Abstract
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.
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References
O. Sudilovsky, and T. K. Hei, Aneuploidy and progression in promoted preneoplastic foci during hepatocarcinogenesis in the rat, Cancer Lett. 56:131–135, 1991.
J. H. Wang, L. I. Hinrichsen, C. M. Whitacre, R. L. Cechner, and O. Sudi-lovsky, Nuclear DNA content of altered hepatic foci in a rat liver carcinogenesis model, Cancer Res. 50:7571–7576, 1990.
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.
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.
D. Solt, and E. Farber, A new principle of the analysis of chemical carcinogenesis, Nature 263:701–703, 1976.
H. C. Pitot, L. Barsness, T. Goldsworthy, and T. Kitagawa, Biochemical characterization of stages of hepatocarcinogenesis after a single dose of diethylnitrosamine, Nature 271:456–458, 1978.
H. Shinozuka, B. Lombardi, S. Sell, and R. M. Iammarino, Enhancement of DL-methionine-induced carcinogenesis in rats fed a choline-devoid diet, J. Natl. Cancer Inst. 61:813–817, 1978.
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.
S. Fiala, and A. E. Fiala, Acquisition of an embryonal biochemical feature by rat hepatomas. Experientia 26:889–890, 1970.
M. H. Hanigan, and H. C. Pitot, Gamma-glutamyltranspeptidase-its role in hepatocarcinogenesis, Carcinogenesis 6:165–172, 1985.
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.
S. Sell, Distribution of α-fetoprotein and albumin-containing cells in the livers of Fischer rats fed four cycles of N-2-fluorenylacetamide, Cancer Res. 38:3107–3113, 1978.
P. Bannasch, Dose-dependence of early cellular changes during liver carcinogenesis, Arch. Toxicol. Suppl 3:111–128, 1980.
K. Sato, A. Kitahara, K. Satoh, T. Ishikawa, M. Tatematsu, and N. Ito, The placental form of glutathione S-transferase as a new marker protein for preneoplasia in rat chemical hepatocarcinogenesis, Gann 75:199–202, 1984.
G. M. Williams, The pathogenesis of rat liver cancer caused by chemical carcinogens, Biochem. Biophys. Acta 605:167–189, 1980.
H. C. Pitot, H. C. Glauert, and M. Hanigan, The significance of selected biochemical markers in the characterization of putative initiated cell populations in rodent liver, Cancer Lett. 29:1–14, 1985.
R. G. Cameron, Identification of the putative first cellular step of chemical hepatocarcinogenesis, Cancer Lett. 47:163–167, 1989.
R. G. Cameron, Comparison of GST-P versus GGT as markers of hepatocellular lineage during analysis of initiation of carcinogenesis, Cancer Invest. 6:725–734, 1988.
M. A. Moore, K. Nakagawa, K. Satoh, T. Ishikawa, and K. Sato, Single GST-P positive liver cells—putative initiated hepatocytes, Carcinogenesis 8:483–486, 1987.
K. Yokota, U. Singh, and H. Shinosuka, Effects of a choline-deficient diet and a hypolipidemic agent on single glutathione S-transferase placental form-positive hepatocytes in rat liver, Jpn. J. Cancer Res. 81:129–134, 1990.
G. W. Teebor, and F. F. Becker, Regression and persistance of hyperplastic hepatic nodules induced by N-2-fluorenylacetamide and their relationship to hepatocarcinogenesis, Cancer Res. 31:1–3, 1971.
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.
K. Enomoto, and E. Farber, Kinetics of phenotypic maturation of remodelling of hyperplastic nodules during liver carcinogenesis, Cancer Res. 42:2330–2335, 1982.
M. A. Moore, H. J. Hacker, and P. Bannasch, Phenotypic instability in foci and nodular lesions induced in a short term system in the rat liver, Carcinogenesis 4:595–603, 1983.
S. Takahashi, B. Lombardi, and H. Shinozuka, Progression of carcinogen-induced foci of γ-glutamyltranspeptidase-positive hepatocytes to hepatomas in rats fed a choline-deficient diet, Int. J. Cancer 29:445–450, 1982.
A. Columbano, G. M. Ledda-Columbano, P. M. Rao, S. Rajalakshmi, and D. S. R. Sarma, Occurrence of cell death (apoptosis) in preneoplastic and neoplastic liver cells. A sequential study. Am. J. Pathol. 116:441–446, 1984.
S. Hendrich, H. P. Glauert, and H. C. Pitot, The phenotypic stability of altered hepatic foci: effects of withdrawal and subsequent readministration of phenobarbital, Carcinogenesis 7:2041–2045, 1986.
P. C. Nowell, The clonal nature of neoplasia, Cancer Cells 1:29–30, 1989.
H. M. Rabes, Th. Bücher, A. Hartmann, I. Linke, and M. Dunnwald, Clonal growth of carcinogen-induced enzyme-deficient preneoplastic cell populations in mouse liver, Cancer Res. 42:3220–3227, 1982.
W. C. Weinberg, L. Berkwits, and P. M. Iannaccone, The clonal nature of carcinogen-induced altered foci of γ-glutamyl transpeptidase expression in rat liver, Carcinogenesis 8:565–570, 1987.
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.
S. Howell, K. A. Wareham, and E. D. Williams, Clonal origin of mouse liver cell tumors, Am. J. Pathol. 121:426–432, 1985.
J. J. Yunis, Specific fine chromosomal defects in cancer: an overview. Human Pathol. 12:503–515, 1981.
N. Böhm, and W. Sandritter, DNA in human tumors: a cytophotometric study, Curr. Top. Pathol. 60:151–219, 1975.
W. Sandritter, Quantitative pathology in theory and practice, Pathol. Res. Pract. 171:2–21, 1981.
T. O. Caspersson, Quantitative tumor cytochemistry, Cancer Res. 39:2341–2355, 1979.
V. Digernes, Chemical liver carcinogenesis: monitoring the process by flow cytometric DNA measurements, Environ. Health Perspect. 50:195–200, 1983.
G. Saeter, P. E. Schwarze, J. M. Nesland, N. Juul, E. O. Pettersen, and P. O. Seglen, The polyploidizing growth pattern of normal rat liver is replaced by divisional diploid growth in hepatocellular nodules and hepatocarcinomas. Carcinogenesis 9:939–945, 1988.
Y. Koike, Y. Suzuki, A. Nagata, S. Furuta, and T. Nagata, T., Studies on DNA content of hepatocytes in cirrhosis and hepatomas by means of microspectrophotometry and radioautography. Histochem. 73:549–562, 1982.
T. Ezaki, T. Kanematsu, T. Okamura, T. Sonoda, and K. Sugimachi, DNA analysis of hepatocellular carcinoma and clinicopathologic implications. Cancer 61:106–109, 1988.
H. F. Stich, The DNA content of tumor cells. II. Alterations during the formation of hepatomas in rats, J. Natl. Cancer Inst. 24:1283–1297, 1960.
F. F. Becker, R. A. Fox, K. M. Klein, and S. R. Wolman, Chromosome patterns in rat hepatocytes during N-2-fluorenylacetamide carcinogenesis, J. Natl. Cancer Inst. 46:1261–1269, 1971.
F. F. Becker, K. M. Klein, S. R. Wolman, R. Asofsky, and S. Sell, Characterization of primary hepatocellular carcinomas and initial transplant generations, Cancer Res. 33:3330–3338, 1973.
H. Mori, T. Tanaka, S. Sugie, M. Takahashi, and G. M. Williams, DNA content of liver cell nuclei of N-2-fluorenylacetamide-induced altered foci and neoplasms in rats and human hyperplastic foci, J. Natl. Cancer Inst. 69:1277–1281, 1982.
M. Sarafoff, H. M. Rabes, and P. Dörmer, Correlations between ploidy and initiation probability determined by DNA cytophotometry in individual altered hepatic foci, Carcinogenesis 7:1191–1196, 1986.
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.
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.
C. Farber, and D. S. R. Sarma, Biology of disease. Hepatocarcinogenesis: a dynamic cellular perspective, Lab. Invest. 56:4–22, 1987.
P. C. Nowell, The clonal evolution of tumor cell populations. Science 194:23–28, 1976.
P. E. Schwarze, E. O. Petterson, M. C. Shoaib, and P. O. Seglen, Emergence of a population of small diploid hepatocytes during hepatocarcinogenesis, Carcinogenesis 5:1267–1275, 1984.
O. Sudilovsky and T. K. Hei, Aneuploid nuclear DNA content in some enzyme-altered foci during chemical hepatocarcinognesis, Fed. Proc. 42:7, 1983.
O. Sudilovsky and T. K. Hei, Prestaining of membrane markers to identify specific areas for Feulgen cytospectrophotometric determinations in a single section, Anal. Quant. Cytol. Histol. 9:323–327, 1987.
P. Bannasch, Preneoplastic lesions as end points in carcinogenicity testing. I. Hepatic preneoplasia, Carcinogenesis 7:689–695, 1986.
Y. S. Fu and T. L. Hall, DNA ploidy measurements in tissue sections, Anal. Quant. Cytol. Histol. 7:90–96, 1985.
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.
G. Saeter, P. E. Schwarze, J. M. Nesland, and P. O. Seglen. Diploid nature of hepatocellular tumors developing from transplanted preneoplastic liver cells, Brit. J. Cancer 59:198–205, 1989.
P. E. Schwarze, G. Saeter, D. Armstrong, R. G. Cameron, E. Laconi, D. S. R. Sarma, V. Preat, P. O. Seglen, Diploid growth pattern of hepatocellular tumours induced by various carcinogenic treatments, Carcinogenesis, 12:325–327, 1991.
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.
H. Danielson, H. B. Steen, T. Lindmo, and A. Reith, Ploidy distribution in experimental liver carcinogenesis in mice, Carcinogenesis 9:59–63, 1988.
S. Haesen, T. Derijke, A. Deleneer, P. Castelain, H. Alexandre, V. Preat, and M. Kirsch-Yolders, The influence of phenobarbital and butylated hydroxytoluene on the ploidy rate in rat hepatocarcinogenesis, Carcinogenesis 9:1755–1761, 1988.
A. G. Knudson and L. C. Strong, Mutation and cancer: a model for Wilm’s tumor of the kidney, J. Natl. Cancer Inst. 48:313–316, 1972.
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Sudilovsky, O. et al. (1991). Genetic Instability Occurs Sooner Than Expected: Promotion, Progression and Clonality During Hepatocarcinogenesis in the Rat. In: Sudilovsky, O., Pitot, H.C., Liotta, L.A. (eds) Boundaries between Promotion and Progression during Carcinogenesis. Basic Life Sciences, vol 57. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5994-4_23
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