Molecular and genetic analysis of liver oncogenesis in transforming growth factor alpha transgenic mice.
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.
Takagi
H
H
Laboratory of Molecular Biology, National Cancer Institute, Bethesda, Maryland 20892.
Sharp
R
R
Hammermeister
C
C
Goodrow
T
T
Bradley
M O
MO
Fausto
N
N
Merlino
G
G
D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000235:genetics; D012739:Gonadal Steroid Hormones / Q000502:physiology; D006133:Growth Substances / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009857:Oncogenes / Q000235:genetics*; D010641:Phenotype; D012334:RNA, Neoplasm / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000235:genetics*
D004273:DNA, Neoplasm; D012739:Gonadal Steroid Hormones; D006133:Growth Substances; D012334:RNA, Neoplasm; D016211:Transforming Growth Factor alpha; D004247:DNA