Promotion of Hepatocarcinogenesis by Phenobarbital in c-myc/TGF-? Transgenic Mice

Sanders, Sean; Thorgeirsson, Snorri S.

doi:10.1002/1098-2744(200007)28:3<168::aid-mc5>3.0.co;2-e

Cited by 11 publications

(5 citation statements)

References 10 publications

(11 reference statements)

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“…Moreover, our observations further validate previous reports that MYC can cooperate with agents that modulate the liver and thereby stimulate hepatocyte proliferation. Most notably, MYC has been shown to cooperate with TGF-alpha and phenobarbital to induce accelerated tumorigenesis in the adult murine liver [37]. Our model recapitulates the latency of tumor formation associated with adult onset HCC.…”

Section: Discussionmentioning

confidence: 55%

Hepatotoxin-Induced Changes in the Adult Murine Liver Promote MYC-Induced Tumorigenesis

et al. 2008

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BackgroundOverexpression of the human c-MYC (MYC) oncogene is one of the most frequently implicated events in the pathogenesis of hepatocellular carcinoma (HCC). Previously, we have shown in a conditional transgenic mouse model that MYC overexpression is restrained from inducing mitotic cellular division and tumorigenesis in the adult liver; whereas, in marked contrast, MYC induces robust proliferation associated with the very rapid onset of tumorigenesis in embryonic and neonatal mice.Methodology/Principal FindingsHere, we show that non-genotoxic hepatotoxins induce changes in the liver cellular context associated with increased cellular proliferation and enhanced tumorigenesis. Both 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4) cooperate with MYC to greatly accelerate the onset of liver cancer in an adult host to less than 7 days versus a mean latency of onset of over 35 weeks for MYC alone. These hepatotoxin-enhanced liver tumors grossly and histologically resemble embryonic and neonatal liver tumors. Importantly, we found that MYC overexpression is only capable of inducing expression of the mitotic Cyclin B1 in embryonic/neonatal hosts or adult hosts that were treated with either carcinogen.Conclusion/SignificanceOur results suggest a model whereby oncogenes can remain latently activated, but exposure of the adult liver to hepatotoxins that promote hepatocyte proliferation can rapidly uncover their malignant potential.

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Section: Discussionmentioning

confidence: 55%

Hepatotoxin-Induced Changes in the Adult Murine Liver Promote MYC-Induced Tumorigenesis

et al. 2008

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“…For instance, growth of preneoplastic lesions, at least in early stages, has been ascribed to proliferative activity, but apoptosis was either not studied (Hanigan et al, 1988;Pereira, 1993) or did not exhibit a significant role for growth of preneoplasia (Goldsworthy and Fransson-Steen, 2002;James and Roberts, 1996;Kamendulis et al, 2001;Stevenson et al, 1999). Other studies reported apoptosis-inhibition by tumor-promoting agents (phenobarbital, peroxisome proliferators) as important determinants for tumor development in mice (James et al, 1998;Sanders and Thorgeirsson, 2000). Moreover, we have found that normal mouse hepatocytes do not undergo apoptosis as readily as rat hepatocytes in response to signals inducing regression of the liver (Bursch et al, accompanying manuscript;Chabicovsky et al, 2003;Parzefall et al, 2002).…”

mentioning

confidence: 75%

Apoptosis in Stages of Mouse Hepatocarcinogenesis: Failure to Counterbalance Cell Proliferation and to Account for Strain Differences in Tumor Susceptibility

Bursch¹,

Chabicovsky²,

Wastl³

et al. 2005

Toxicological Sciences

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C3H/He and B6C3F1 show much higher liver cancer susceptibility than C57BL/6J mice. We studied the hypothesis that this difference might result from failure of apoptosis. Hepatocarcinogenesis was induced by a single dose of N-nitrosodiethylamine (NDEA), followed by phenobarbital (PB) for up to 90 weeks. We observed (1) earlier appearance of putative preneoplastic foci (PPF), hepatocellular adenoma (HCA), and carcinoma (HCC) in C3H/He than in C57Bl/6J mice and (2) an increase of hepatocellular DNA synthesis in C3H/He and C57Bl/6J mice, compared to normal liver, via PPF and HCA to HCC. PB enhanced DNA synthesis and growth of PPF, in the C3H/He strain only, and of HCA and HCC of both strains. Apoptoses were rare in unaltered livers as well as in preneoplastic lesions, but tended to increase in HCA and HCC of both strains. PB lowered apoptotic activity in PPF of C3H/He mice, but enhanced it in HCA and HCC of C57Bl/6J mice at late stages. In conclusion, the strain difference in growth rates of PPF and tumors is largely determined by higher rates of cell proliferation in C3H/He mice, with and without promotion by PB. Moreover, in C57Bl/6J mice the promoting effect of PB was restricted to HCA and HCC and was not seen in PPF. Apoptosis was generally low and was not a major cause of the strain difference in tumor susceptibility. In contrast with rat liver, inhibition of apoptosis appears to be a minor determinant of tumor promotion in mice.

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“…Although the exact mechanism by which Smad3 deletion blocks TGF-␣ overexpression remains to be determined, it is likely that loss of Smad3 abrogates TGF-␤1-induced TGF-␣ overexpression, consequently perturbing the autoinduction of TGF-␣ expression. TGF-␣ is overexpressed in many cancer types and functions as a potent mitogen for cancer cell proliferation (61,62). In addition, TGF-␣ is a critical survival factor against apoptosis for cancer cells (37,38).…”

Section: Discussionmentioning

confidence: 99%

Smad3 Knockout Mice Exhibit a Resistance to Skin Chemical Carcinogenesis

Zhang

et al. 2004

Cancer Research

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ABSTRACT؉/؉ mice, suggesting a Smad3 gene dosage effect. Given that TGF-␤1 is a well-documented TPA-responsive gene and also has a potent chemotactic effect on macrophages, our study suggests that Smad3 may be required for TPA-mediated tumor promotion through inducing TGF-␤1-responsive genes, which are required for tumor promotion, and through mediating TGF-␤1-induced macrophage infiltration.

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Promotion of Hepatocarcinogenesis by Phenobarbital in c-myc/TGF-? Transgenic Mice

Cited by 11 publications

References 10 publications

Hepatotoxin-Induced Changes in the Adult Murine Liver Promote MYC-Induced Tumorigenesis

Hepatotoxin-Induced Changes in the Adult Murine Liver Promote MYC-Induced Tumorigenesis

Apoptosis in Stages of Mouse Hepatocarcinogenesis: Failure to Counterbalance Cell Proliferation and to Account for Strain Differences in Tumor Susceptibility

Smad3 Knockout Mice Exhibit a Resistance to Skin Chemical Carcinogenesis

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