Reference SummaryTakagi H, Cancer Res 1992 Oct 1;52(19):5171-7

Title

Molecular and genetic analysis of liver oncogenesis in transforming growth factor alpha transgenic mice.

Authors

Takagi H; Sharp R; Hammermeister C; Goodrow T; Bradley MO; Fausto N; Merlino G

Journal

Cancer Res

Volume

Issue

Year

1992

Pages

5171-7

Abstract

Overexpression of a transforming growth factor alpha (TGF-alpha) transgene induced the development of liver tumors in 69 of 93 (74%) adult male mice. To identify factors associated with oncogenesis, liver tumors from transgenic animals were characterized at the molecular level. TGF-alpha RNA transcripts were elevated in 17 of 25 (68%) liver tumors, relative to adjacent nontumorous tissue. Expression of the endogenous c-myc and insulin-like growth factor II genes was enhanced in 7 of 19 (37%) and 12 of 16 (75%) tumors, respectively. In contrast, epidermal growth factor receptor RNA levels were unchanged or reduced in all liver tumors, and mutations were not detected in either the Ha-ras or Ki-ras genes. The occurrence of liver tumors in castrated TGF-alpha transgenic mice was reduced about 7-fold, while in ovariectomized transgenic animals the incidence was increased about 6-fold. The progeny of a cross between CD1-derived TGF-alpha transgenic (MT42) and C57BL/6 mice exhibited no reduction in tumor burden (83%); however, the incidence of tumor formation in MT42 x FVB/N offspring was substantially lower (19%). We conclude that in these transgenic mice TGF-alpha promotes tumor formation and appears to play a major role in tumor progression. Moreover, other factors that may collaborate in TGF-alpha-induced hepatocarcinogenesis include c-myc, insulin-like growth factor II, sex hormones, and the genetic background upon which the transgene operates.

Links

J:2578 – MGI References
1394122 – National Library of Medicine/PubMed

Strain Notes

Strain	Note
B6;CD-1-Tg(MtTGFA)42Lmb	Hemizygous mice were used in these experiments. The genetic background of these mice is mixed C57BL/6J and CD-1. Transgenic mice on a CD-1 background had been backcrossed 2 times to C57BL/6.
C57BL/6J	Inbred mice from the Jackson Laboratory.
CD-1-Tg(MtTGFA)42Lmb	Results were combined for transgenic mice that were either hemizygous or homozygous. The transgene was expressed in the liver of both intact and castrated mice.
FVB;CD-1-Tg(MtTGFA)42Lmb	Hemizygous mice. The genetic background of these mice is mixed C57BL/6J and FVB/NHsd.

Models
Strain	Model Name	Treatment Agent(s)	Organ Affected	Frequency
CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular adenoma		Liver	observed
CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular adenoma	ZnSO4 castration	Liver	10
CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular adenoma	(see notes)	Liver	very low
CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular carcinoma		Liver	observed
CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular carcinoma	ZnSO4	Liver	0 - 43
CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular carcinoma	ZnSO4 castration	Liver	0
CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular carcinoma	(see notes)	Liver	0
CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular carcinoma	ZnSO4 testosterone ovariectomy	Liver	50
CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular carcinoma	ZnSO4 ovariectomy	Liver	14
B6;CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular carcinoma		Liver	67
FVB;CD-1-Tg(MtTGFA)42Lmb	Liver hepatocellular carcinoma	(see notes)	Liver	0
CD-1-Tg(MtTGFA)42Lmb	Liver tumor	(see notes)	Liver	very low - 74
CD-1-Tg(MtTGFA)42Lmb	Liver tumor	ZnSO4	Liver	11 - 86
CD-1-Tg(MtTGFA)42Lmb	Liver tumor		Liver	62
CD-1-Tg(MtTGFA)42Lmb	Liver tumor	ZnSO4 castration	Liver	10
CD-1-Tg(MtTGFA)42Lmb	Liver tumor	ZnSO4 ovariectomy	Liver	57
CD-1-Tg(MtTGFA)42Lmb	Liver tumor	ZnSO4 testosterone ovariectomy	Liver	67
CD-1	Liver tumor	(see notes)	Liver	0 - 4.8
CD-1	Liver tumor	ZnSO4	Liver	0
CD-1	Liver tumor	ZnSO4 castration	Liver	0
CD-1	Liver tumor	ZnSO4 ovariectomy	Liver	0
CD-1	Liver tumor	ZnSO4 testosterone ovariectomy	Liver	0
B6;CD-1-Tg(MtTGFA)42Lmb	Liver tumor		Liver	83
FVB;CD-1-Tg(MtTGFA)42Lmb	Liver tumor	(see notes)	Liver	19
FVB/NHsd	Liver tumor		Liver	0
C57BL/6J	Liver tumor		Liver	low