Toxicologic Pathology

 

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

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.


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