Abstract
Cell proliferation is the most central and key phenotypic property of cancer including hepatocellular carcinoma. Hepatocyte proliferation is central not only at the late steps in carcinogenesis, the cancer, but at the earliest known step, initiation. Compensatory or regenerative hepatocyte proliferation is essential to initiation with chemical carcinogens but primary hyperplasia is ineffective. During promotion, hepatocyte proliferation is the major change seen as clonal proliferation to generate nodules occurs. During progression, autonomous hepatocyte proliferation balanced by cell loss makes its appearance. This continues in a balanced fashion with only a slight excess of proliferation over loss until the earlier steps in malignancy at which time the balance is disrupted.
References
Farber E, Chen Z-Y, Harris L, Lee G, Rinaudo JS, Roomi MW, Rotstein J, Semple E: The biochemical-molecular pathology of the stepwise development of liver cancer: new insights and problems.In Liver Cell Carcinoma. P Bannasch, D Keppler, G Weber (eds). Lancaster, Kluwer Academic Publishers, 1989, pp. 273–291
Chisari FV, Filippi P, Buras J, McLachlan A, Popper H, Pinkert CA, Palmiter RD, Brinster RL: Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Proc Natl Acad Sci USA 84:6909–6913, 1987
Farber E, Sarma DSR: Biology of disease: hepatocarcinogenesis: A dynamic cellular perspective. Lab Invest 56:4–22, 1987
Foulds L: Neoplastic Development, Vol 2, London, Academic Press, 1975
Sell S, Hunt JM, Knoll BJ, Dunsford HA: Cellular events during hepatocarcinogenesis in rats and the question of premalignancy. Adv Cancer Res 48:37–111, 1987
Farber E: Pathogenesis of experimental liver cancer: Comparison with humans. Arch Toxicol Suppl 10:281–288, 1987
Farber E: Similarities in sequence of early histologic changes induced by ethionine, 3′-methyl-4-dimethylaminoazobenzene and 2-acetylaminofluorene. Cancer Res 16:142–148, 1956
Sasaki T, Yoshida T: Experimentelle Erzeugung des Lebercarcinoms durch Fütterung mitO-Amidoazotoluol. Virchow's Arch 295:175–200, 1935
Kinosita R: Studies on the carcinogenic substances. Trans Jpn Pathol Soc 27:665–727, 1937
Craddock VM: Cell proliferation and experimental liver cancer.In Liver Cell Cancer. HN Cameron, DA, Linsell, GP Warwick (eds). Amsterdam, Elsevier/North Holland Biochemical Press, 1976, pp 153–301
Cayama E, Tsuda H, Sarma DSR, Farber E: Initiation of liver carcinogenesis requires cell proliferation. Nature (London) 275:60–61, 1978
Columbano A, Rajalakshmi S, Sarma DSR: Requirement of cell proliferation for the intiation of liver carcinogenesis as assayed by three different procedures. Cancer Res 41:2079–2083, 1981
Pitot HC, Sirica AE: The stages of initiation and promotion in hepatocarcinogenesis. Biochim Biophys Acta 605:191–215, 1980
Emmelot P, Scherer E: The first relevant cell stage in rat liver carcinogenesis. Biochim Biphys Acta 605:247–304, 1980
Ying TS, Enomoto K, Sarma DSR, Farber E: Effects of delays in the cell cycle on the induction of preneoplastic and neoplastic lesions in rat liver by 1,2-dimethylhydrazine. Cancer Res 42:876–880, 1982
Columbano A, Ledda-Columbano GM, Coni P, Pani P: Failure of mitogen-induced cell proliferation to achieve initiation of rat liver carcinogenesis. Carcinogenesis (London) 8:345–347, 1987
Columbano A, Ledda-Columbano GM, Lee G, Rajalakshmi S, Sarma DSR: Inability of mitogen-induced liver hyperplasia to support the induction of enzyme-altered islands induced by liver carcinogens. Cancer Res 47:5557–5559, 1987
Ledda-Columbano GM, Columbano A, Curto M, Ennas MG, Coni P, Sarma DSR, Pani P: Further evidence that mitogen-induced cell proliferation does not support the formation of enzyme-altered islands in rat liver by carcinogens. Carcinogenesis (London) 10:847–850, 1989
Schulte-Hermann R: Adaptive liver growth induced by xenobiotic compounds and other stimuli. Crit Rev Toxicol 3:97–158, 1974
Schulte-Hermann R: Reactions of the liver to injury: adaptation.In Toxic Injury of the Liver. E Farber, and MM Fisher (eds). New York, Marcel Dekker, 1979, pp 385–445.
Schulte-Hermann R, Hoffman V, Parzefall W, Kallenbach M, Gerhard A, Schuppler J: Adaptive responses of rat liver to the gestagen and anti-androgen cyproterone acetate and other inducers. II. Induction of growth. Chem Biol Interact 31:287–300, 1980
Bursch W, Lauer B, Timmermann-Trosiener I, Barthel G, Schuppler J, Schulte-Hermann R: Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters. Carcinogenesis 5:453–458, 1984
Rotstein J, Macdonald PDM, Rabes HM, Farber E: Cell Cycle kinetics of rat hepatocytes in early putative preneoplastic lesions in hepatocarcinogenesis. Cancer Res 44:2913–2917, 1984
Enomoto K, Farber E: Kinetics of phenotypic maturation of remodeling of hyperplastic nodules during liver carcinogenesis. Cancer Res 42:2330–2335, 1982
Tatematsu M, Nagamine Y, Farber E: Redifferentiation as a basis for emodeling of carcinogen-induced hepatocyte nodules to normal-appearing liver. Cancer Res 43:5049–5058, 1983
Rotstein J, Sarma DSR, Farber E: Sequential alterations in growth control and cell dynamics of rat hepatocytes in early precancerous steps in hepatocarcinogenesis. Cancer Res 46:2377–2385, 1986
Tatematsu M, Lee G, Hayes MA, Farber E: Progression of hepatocarcinogenesis: Differences in growth and behaviour of transplants of early and late hepatocyte nodules in the spleen. Cancer Res 47:4699–4705, 1987
Columbano A, Ledda-Columbano GM, Rao PM, Rajalakshmi S, Sarma DSR: Occurrence of cell death (apoptosis) in preneoplastic and neoplastic liver cells. Am J Pathol 116:441–446, 1984
Farber E, Rotstein J, Harris L, Lee G, Chen Z-Y: Cell proliferation and cell loss in progression in liver carcinogenesis: A new hypothesis.In Chemical Carcinogenesis: Models and Mechanisms. F Feo, P Pani, A Columbano, R Garcea (eds). New York, Plenum Publishing, 1988, pp 167–172.
Farber E: Some emerging general principles in the pathogenesis of hepatocellular carcinoma. Cancer Surv 5:695–718, 1986
Farber E: Cellular biochemistry of the stepwise development of cancer with chemicals: GHA Clowes Memorial Lecture. Cancer Res 44:5463–5474, 1984
Popper H, Sternberg SS, Oser BC, Oser M: The carcinogenic effect of aramite in rats. A study of hepatic nodules. Cancer 13:1035–1046, 1960
Bos JL: ras oncogenes in human cancer: A review. Cancer Res 49:4682–4689, 1989
Author information
Authors and Affiliations
Additional information
Research supproted by research grants from the National Cancer Institute of Canada and the Medical Research Council of Canada (MT-5994).
Rights and permissions
About this article
Cite this article
Farber, E. Hepatocyte proliferation in stepwise development of experimental liver cell cancer. Digest Dis Sci 36, 973–978 (1991). https://doi.org/10.1007/BF01297150
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01297150