Cell proliferation and renal carcinogenesis.
Enhanced cell proliferation occurs at several stages of renal tumorigenesis. Initiation by genotoxic nephrocarcinogens such as dimethylnitrosamine (DMN) is likely a result of DNA damage coupled with an initial burst of DNA synthesis associated with the cytotoxic effects of the compound. The level of initiation by DMN can be further enhanced by unilateral nephrectomy or hydronephrosis, which induces a brief burst of cell proliferation followed by tumorigenesis in the contralateral kidney. The role of sustained cell proliferation in renal tumor development is less well understood. The most compelling evidence comes from studies with nongenotoxic renal carcinogens such as unleaded gasoline and d-limonene, which induce alpha 2u-globulin (alpha G) nephropathy and renal epithelial tumors exclusively in male rats. Sustained increases in cell proliferation in these studies depend on the presence of a chemical-alpha G complex in phagolysosomes of P2 proximal tubule cells, which results in cytotoxicity and compensatory hyperplasia only in male F344 rats, but not female F344 rats or alpha G deficient male NBR rats. Furthermore, initiation-promotion experiments demonstrated a strong correlation between the dose-response of cell proliferation and the incidence of preneoplastic and neoplastic lesions. Clearly, similar correlative studies with a number of other renal carcinogens and non-carcinogens are warranted before general conclusions can be made. Cell proliferation is excessively elevated in tubules affected by chronic progressive nephropathy, but the significance of the lesion to renal carcinogenesis is unclear. Elucidating mechanisms of renal cell proliferation are necessary for our understanding of cause and effect relationships. An exciting recent finding is altered expression of transforming growth factor-alpha in hereditary rat renal cell carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)
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Department of Toxicology-U.S., SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
D000510:Alpha-Globulins / Q000096:biosynthesis; D000818:Animals; D001462:Barbital / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004128:Dimethylnitrosamine / Q000633:toxicity; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000209:etiology* / Q000473:pathology*; D008297:Male; D008954:Models, Biological; D051381:Rats; D011916:Rats, Inbred F344
D000510:Alpha-Globulins; D001462:Barbital; D004128:Dimethylnitrosamine