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Carcinogenesis Advance Access published online on February 26, 2004
Carcinogenesis, doi:10.1093/carcin/bgh129
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CARCINOGENESIS

Fumonisin B1-induced hepatocellular and cholangiocellular tumors in male Fischer 344 rats: potentiating effects of 2-acetylaminofluorene on oval cell proliferation and neoplastic development in a discontinued feeding study

Eric R. Lemmer 1, Carina J. Vessey 2, Wentzel C. A. Gelderblom 3*, Enid G. Shephard 1, Dirk J. Van Schalkwyk 4, Rochelle A. Van Wijk 2, Walter F. O. Marasas 3, Ralph E. Kirsch 5, and Pauline de la M. Hall 2

1 1MRC/UCT Liver Research Center, University of Cape Town, Observatory, Cape Town, South Africa
2 2Department of Anatomical Pathology, University of Cape Town, Observatory, Cape Town, South Africa
3 3Program on Mycotoxins and Experimental Carcinogenesis (PROMEC), Medical Research Council, Tygerberg, South Africa
4 4Business Informatics, Cape Technicon, Cape Town, South Africa
5 2MRC/UCT Liver Research Center, University of Cape Town, Observatory, Cape Town, South Africa

* Corresponding author. E-mail: wentzel.gelderblom{at}mrc.ac.za.

Received 11 September 2003 ; revised 6 February 2004 ; accepted 19 February 2004

Abstract

Fumonisin B1 (FB1) is a naturally occurring mycotoxin produced by Fusarium verticillioides. Dietary exposure to FB1 has been linked to human cancer in certain parts of the world, and treatment with FB1 causes oval cell proliferation and liver tumors in rats. To study the potential role of oval (liver progenitor) cells in the cellular pathogenesis of FB1-induced liver tumors, we gave male F344 rats prolonged treatment with FB1 for 25 weeks, followed by return to control diet until 50 weeks ("stop study"). The time course of FB1-induced liver lesions were followed by examination of serial liver biopsies at set time intervals and postmortem liver tissue at the end of the study. The effects of different FB1 treatment regimens (5 weeks vs. 25 weeks), as well as the modulating effect of 2-acetylaminofluorene (2-AAF), on the kinetics of oval cell proliferation and development of liver tumors were compared. Prolonged treatment with FB1 in normal diet caused persistent oval cell proliferation and generation of both hepatic adenomas and cholangiofibromas. These liver lesions occurred in the setting of chronic toxic hepatitis and liver fibrosis/cirrhosis, similar to that seen in human hepatocarcinogenesis. Some adenomas and cholangiofibromas were dysplastic, and one postmortem liver contained a hepatocellular carcinoma. OV-6+ oval cells were noted in close relation to proliferative neoplastic liver lesions, and some of these lesions expressed OV-6, suggesting that all these cell types were derived from a common progenitor cell. 2-AAF enhanced the size of FB1-induced GSTP+ hepatocellular lesions and the incidence of cholangiofibromas in postmortem liver specimens, but this was not statistically significant. In conclusion, this study supports the involvement of dietary FB1 in liver carcinogenesis in male F344 rats. Oval cells may be the source of both the hepatocellular and cholangiocellular tumors induced by prolonged treatment with FB1. 2-AAF appears to have an enhancing effect on FB1-induced liver tumors, presumably due to its potent inhibitory effects on hepatocyte regeneration.

liver, hepatocarcinogenesis, hepatic foci, hepatic adenoma, hepatocellular carcinoma, cholangiofibroma, stem cells, liver biopsy, hepatic fibrosis, stop study
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