Early aberrations of energy metabolism in carcinogenesis

Abstract

Cancer cells are characterized by fundamental aberrations in energy metabolism, which are regarded as secondary events appearing in late stages of the carcinogenic process by most authors. However, more recent biochemical and molecular biological approaches in situ provided compelling evidence for an essential role of early changes in energy metabolism during neoplastic development. Hepatic and renal carcinogenesis induced by various agents in rodents and some observations in humans will be used to exemplify this concept. In both the liver parenchyma and the renal tubular system two outstanding 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 and sometimes also mitochondria, and (2) an accumulation of atypical mitochondria in so-called oncocytes or amphophilic cells, giving rise to well differentiated neoplasms. In the liver, the preneoplastic focal glycogenosis is characterized by an altered metabolic pattern resembling an insulin effect. The progression from the focal glycogenosis to glycogen-poor neoplasms is usually associated with a reduction in gluconeogenesis, an activation of the pentose phosphate pathway and glycolysis, and an ever increasing cell proliferation. A similar, albeit not identical metabolic shift and gradual increase in cell proliferation takes place during progression from glycogenotic rat renal cell tubules (originating from the collecting duct system) to renal cell carcinomas. The metabolic pattern of preneoplastic, oncocytic and amphophilic cell populations has not been analyzed in comparable detail but an important difference to the other cell lineages appears to be that the activity of the key enzyme of the pentose phosphate pathway, the glucose 6-phosphate dehydrogenase, is not increased but rather normal or even decreased in the early lesions and in the resulting neoplasms. At least in the case of the preneoplastic glycogenotic foci, the emergence of these cell populations appears to be a consequence of an early disturbance in signal transduction pathways. The later shift towards a glycogen-poor malignant phenotype might indicate a metabolic adaptation to the primary molecular lesion.