Quantitative Relationship Between Transforming Growth Factor-Alpha and Hepatic Focal Phenotype and Progression in Female Mouse Liver

Abstract

Modulations in the positive hepatocyte growth factor, transforming growth factor-alpha (TGF-α) and its receptor epidermal growth factor receptor (EGFR), occur in rat and human liver tumors. The purpose of this study was to determine if TGF-α and EGFR are altered in basophilic and acidophilic preneoplastic and neoplastic liver lesions generated in DEN-initiated mice exposed to a variety of hepatocarcinogens. Female B6C3F1 mice were initiated with N -nitrosodiethylamine (DEN) and treated with hepatocarcinogenic concentrations of unleaded gasoline vapor (2,000 ppm), methyl tertiary butyl ether vapor (7,814 ppm), phenobarbital (500 ppm, diet), or chlordane (25 ppm, diet). Hepatic foci and tumors were identified and evaluated immunohistochemically with antibodies for TGFα and EGFR. In all treatment groups, basophilic hepatic foci were negative for TGF-α immunoreactivity (554/564, 98%). In contrast, regardless of treatment, acidophilic hepatic foci were immunoreactive for TGF-α (107/108, 99%). There was no significant difference in mean hepatic labeling index as measured by the incorporation of 5-bromo-2'-deoxyuridine between foci immunoreactive and nonimmunoreactive for TGF-α. The incidence of immunoreactivity for TGF-α increased in hepatocellular tumors that were predominantly of the basophilic phenotype. Of basophilic hepatocellular adenomas, 16/81 (20%) were immunoreactive for TGF-α, while 17/29 (59%) of hepatocellular carcinomas stained positive for TGF-α. A similar increased incidence of EGFR immunoreactivity was found in basophilic hepatocellular adenomas (17/67, 25%) and carcinomas (19/28, 68%) relative to basophilic foci (11/367, 3%), suggesting an autocrine mechanism for the development of mouse liver tumors. The increased incidence of TGF-α immunoreactivity in basophilic liver tumors suggests that TGF-α is a marker of tumor progression in mouse liver. Furthermore, TGF-α modulations were dependent on phenotype rather than treatment, indicating inherent differences in the expression of TGF-α in basophilic and acidophilic hepatic lesions.

Quantitation of the Cancer Process in C57BL/6J, B6C3F1 and C3H/HeJ Mice

“…The suppressing properties of PB on foci and mass growth con rm previous observations using carcinogen-treated infant male B6C3F1 mice followed by long-term PB treatment starting at weaning (3,25). The present study further demonstrates a strain speci c hepatocarcinogenic inhibitory response to PB (23).…”

Growth Suppression of Human Hepatocellular Carcinoma Xenografts by a Monoclonal Antibody CH12 Directed to Epidermal Growth Factor Receptor Variant III

“…EGFR expression in HCC has been reported (6). EGFR expression has been suggested to contribute to the aggressive growth characteristics of HCC tumors (7)(8)(9). EGFR overexpression has been demonstrated to be positively correlated with early tumor recurrence and a negative prognostic factor in poorly differentiated HCCs (6,10).…”

Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma

“…A great variety of tumors show abnormal, enhanced and/or constitutive expression of EGFR. Several reports indicate that EGFRs are expressed frequently in HCC [5], most likely contributing to the aggressive growth characteristics of these tumors [6][7][8]. Especially in poorly differentiated HCCs, EGFR overexpression has been demonstrated to be a negative prognostic factor, since it positively correlated with early tumor recurrence [5].…”