Aberrant regulation of carbohydrate metabolism and metamorphosis during renal carcinogenesis

Abstract

Systematic studies of the sequence of cellular changes during renal carcinogenesis induced in rats by stop experiments with N-nitrosomorpholine or streptozotocin and of human renal cell carcinomas led to the following main results and conclusions: All types of epithelial kidney tumors known from human pathology, namely clear-cell, acidophilic (granular), basophilic, chromophobic and oncocytic tumors, can be induced by the chemicals. Phenotypically altered epithelia resembling those in the tumors appear in single or multiple tubules long before unequivocal tumors develop. The progression from the preneoplastic tubular lesions to the tumors is an autogenous process which is independent of the further action of the carcinogen. At least three different types of tubular lesions can be distinguished: (a) Clear cell tubules storing glycogen in excess, (b) chromophobic or basophilic tubules frequently accumulating acid mucopolysaccharides (glycosaminoglycans, proteoglycans), and (c) oncocytic tubules accumulating atypical mitochondria. Whereas the precise site of origin of the clear cell tubules within the nephron remains unclear, the fine structural and cytochemical findings suggest that the chromophobic and basophilic tubules originate from the proximal and the oncocytic tubules from the distal nephron. Each type of tubular lesion is apparently the precursor of a cytologically specific tumor type. The well-known aberration in carbohydrate metabolism in renal tumors might occur in response to a carcinogen-induced metabolic derangement which is frequently associated with excessive storage of polysaccharides or lipids persisting for weeks and months until fast-growing tumors appear. Whereas the primary biochemical lesion leading to the persisting storage phenomena is most probably fixed at the genetic level, epigenetic changes, namely an adaptation of cellular enzymes gradually activating alternative metabolic pathways, might be responsible for the ultimate neoplastic transformation of the cell.