Induction of apoptosis in mouse liver adenoma and carcinoma in vivo by transforming growth factor-?1

Chabicovsky, Monika; Wastl, Ute; Taper, Henryk; Grasl‐Kraupp, Bettina; Schulte‐Hermann, Rolf; Bursch, Wilfried

doi:10.1007/s00432-003-0460-8

Cited by 16 publications

(11 citation statements)

References 52 publications

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“…It also explains the slow growth of hepatocellular tumors in DEN-treated rodent models, that, as in the present study, are not further manipulated to promote tumor initiation and growth (1,2). Similarly to proliferation, apoptosis in hepatocellular adenomas of mice has also been reported to be as low as 0.02 to 0.44% regardless of mouse strain and induction of carcinogenesis protocol (29,(31)(32)(33). The results of caspase-3 specific IHC performed in the present study further confirm that apoptosis in mouse hepatocellular adenomas is rather rare.…”

Section: Discussionmentioning

confidence: 53%

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

et al. 2017

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Abstract. Recent evidence has suggested that downregulation of the Wnt/β-catenin signaling pathway may contribute to the development and growth of HCC. Consequently, elements of this pathway have begun to emerge as potential targets for improving outcomes of anti-HCC. Thus, the present study sought to examine the effects of Wnt-1 blockade using the classical diethylnitrosamine (DEN)-induced chemical carcinogenesis mouse model of HCC. The depletion of Wnt-1 using neutralizing antisera was done for ten consecutive days at the age of 9 months and mice were examined for the following 20 days. At that time, DEN-treated mice had multiple variably-sized hepatic cell adenomas. Anti-Wnt-1 was particularly potent in suppressing the expression of critical elements of the Wnt/β-catenin signaling pathway, such as β-catenin and Frizzled-1 receptor, however, not Dickkopf-related protein 1. This effect co-existed with the suppression of Cyclin D1, FOXM1, NF-κΒ and c-Jun commensurate with proliferation and apoptosis blockade in hepatocellular adenomas, and reduced Bcl-2 and c-Met in the serum of mice. Nonetheless, tumor size and multiplicity were found to be unaffected, suggesting that apoptosis may be equally important to proliferation in the context of counteracting DEN induced hepatocellular adenomas of mice.

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Section: Discussionmentioning

confidence: 53%

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

et al. 2017

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“…Furthermore, TGF‐β1 is shown to induce apoptosis in several human HCC cell lines (30). Chabicovsky et al (31) suggested that during chemically induced liver carcinogenesis in B6C3F1 mice, basal rates of apoptosis in adenoma and carcinoma are higher than that in normal liver and can be further increased by direct injection of TGF‐β1 into the tail vein. Carillo et al demonstrated that IFN‐α2b administration significantly decreased both the number and the volume percentage of altered hepatitis foci by an induced programmed cell death in the foci.…”

Section: Discussionmentioning

confidence: 99%

Chemopreventive effect of selenium and Chinese medicinal herbs on N‐nitrosobis(2‐oxopropyl)amine‐induced hepatocellular carcinoma in Syrian hamsters

Lee¹,

Hsu²,

Wang³

et al. 2008

Liver International

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Background/Aims: Oxidative DNA damage by reactive oxygen species is involved in the process of liver carcinogenesis. To test the hypothesis that a remedy containing Scutellaria baicalensis Georgi (Sb) and Bupleurum scorzonerifolfium Willd (Bs) (Sb/Bs remedy) modulates hepatic neoplastic growth, BOP (Nnitrosobis(2-oxopropyl)amine)-induced liver cancers in hamsters were established. Methods: Parameters such as survival rate, tumour area, tumour foci, 8-hydroxydeoxyguanosine (8-OHdG), caspase-3, transforming growth factor (TGF-b1) and tumour necrosis factor-a (TNF-a) were measured after Sb/Bs remedy treatment during BOP-induced carcinogenesis. Results: The results showed that the Sb/Bs remedy and its constituents Sb and Bs suppressed the tumour area in BOP-induced liver tumours. Because selenium (Sel) is toxic at a high dose (10 mg/kg), with a low survival rate (0%), the combination of Sb/Bs remedy and low-dose Sel (1 mg/kg) was found to decrease the tumour area and the number of tumour foci while increasing serum TNF-a and TGF-b1, but not IL-6 levels. Besides, the Sb/Bs remedy, when combined with low-dose Sel, not only decreased the expression of 8-OHdG and increased caspase-3 expression within the glutathione S-transferase placental form-positive tumour foci but also increased tumour apoptosis in BOP-induced hamsters. Conclusions: We conclude that low-dose Sel has a chemoprevention effect on BOP-induced liver tumours and such an effect was more enhanced when combined with Sb/Bs treatment.Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

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“…2A). In comparison, an apoptotic incidence of less than 0.01% is typically observed in the vertebrate liver, such as in mice [36] as well as in rats and humans [37,38]. Thus, our observation (supported by preliminary additional data regarding the cell proliferation rate [R. Dallinger et al, unpublished data]) gives some evidence for an elevated cell renewal rate in snail hepatopancreas under physiological conditions, comparable only with the increased levels of cell turnover reported for proliferating digestive organs in vertebrates, such as the intestine of young rats [39].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of cadmium toxicity in terrestrial pulmonates: Programmed cell death and metallothionein overload

Chabicovsky

Klepal

Dallinger

2004

Enviro Toxic and Chemistry

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A sublethal dose of cadmium (Cd2+) administered via the diet during short-term exposure over 10 d induced programmed cell death in the hepatopancreas of the terrestrial pulmonate snail Helix pomatia. Condensed cell residues were predominantly phagocytosed by calcium cells, suggesting a specific function of these epithelial cells in metal detoxification or in clearing the organ of cellular debris from cell death. The considerable cell loss recorded by histological analysis was accompanied by enhanced cell proliferation. Intoxication with Cd was further associated with the pronounced abundance of residual bodies, predominantly recorded in excretory cells, and with pathological changes in the endoplasmic reticulum. During long-term Cd exposure, mortality increased with increasing Cd concentrations in the diet, as demonstrated by feeding experiments in the laboratory. Lethal effects of Cd appeared to be correlated with Cd overloading of the Cd-specific metallothionein isoform (Cd-MT), isolated and characterized previously from the animal's hepatopancreas. Stoichiometric analysis shows that the capacity of Cd-MT to bind six molar equivalents of Cd corresponds to a tissue Cd concentration of approximately 4 micromol/g dry weight. At this tissue concentration, all high-affinity metal-binding sites of Cd-MT are occupied by Cd2+. Cadmium exposure beyond this level gives rise to progressive destabilization of Cd-MT cluster structure in vitro, resulting in increasing proportions of weakly bound, or even unbound, Cd2+ ions. Our results suggest that in vivo, the observed overburdening of Cd-MT with Cd2+ reduces the viability of affected animals.

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Induction of apoptosis in mouse liver adenoma and carcinoma in vivo by transforming growth factor-?1

Abstract: These observations indicate that during chemically induced liver carcinogenesis in B6C3F1 mice basal rates of apoptoses in adenoma and carcinoma are higher than in normal liver and can be further increased by a proapoptotic cytokine.

Cited by 16 publications

References 52 publications

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

Effects of Wnt‑1 blockade in DEN‑induced hepatocellular adenomas of mice

Chemopreventive effect of selenium and Chinese medicinal herbs on N‐nitrosobis(2‐oxopropyl)amine‐induced hepatocellular carcinoma in Syrian hamsters

Mechanisms of cadmium toxicity in terrestrial pulmonates: Programmed cell death and metallothionein overload

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