sox9. Interestingly, epithelial to mesenchymal transition (EMT) was found in the tumors of Kras + Cdh1 ∆ Liv mice. We also found that diethylnitrosamine-induced tumorigenesis was signifi cantly accelerated in Cdh1 ∆ Liv mice. In summary, loss of E-cadherin in the liver leads to sclerosing cholangitis and promotes tumorigenesis. Its tumor-promoting function seemed to be caused by gain of stem cell properties as well as induction of EMT.

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“…This was established by stably labelling hepatocytes at 1 day after a two-thirds PH with β-galactosidase, using a recombinant retroviral vector containing the β-galactosidase gene; subsequent feeding with 2-acetylaminofluorene led to foci, some of which were composed of β-galactosidaseexpressing cells. Using the same labelling protocol, Bralet et al [135] observed that 18% of hepatocytes expressed β-galactosidase at the completion of regeneration after a two-thirds PH; subsequent chronic treatment with diethylnitrosamine (DEN) resulted in many HCCs, of which 17.7% of the tumours expressed β-galactosidase, leading to the conclusion that a random clonal origin of HCC from mature hepatocytes was operative in the model.…”

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

199

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

Cited by 68 publications

References 26 publications

Transplanted bone marrow stromal cells are not cellular origin of hepatocellular carcinomas in a mouse model of carcinogenesis

Transplanted bone marrow stromal cells are not cellular origin of hepatocellular carcinomas in a mouse model of carcinogenesis

Roles of E-cadherin in Hepatocarcinogenesis

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

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