Genetic Instability Occurs Sooner Than Expected: Promotion, Progression and Clonality During Hepatocarcinogenesis in the Rat
The basic question of “at which point in time does genetic instability occur in the natural history of cancer” can be answered only with another question: in which organ or model? Dr. Shapiro has just given us an impressive account of her work in human malignant gliomas. We also attempted to explore the problem but in a different organ, species and model system. We found that in the rat liver treated with diethylnitrosamine (DEN) and a choline deficient (CD) diet, genomic instability expressed by aneuploidy takes place during the promotion treatment, long before hepatocarcinomas can be diagnosed (1, 2). The presence of aneuploidy implies that irreversible genetic changes, characteristic of progression, occur during dietary promotion (Fig. 1). Since increasing evidence points out that most malignant hepatomas are monoclonal in origin, this fact and the studies previously mentioned have led us to propose now a scheme of cell renewal which explains the overlapping of promotion with progression arising in the clonally replicating foci of preneoplastic populations.
KeywordsIndividual Focus Aneuploid Cell Liver Carcinogenesis Clonal Nature Choline Deficient
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- 3.C. Peraino, R. J. M. Fry, and E. Staffeldt, Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetylaminofluorene, Cancer Res. 31:1506–1512, 1971.Google Scholar
- 4.E. Scherer, and P. Emmelot, Foci of altered liver cells induced by a single dose of diethylnitrosamine and partial hepatectomy: their contribution to hepatocarcinogenesis in the rat, Eur. J. Cancer 11:145–154, 1975.Google Scholar
- 8.J. K. Reddy, M. S. Rao, and D. E. Moody, Hepatocellular carcinomas in acatalasemic mice treated with nafenopin, a hypolipidemic peroxisome proliferator, Cancer Res. 36:1211–1217, 1976.Google Scholar
- 11.T. D. Pugh, and S. Goldfarb, Quantitative histochemical and autoradiograph studies of hepatocarcinogenesis in rats fed 2-acetylaminofluorene followed by phenobarbital, Cancer Res. 38:4450–4457, 1978.Google Scholar
- 22.G. M. Williams, and K. Watanabe, Quantitative kinetics of development of N-2-fluorenylacetamide-induced, altered (hyperplastic) hepatocellular foci resistant to iron accumulation and their reversion or persistance following removal of carcinogen. J Natl. Cancer Inst. 61:113–121, 1978.PubMedGoogle Scholar
- 31.M. Esumi, T. Aritaka, M. Arii, K. Suzuki, H. Mizuo, T. Mima, and T. Shikata. Clonal origin of human hepatoma determined by integration of hepatitis B virus DNA. Cancer Res. 16:5767–5771, 1986.Google Scholar
- 46.L. Hinrichsen, S. Miron, R. Cechner, and O. Sudilovsky. Hepatocarcinogenesis in the rat: nuclear DNA content in hepatocarcinomas, Proc. Am. Assoc. Cancer Res. 31:155, 1990.Google Scholar
- 47.H. C. Pitot, and H. A. Campbell, Quantitative studies on multistage carcinogenesis in the rat. In Tumor Promoters: Biological approaches for mechanistics studies and assay system (Progr. Cancer Res. Ther. V. 34), R. Langenbach, E. Elmore, and J. Carl Barrett, eds., Raven Press, New York, 1988, pp 79–95.Google Scholar
- 51.O. Sudilovsky and T. K. Hei, Aneuploid nuclear DNA content in some enzyme-altered foci during chemical hepatocarcinognesis, Fed. Proc. 42:7, 1983.Google Scholar
- 55.J. D. Crissman and Y. S. Fu, Intraepithelial neoplasia (CIS) of the larynx. A clinicopathological study of six cases with DNA analysis, Arch. Otorinolaryngol. Head Neck Surg. 111:522–528, 1985.Google Scholar
- 58.J. W. Grisham, M.-S. Tsao, L. W. Lee, and G. J. Smith, Clonal analysis of neoplastic transformation in cultured diploid rat liver epithelial cells. In: O. Sudilovsky, L. A. Liotta, and H. C. Pitot (eds.), The Boundaries Between Promotiona nd Progression during Carcinogenesis (this volume: article and discussion), New York, Plenum Press, 1991.Google Scholar