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Early Bioenergetic Changes in Hepatocarcinogenesis: Preneoplastic Phenotypes Mimic Responses to Insulin And Thyroid Hormone

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Abstract

Biochemical and molecular biological approaches in situ have provided compelling evidence for early bioenergetic changes in hepatocarcinogenesis. Hepatocellular neoplasms regularly develop from preneoplastic foci of altered hepatocytes, irrespective of whether they are caused by chemicals, radiation, viruses, or transgenic oncogenes. Two striking early metabolic aberrations were discovered: (1) a focal excessive storage of glycogen (glycogenosis) leading via various intermediate stages to neoplasms, the malignant phenotype of which is poor in glycogen but rich in ribosomes (basophilic), and (2) an accumulation of mitochondria in so-called oncocytes and amphophilic cells, giving rise to well-differentiated neoplasms. The metabolic pattern of human and experimentally induced focal hepatic glycogenosis mimics the phenotype of hepatocytes exposed to insulin. The conversion of the highly differentiated glycogenotic hepatocytes to the poorly differentiated cancer cells is usually associated with a reduction in gluconeogenesis, an activation of the pentose phosphate pathway and glycolysis, and an ever increasing cell proliferation. The metabolic pattern of preneoplastic amphophilic cell populations has only been studied to a limited extent. The few available data suggest that thyromimetic effects of peroxisomal proliferators and hepadnaviral infection may be responsible for the emergence of the amphophilic cell lineage of hepatocarcinogenesis. The actions of both insulin and thyroid hormone are mediated by intracellular signal transduction. It is, thus, conceivable that the early changes in energy metabolism during hepatocarcinogenesis are the consequence of alterations in the complex network of signal transduction pathways, which may be caused by genetic as well as epigenetic primary lesions, and elicit adaptive metabolic changes eventually resulting in the malignant neoplastic phenotype.

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  1. Abteilung für Cytopathologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany

    P. Bannasch, F. Klimek & D. Mayer

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  1. P. Bannasch
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Bannasch, P., Klimek, F. & Mayer, D. Early Bioenergetic Changes in Hepatocarcinogenesis: Preneoplastic Phenotypes Mimic Responses to Insulin And Thyroid Hormone. J Bioenerg Biomembr 29, 303–313 (1997). https://doi.org/10.1023/A:1022438528634

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