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Toxicologic Pathology
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Induction and Modulation of Hepatic Preneoplasia and Neoplasia in the Rat by Dehydroepiandrosterone

Doris Mayer

Research Group Hormones and Signal Transduction, Deutsches Krebsforschungszentrum, Heidelberg, Germany, d.mayer{at}dkfz-heidelberg.de

Klaus Forstner

Research Group Hormones and Signal Transduction, Deutsches Krebsforschungszentrum, Heidelberg, Germany

Kathrin Kopplow

Research Group Hormones and Signal Transduction, Deutsches Krebsforschungszentrum, Heidelberg, Germany

Dehydroepiandrosterone (DHEA), the main adrenal steroid in humans and a precursor in androgen and estrogen biosynthesis, acts as a peroxisome proliferator and as a hepatocarcinogen in rats. Neoplasms emerge from a glycogenotic/amphophilic/basophilic preneoplastic cell lineage. A higher female tumor incidence suggests a relevant influence of sex hormones. DHEA enhances hepatocarcinogenesis induced byN-nitrosomorpholine (NNM), which is characterized by the glycogenotic/basophilic cell lineage. The tumor promoting effect is related to an additional amphophilic/basophilic preneoplastic lesion sequence and to faster proliferation of the basophilic preneoplastic lesions. Nevertheless, hepatocellular carcinomas provided under DHEA treatment seem to have a less malignant phenotype compared to tumors induced by NNM only. Further, DHEA treatment reduces growth and generation of glycogen storage foci (GSF) in initial NNM-treated rats. Thus, DHEA treatment results in both, a growth stimulation of the late basophilic lesion type with an additional amphophilic lesion sequence, and in a growth inhibition of early preneoplastic lesions, addressing especially GSF. DHEA also inhibits the growth of physiologically proliferating liver tissue. This might be explained by a DHEA related cellular metabolism, which results in significant energy consumption. Additionally, a DHEA-induced alteration of cytokine levels might contribute to this growth inhibition as well.

Key Words: Dehydroepiandrosterone • N-nitrosomorpholine • rat liver • preneoplasia • hepatocarcinogenesis • cellular lineages • tumor promotion • growth inhibition • energy metabolism • cell signaling • cytokines.

References

  • Bannasch P. (1996). Pathogenesis of hepatocellular carcinoma: Sequential cellular, molecular, and metabolic changes. In: Progress in Liver Diseases, Vol XIV, Boyer JL, Ockner RK (eds). WB Saunders Company, Philadelphia, pp 161—197.
  • Bannasch P., Klimek F., Mayer D. (1997). Early bioenergetic changes in hepatocarcinogenesis: Preneoplastic phenotypes mimic responses to insulin and thyroid hormone. J Bioenerg Biomemb 29: 303—313.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Bannasch P., Metzger C., Mayer D. (2000). Hepatocarcinogenesis by dehydroepiandrosterone. I. Sequential cellular changes during neoplastic develoment. In: Dehydroepiandrosterone (DHEA). Biochemical, Physiological and Clinical Aspects, Regelson W, Kalimi M (eds). Walter de Gruyter, Berlin, pp 237—249.
  • Bannasch P., Nehrbass D., Kopp-Schneider A. (2001). Significance of hepatic preneoplasia for cancer prevention. In: Biomarkers in Cancer Chemoprevention, Miller AB, Bartsch H, Boffetta P, Dragsted L, Vainio H (eds). IARC Scientific Publications No. 154, International Agency for Research on Cancer, Lyon, pp 223—240.
  • Bellino FL, Daynes RA, Hornsby PJ, Lavrin DH, Nestler JE (eds) ( 1995). Dehydroepiandrosterone and Aging. Ann NY Acad Sci 774: 1—350.[Web of Science][Medline] [Order article via Infotrieve]
  • Feo F., Daino L., Seddaiu MA, Simile MM, Pascale RM, McKeating JA, Davliakos GP, Sudol KS, Melhem MF, Rao KN (1991). Differential effects of dehydroepiandrosterone and deoxyribonucleotides on DNA synthesis and de novo cholesterogenesis in hepatocarcinogenesis in rat. Carcinogenesis 12: 1581—1586.[Abstract/Free Full Text]
  • Feo F., Pascale RM, Simile MM, De Miglio MR (2000). Role of dehydroepiandrosterone in experimental and human carcinogenesis. In: Dehydroepiandrosterone (DHEA), Biochemical, Physiological and Clinical Aspects, Kalimi M, Regelson W (eds). Walter de Gruyter, Berlin, pp 215—236.
  • Garcea R., Daino L., Frassetto S., Cozzolino P., Ruggiu ME, Vannini MG, Pascale R., Lenzerini L., Simile MM, Puddu M., Feo F. (1988). Reversal by ribo- and deoxyribonucleosides of dehydroepiandrosterone-induced inhibition of enzyme altered foci in the liver of rats subjected to the initiation-selection process of experimental hepatocarcinogenesis. Carcinogenesis 9: 931—938.[Abstract/Free Full Text]
  • Garcea R., Daino L., Pascale R., Frassetto S., Cozzolino P., Ruggiu ME, Feo F. (1987). Inhibition by dehydroepiandrosterone of liver preneoplastic foci formation in rats after initiation-selection in experimental carcinogenesis. Toxicol Pathol 15: 164—169.[Web of Science][Medline] [Order article via Infotrieve]
  • Hayashi F., Tamura H., Yamada J., Kasai H., Suga T. ( 1994). Characteristics of the hepatocarcinogenesis caused by dehydroepiandrosterone, a peroxisome proliferator, in male F-344 rats. Carcinogenesis 15: 2215—2219.[Abstract/Free Full Text]
  • Hobe G., Hillesheim HG, Schön R., Reddersen G., Knappe R., Bannasch P., and Mayer D. (1994). Sex differences in dehydroepiandrosterone metabolism in the rat: Different plasma levels following ingestion of DHEA-supplemented diet and different metabolite patterns in plasma, bile and urine. Horm Metab Res 26: 326—329.[Web of Science][Medline] [Order article via Infotrieve]
  • Kalimi M, Regelson W (eds) (1990). The Biologic Role of Dehydroepiandrosterone (DHEA). Walter de Gruyter, Berlin, New York.
  • Kalimi M, Regelson W (eds) (2000). Dehydroepiandrosterone (DHEA). Biochemical, Physiological and Clinical Aspects. Walter de Gruyter, Berlin, New York.
  • Labrie C., Simard J., Zhao HF, Bélanger A., Pelletier G., Labrie F. (1989). Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate. Endocrinology 124: 2745—2754.[Abstract/Free Full Text]
  • Mayer D. (1998.) Carcinogenic and anticarcinogenic effects of dehydroepiandrosterone in the liver of male and female rats. Aging Male 1: 56—66.
  • Mayer D. (2002). DHEA effects on liver. In: DHEA and the Brain, Morfin R (ed). Harwood Academic Publishers, London, pp 81—100.
  • Mayer D., Metzger C., Bannasch P. (2000). Hepatocarcinogenesis by dehydroepiandrosterone. II. Biochemical and molecular changes during neoplastic development. In: Dehydroepiandrosterone (DHEA). Biochemical, Physiological and Clinical Aspects, Regelson W, Kalimi M (eds). Walter de Gruyter, Berlin, pp 251—260.
  • Mayer D., Metzger C., Leonetti P., Beier K., Benner A., Bannasch P. (1998). Differential expression of key enzymes of energy metabolism in preneoplastic and neoplastic rat liver lesions induced by N-nitrosomorpholine and dehydroepiandrosterone. Int J Cancer (Pred Oncol) 79: 232—240.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Mayer D., Metzger C., Nehrbass D., Bannasch P. (1998). Hepatocarcinogenesis by dehydroepiandrosterone. Curr Topics Steroid Res 1: 135—144.
  • Mayer D., Reuter S., Hoffmann H., Bocker T., Bannasch P. (1996). Dehydroepiandrosterone reduces expression of glycolytic and gluconeogenic enzymes in the liver of male and female rats. Int J Oncol 8: 1069—1078.[Web of Science]
  • Mayer D., Weber E., Moore MA, Letsch I., Filsinger E., Bannasch P. (1988). Dehydroepiandrosterone (DHEA) induced alterations in rat liver carbohydrate metabolism. Carcinogenesis 11: 2039—2049.
  • McIntosh MK, Berdanier C. (1992). Influence of DHEA on the thyroid hormone status of BHE/cdb rats. J Nutr Biochem 3: 194—199.[CrossRef][Web of Science]
  • Metzger C., Bannasch P., Mayer D. (1997). Enhancement and phenotypic modulation of N-nitrosomorpholine-induced hepatocarcinogenesis by dehydroepiandrosterone. Cancer Lett 121: 125—131.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Metzger C., Mayer D., Hobe G., Hoffmann H., Bocker T., Benner A., Bannasch P. (1995). Sequential appearance and ultrastructure of amphophilic cell foci, adenomas, and carcinomas in the liver of male and female rats treated with dehydroepiandrosterone. Toxicol Pathol 23: 591—605.[Abstract/Free Full Text]
  • Moore MA, Thamavit W., Tsuda H., Sato K., IchiharaA., Ito N. (1986). Modifying influence of dehydroepiandrosterone on the development of dihydroxydi-N-propylnitrosamine-initiated lesions in the thyroid, lung and liver of F344 rats. Carcinogenesis 7: 311—316.[Abstract/Free Full Text]
  • Moore MA, Weber E., Mayer D., Bannasch P. (1989). Adrenal cortical foci and nodules in Sprague-Dawley rats treated with N-nitrosomorpholine. Light and electron microscopic findings. Virchows Arch B Cell Pathol Incl Mol Pathol 57: 91—97.[Web of Science][Medline] [Order article via Infotrieve]
  • Nehrbass D., Klimek F., Bannasch P. (1998). Overexpression of insulin receptor substrate-1 emerges early in hepatocarcinogenesis and elicits preneoplastic hepatic glycogenosis. Am J Pathol 152: 341—345.[Abstract]
  • Nehrbass D., Klimek F., Bannasch P., Mayer D. (1999). Insulin receptor substrate-1 is overexpressed in glycogenotic but not in amphophilic preneoplastic hepatic foci induced in rats by N-nitrosomorpholine and dehydroepiandrosterone. Cancer Lett 140: 75—79.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Orner GA, Hendricks JD, Arbogast D., Williams DE (1998). Modulation of aflatoxin-B1 hepatocarcinogenesis in trout by dehydroepiandrosterone: Initiation/post-initiation and latency effects. Carcinogenesis 19: 161— 167.[Abstract/Free Full Text]
  • Orner GA, Mathews C., Hendricks JD, Carpenter HM, Bailey GS, Williams DE (1995). Dehydroepiandrosterone is a complete hepatocarcinogen and potent tumor promoter in the absence ofperoxisome proliferation in rainbow trout. Carcinogenesis 16: 2893—2898.[Abstract/Free Full Text]
  • Rao MS, Reid B., Ide H., Subbarao V., Reddy, JK (1994). Dehydroepiandrosterone-induced peroxisome proliferation in the rat: Evaluation of sex differences. Proc Soc Exp Biol Med 207: 186—190.[CrossRef][Medline] [Order article via Infotrieve]
  • Rao MS, Subbarao V., Kumar S., Yeldandi AV, Reddy JK (1992). Phenotypic properties of liver tumors induced by dehydroepiandrosterone in F-344 rats. Jpn J Cancer Res 83: 1179—1183.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Rao MS, Subbarao V., Yeldandi AV, Reddy JK (1992). Hepatocarcinogenicity of dehydroepiandrosterone in the rat. Cancer Res 52: 2977—2979.[Abstract/Free Full Text]
  • Schwartz AG, Whitcomb JM, Nyce JW, Lewbart ML, Pashko LL (1988). Dehydroepiandrosterone and structural analogs: A new class of cancer chemopreventive agents. Adv Cancer Res 51: 391—424.[Web of Science][Medline] [Order article via Infotrieve]
  • Simile A., Pascale RM, De Miglio MR, Nufris A., Daino L., Seddaiu MA, Muroni MR, Rao KN, Feo F. (1995). Inhibition by dehydroepiandrosterone of growth and progession of persistent liver nodules in experimental rat liver carcinogenesis. Int J Cancer 62: 210—215.[Web of Science][Medline] [Order article via Infotrieve]
  • Song MK, Grieco D., Rall JE, Nikodem VM (1989). Thyroid hormone-mediated transcriptional activation of the rat liver malic enzyme gene by dehydroepiandrosterone. J Biol Chem 264: 18981—18985.[Abstract/Free Full Text]
  • Sourla A., Martel C., Labrie C., Labrie F. (1998). Almost exclusive androgenic action of dehydroepiandrosterone in the rat mammary gland. Endocrinology 139: 753—764.[Abstract/Free Full Text]
  • Swierczynski J., Mayer D. (1996). Increase of lipid peroxidation in rat liver mitochondria by dehydroepiandrosterone (DHEA) feeding. J Steroid Biochem Molec Biol 58: 599—603.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Swierczynski J., Bannasch P., Mayer D. (1996). Increase of lipid peroxidation in rat liver microsomes by dehydroepiandrosterone (DHEA) feeding. Biochim Biophys Acta 1315: 193—198.[Medline] [Order article via Infotrieve]
  • Swierczynski J., Kochan Z., Mayer D. (1997). Dietary {alpha}-tocopherol prevents DHEA-induced lipid peroxidation in rat liver microsomes and mitochondria. Toxicol Lett 91: 129—136.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Swierczynski J., Mayer D. (1998). Vitamin E prevents induction of carbonyl group formation in microsomal protein by dehydroepiandrosterone. Nutr Cancer 32: 101—106.[Web of Science][Medline] [Order article via Infotrieve]
  • Thornton M., Moore MA, Ito N. (1989). Modifying influence of dehydroepiandrosterone or butylated hydroxytoluene treatment on initiation and development stages of azaserine-induced acinar pancreatic lesions in the rat. Carcinogenesis 10: 407—410.[Abstract/Free Full Text]
  • Weber E., Moore MA, Bannasch P. (1988). Phenotypic modulation of hepatocarcinogenesis and reduction in N-nitrosomorpholine-induced hemangiosarcoma and adrenal lesion development in Sprague-Dawley rats by dehydroepiandrosterone. Carcinogenesis 9: 1191—1195.[Abstract/Free Full Text]
  • Weber E., Moore MA, Bannasch P. (1988). Enzyme histochemical and morphological phenotype of amphophilic foci and amphophilic/tigroid cell adenomas in rat liver after combined treatment with dehydroepiandrosterone and N-nitrosomorpholine. Carcinogenesis 9: 1049—1054.[Abstract/Free Full Text]
  • Yen SS (2001). Dehydroepiandrosterone sulfate and longevity: New clues for an old friend. Proc Natl Acad Sci USA 98: 8167—8169.[Free Full Text]

Toxicologic Pathology, Vol. 31, No. 1, 103-112 (2003)
DOI: 10.1080/01926230390173914
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