A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice.
Most mouse models of hepatocellular carcinoma have expressed growth factors and oncogenes under the control of a liver-specific promoter. In contrast, we describe here the formation of liver tumors in transgenic mice overexpressing human fibroblast growth factor 19 (FGF19) in skeletal muscle. FGF19 transgenic mice had elevated hepatic alpha-fetoprotein mRNA as early as 2 months of age, and hepatocellular carcinomas were evident by 10 months of age. Increased proliferation of pericentral hepatocytes was demonstrated by 5-bromo-2'-deoxyuridine incorporation in the FGF19 transgenic mice before tumor formation and in nontransgenic mice injected with recombinant FGF19 protein. Areas of small cell dysplasia were initially evident pericentrally, and dysplastic/neoplastic foci throughout the hepatic lobule were glutamine synthetase-positive, suggestive of a pericentral origin. Consistent with chronic activation of the Wingless/Wnt pathway, 44% of the hepatocellular tumors from FGF19 transgenic mice had nuclear staining for beta-catenin. Sequencing of the tumor DNA encoding beta-catenin revealed point mutations that resulted in amino acid substitutions. These findings suggest a previously unknown role for FGF19 in hepatocellular carcinomas.
Nicholes
Katrina
K
Department of Pathology, Genentech Incorporated, South San Francisco, California 94080, USA.
Guillet
Susan
S
Tomlinson
Elizabeth
E
Hillan
Kenneth
K
Wright
Barbara
B
Frantz
Gretchen D
GD
Pham
Thinh A
TA
Dillard-Telm
Lisa
L
Tsai
Siao Ping
SP
Stephan
Jean-Philippe
JP
Stinson
Jeremy
J
Stewart
Timothy
T
French
Dorothy M
DM
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism; D004273:DNA, Neoplasm / Q000737:chemistry; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005346:Fibroblast Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; C117476:FGF19 protein, human; D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; D011994:Recombinant Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D005346:Fibroblast Growth Factors; C496371:FGFR4 protein, human; C496372:Fgfr4 protein, mouse; D051499:Receptor, Fibroblast Growth Factor, Type 4; D001973:Bromodeoxyuridine