A Mouse Model of Hepatocellular Carcinoma

Abstract

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.

FGF19-induced Hepatocyte Proliferation Is Mediated through FGFR4 Activation

“…In the case of FGF19, hepatocellular carcinoma (HCC) formation was observed in transgenic mice overexpressing FGF19 in skeletal muscle (10). In addition, increases in the proliferation of pericentral hepatocytes, as measured by enhanced BrdU labeling, was observed both in FGF19 transgenic animals and wild-type mice administered recombinant FGF19 (10).…”

“…In the case of FGF19, hepatocellular carcinoma (HCC) formation was observed in transgenic mice overexpressing FGF19 in skeletal muscle (10). In addition, increases in the proliferation of pericentral hepatocytes, as measured by enhanced BrdU labeling, was observed both in FGF19 transgenic animals and wild-type mice administered recombinant FGF19 (10). Because constitutive hepatocellular proliferation may be a prerequisite for transformation (11), it is interesting to note that cell lineage analysis of FGF19-induced tumors suggests that dysplastic and neoplastic hepatocytes originated adjacent to central veins, where increased proliferation was localized as determined by BrdU labeling (10).…”

“…Because constitutive hepatocellular proliferation may be a prerequisite for transformation (11), it is interesting to note that cell lineage analysis of FGF19-induced tumors suggests that dysplastic and neoplastic hepatocytes originated adjacent to central veins, where increased proliferation was localized as determined by BrdU labeling (10). These results suggest that FGF19 induced hepatocyte proliferation may ultimately lead to HCC formation (10). FGFR4 has been proposed to play a role in the observed induction of hepatocyte proliferation and carcinogenesis by FGF19 (10); however, contradicting evidence proposing a protective role for FGFR4 in suppressing hepatoma progression has also been proposed (12).…”

The Crystal Structure of Fibroblast Growth Factor (FGF) 19 Reveals Novel Features of the FGF Family and Offers a Structural Basis for Its Unusual Receptor Affinity,

“…FGF19 is located on a region of chromosome 11 that has been linked to the rare disorder osteoporosis pseudoglioma syndrome, consistent with FGF19 expression in the fetal muscle and cartilage. FGF19 is upregulated in one human colon cancer cell line (34), and ectopic expression of FGF19 in murine skeletal muscle can lead to cancer formation (36). Perhaps the most intriguing observation is that the ectopic expression of FGF19 under the control of the myosin light chain promoter leads to chronic weight loss in the mice, even in genetic backgrounds where obesity is the expected phenotype.…”

Mechanism of Action of Determining Target Cell Specificity of Endocrine FGF : Regulation by Sulfated Glycosaminoglycans

“…It is intriguing that hFGF19 expression is elevated in the cancerous tissue of some patients with liver cancer, colon cancer, and lung cancer (17)(18)(19)(20)(21)(22) and some cancers show up-regulation of hFGFR4. In this paper, we suggest that sGAG-assisted hFGF19 activity at blood levels is different from that at higher levels.…”