CELL-PROLIFERATION AND RENAL CARCINOGENESIS

Enhanced cell proliferation occurs at several stages of renal tumorige nesis. Initiation by genotoxic nephrocarcinogens such as dimethylnitro samine (DMN) is likely a result of DNA damage coupled with an initial burst of DNA synthesis associated with the cytotoxic effects of the co mpound. The level of initiation by DMN can be further enhanced by unil ateral nephrectomy or hydronephrosis, which induces a brief burst of c ell proliferation followed by tumorigenesis in the contralateral kidne y. The role of sustained cell proliferation in renal tumor development is less well understood. The most compelling evidence comes from stud ies 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 che mical-alpha G complex in phagolysosomes of P-2 proximal tubule cells, which results in cytotoxicity and compensatory hyperplasia only in mal e F344 rats, but not female F344 rats or alpha G deficient male NBR ra ts. Furthermore, initiation-promotion experiments demonstrated a stron g correlation between the dose-response of cell proliferation and the incidence of preneoplastic and neoplastic lesions. Clearly, similar co rrelative studies with a number of other renal carcinogens and noncarc inogens are warranted before general conclusions can be made. Cell pro liferation is excessively elevated in tubules affected by chronic prog ressive nephropathy, but the significance of the lesion to renal carci nogenesis is unclear. Elucidating mechanisms of renal cell proliferati on are necessary for our understanding of cause and effect relationshi ps. An exciting recent finding is altered expression of transforming g rowth factor-alpha in hereditary rat renal cell carcinoma. This animal model may be useful for studying detailed histochemical relationships between altered growth factors and cell proliferation in various stag es of renal carcinogenesis.