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Toxicologic Pathology
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Importance of and Approaches to Quantification of Hepatocyte Apoptosis

Thomas L. Goldsworthy

Chemical Industry Institute of Toxicology, P.O. Box 12137, Research Triangle Park, North Carolina 27709

Ronny Fransson-Steen

Chemical Industry Institute of Toxicology, P.O. Box 12137, Research Triangle Park, North Carolina 27709

Robert R. Maronpot

National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709

Abnormal regulation of the life cycle of cells is a key feature of neoplasia. The net increase and growth of initiated cells, preneoplastic lesions, and tumors is highly dependent on rates of both cell proliferation and cell death. Studies of mechanisms involved in regulation of cell death and the development of methods to detect dying and dead cells thus appear to be as important as measurements of cell proliferation in understanding the growth of both normal, preneoplastic and neoplastic lesions. This article describes apoptosis in the mouse liver and its potential role in liver carcinogenesis. Quantitation of hepatocyte apoptosis is a emerging and evolving research area that will require evaluations as thoroughly as those performed with cell proliferation in order to understand all the variables that might influence its occurrence, measurement, and interpretations. Utilizing available data, various methodologies for identifying hepatocyte apoptosis are presented and compared, Aspects important for the quantitation of apoptosis in liver are emphasized. Accurate quantitation of apoptosis, in conjunction with proliferation measurements, is critical for investigations of the mechanisms of chemically induced carcinogenesis and the development of assays for growth alterations and can be applied to biologically based cancer models.

Key Words: Carcinogenesis • cell growth • liver • TGF-β • Apoptotic bodies

  • Alison MR and Sarraf CE (1995). Apoptosis: Regulation and relevance to toxicology. Human Exp. Toxicol. 14: 234-247.[Abstract/Free Full Text]
  • Ansari B., Coates PJ, Greenstein BD, and Hall PA (1993). In situ end-labelling detects DNA strand breaks in apoptosis and other physiological and pathological states. J. Pathol. 170: 1-8.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Bellamy COC, Malcomson RDG, Harrison DJ, and Wyllie AH (1995). Cell death in health and disease: The biology and regulation of apoptosis. Cancer Biol. 6: 3-16.[CrossRef]
  • Bursch W., Oberhammer F., and Schulte-Hermann R. (1992). Cell death by apoptosis and its protective role against disease. TIPS 13: 245-251.[Medline] [Order article via Infotrieve]
  • Bursch W., Paffe S., Putz B., Barthel G., and Schulte-Hermann R. (1990). Determination of the length of the histological stages of apoptosis in normal and in altered hepatic foci of rats. Carcinogenesis 11: 847-853.[Abstract/Free Full Text]
  • Bursch W., Taper HS, Lauer B., and Schulte-Hermann R. (1985). Quantitative histological and histochemical studies on the occurrence and stages of controlled cell death (apoptosis) during regression of rat liver hyperplasia. Virchows Arch. Cell Pathol. 50: 153-166.
  • Butterworth BE, Popp JA, Conolly RB, and Goldsworthy TL (1992). Chemically induced cell proliferation in carcinogenesis. In: Mechanism of Carcinogenesis in Risk Identification, H Vainio, PN Magee, DB McGregor, and AJ McMichael (eds). IARC Publication 116: 279-305.
  • Canman CE and Kastan MB (1995). Induction of apoptosis by tumor suppressor genes and oncogenes. Semin. Cancer Biol. 6: 17-26.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Coffey RJ, Kost LJ, Lyons RM, Moses HL, and LaRusso NF (1987). Hepatic processing of transformed growth factor beta in the rat. J. Clin. Invest. 80: 750-757.[Web of Science][Medline] [Order article via Infotrieve]
  • Cohen SM and Ellwein LB (1991). Genetic errors, cell proliferation, and carcinogenesis. Cancer Res. 51: 6493-6505.[Free Full Text]
  • Craig RW (1995). The BCL-2 gene family. Semin. Cancer Biol. 6: 35-44.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Darzynkiewicz Z., Bruno S., Del Bino G., Gorczyca W., Motz MA, Lassota P., and Traganes F. (1992). Features of apoptotic cells measured by flow cytometry. Cytometry 13: 795-808.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Eastman A. (1995). Survival of factors, intracellular signal transduction, and the activation of endonucleases in apoptosis. Semin. Cancer Biol. 6: 45-52.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Eldridge SR, Butterworth BE, and Goldsworthy TL (1993). Proliferating cell nuclear antigen (PCNA): A marker for hepatocellular proliferation in rodents. Environ. Health Perspect. 101: 211-218.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Eldridge SR, Tilbury LF, Goldsworthy TL, and Butterworth BE (1991). Measurement of chemically-induced cell proliferation in rodent liver and kidney: A comparison of 5-bromo-2'-deoxsuridine and 3H-thymidine administered by injection or osmotic pump. Carcinogenesis 11: 2245-2251.[CrossRef][Web of Science]
  • Foley JF, Dietrich DR, Swenberg JA, and Maronpot RR (1991). Detection and evaluation of proliferating cell nuclear antigen (PCNA) in rat tissue by an improved immunohistochemical procedure. J. Histotechnol. 14: 237-241.[Medline] [Order article via Infotrieve]
  • Foley J., Tan T., Maronpot R., Butterworth BE, and Goldsworthy TL (1993). Comparison of proliferating cell nuclear antigen (PCNA) to tritiated thymidine. Environ. Health Perspect. 101: 199-206.
  • Goldsworthy TL, Butterworth BE, and Maronpot RR (1993). Concepts, labeling procedures, and design of cell proliferation studies relating to carcinogenesis. Environ. Health Perspect. 101: 59-66.
  • Goldsworthy TL, Morgan KT, Popp JA, and Butterworth BE (1991). Guidelines for measuring chemically-induced cell proliferation in specific rodent target organs. In: Chemically-Induced Cell Proliferation: Implications for Risk Assessment, BE Butterworth, TJ Slaga, W Farland, and M McClain (eds). Wiley-Liss, New York, pp. 253-284.
  • Grasl-Kraupp B., Bursch W., Ruttkay-Nedecky B., Wagner A., Lauer B., and Schulte-Hermann R. (1994). Food restriction eliminates preneoplastic cells through apoptosis and antagonizes carcinogenesis in rat liver. Proc. Natl. Acad. Sci. USA 91: 9995-9999.[Abstract/Free Full Text]
  • Greenwell A., Foley JF, and Maronpot RR (1991). An enhancement method for immunohistochemical staining of proliferating cell nuclear antigen in archival rodent tissue. Cancer Lett. 59: 251-256.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Hall PA and Wood AL (1990). Immunohistochemical markers of cellular proliferation: Achievements, problems and prospects. Cell Tissue Kinet. 33: 502-522.
  • Harrington EA, Fanidi A., and Evan GI (1994). Oncogenes and cell death. Curr. Opinion Gen. Devel. 4: 120-129.[CrossRef]
  • Hockenbury D. (1995) Defining apoptosis. Am. J. Pathol. 146: 16-19.[Web of Science][Medline] [Order article via Infotrieve]
  • Hully JR, Chang L., Schwall RH, Widmer HR, Terrell TG, and Gillett NA (1994). Induction of apoptosis in the murine liver with recombinant human activin A. Hepatology 20: 854-862.[Web of Science][Medline] [Order article via Infotrieve]
  • Kerr JFR, Wyllie AH, and Currie AR (1972). Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Brit. J. Cancer 68: 239-257.
  • Lanier TL, Berger EK, and Eacho PI (1989). Comparison of 5-bromo-2-deoxyuridine and [3H]thymidine for studies of hepatocellular proliferation in rodents. Carcinogenesis 10: 1341-1343.[Abstract/Free Full Text]
  • Majno G. and Joris I. (1995). Apoptosis, oncosis, and necrosis: An overview of cell death. Am. J. Pathol. 146: 3-15.[Abstract]
  • Maronpot RR, Foley JF, Takahashi K., Goldsworthy TL, Clark G., Tritscher A., Portier C., and Lucier G. (1993). Dose response for TCDD promotion of hepatocarcinogenesis in rats initiated with DEN: Histologic, biochemical and cell proliferation endpoints. Environ. Health Perspect. 101: 634-642.[Web of Science][Medline] [Order article via Infotrieve]
  • Mills JJ, Chari RS, Boyer U., Gould MN, and Jirtle RY (1995). Induction of apoptosis in liver tumors by the monoterpene perillyl alcohol. Cancer Res. 55: 979-983.[Abstract/Free Full Text]
  • Moolgavkar SH and Luebeck EG (1992). Interpretation of labeling indices in the presence of cell death. Carcinogenesis 13: 1007-1010.[Abstract/Free Full Text]
  • Nagata S. and Goldstein P. (1995). The fas death factor. Science 267: 1449-1456.[Abstract/Free Full Text]
  • Oberhammer FA Pavelka M. Sharma A. Tiefenbacher R. Purchio A. Bursch W. and Schulte-Hermann R. (1992 ). Induction of apoptosis in cultured hepatocytes and in regression liver by transforming growth factor β1. Proc. Natl. Acad. Sci. USA 89: 5408-5412.[Abstract/Free Full Text]
  • Oberhammer FA and Roberts RA (1994). Apoptosis: A widespread process involved in liver adaptation and carcinogenesis. In: The Liver: Biology and Pathobiology. 3rd ed., IM Arias. J Boyer. N Fausto, WB Jakoby. DA Schachter. and DA Shafritz (eds). Raven Press, New York. pp. 1547-1556.
  • Pitot HC (1988). Hepatic neoplasia: Chemical induction. In: The Liver: Biology and Pathology, 2nd ed.. IM Arias, WB Jakoby, H Popper, D Schachter, and DA Shafritz (eds). Raven Press, New York, pp. 1125-1146.
  • Savill J., Dransfield I. Hogg N., and Haslett C. (1990). Vitronectin receptor-mediated phagocytosis of cells undergoing apoptosis. Nature (London) 343: 170-173.[CrossRef][Medline] [Order article via Infotrieve]
  • Schulte-Hermann R., Bursch W., Kraupp-Grasl B., Oberhammer F., Wagner A., and Jirtle R. (1993). Cell proliferation and apoptosis in normal liver and preneoplastic foci. Environ. Health Perspect. 101(suppl. 5): 87-90.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Standeven AS, Wolf DC, and Goldsworthy TL (1995). Promotion of hepatic preneoplastic lesions in male B6C3F1 mice by unleaded gasoline. Environ. Health Perspect. 103: 2-6.
  • Steller H. (1995). Mechanisms and genes of cellular suicide. Science 267: 1445-1449.[Abstract/Free Full Text]
  • Stinchcombe S., Buchmann A., Boch KW, and Schwarz M. (1995). Inhibition of apoptosis during 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated tumor promotion in rat liver. Carcinogenesis 16: 1271-1275.[Abstract/Free Full Text]
  • Terada T. and Nakanuma Y. (1995). Detection of apoptosis and expression of apoptosis-related proteins during human intrahepatic bile duct development. Am. J. Pathol. 146: 67-74.[Abstract]
  • Thompson CB (1995). Apoptosis in the pathogenesis and treatment of disease. Science 267: 1456-1462.[Abstract/Free Full Text]
  • Trosko JE and Goodman JI (1994). Intracellular communication may facilitate apoptosis: Implications for tumor promoters. Mol. Carc. 11: 8-12.[CrossRef]
  • Wakefield LM, Winokur TS, Hollands RS, Chrostopherson K. Levinson AD, and Sporn MB (1990). Recombinant latent transformed growth factor beta has a longer plasma half-life in rats than active transforming growth factor beta 1. and a different tissue distribution. J. Clin. Invest. 86: 1976-1984.[Web of Science][Medline] [Order article via Infotrieve]
  • Wheeldon EB, Williams SM, Soames AR, James NH, and Roberts RA (1995). Quantitation of apoptotic bodies in rat liver by in situ end labelling (ISEL): Correlation with morphology. Toxicol. Pathol. 23: 410.[Abstract/Free Full Text]
  • Wijseman JH, Jonker RR Keijzer R., Van de Velde CJH, Cornelisse CJ, and Van Dierendonck JH (1993). A new method to detect apoptosis in paraffin sections: In situ end-labeling of fragmented DNA. J. Histochem. Cytochem. 41: 7-12.[Abstract]
  • Wyllie AH, Kerr JFR, and Currie AR (1980). Cell death: The significance of apoptosis. Int. Rev. Cytol. 68: 251-307.[Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 24, No. 1, 24-35 (1996)
DOI: 10.1177/019262339602400105


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