Urothelial overexpression of insulin-like growth factor-1 increases susceptibility to p-cresidine-induced bladder carcinogenesis in transgenic mice

To establish a role for insulin‐like growth factor‐1 (IGF‐1) in bladder cancer susceptibility, we tested the effect of p‐cresidine, a potent bladder carcinogen, in transgenic (TG) mice with human IGF‐1 expression in the bladder driven by the bovine keratin 5 promoter (referred to as BK5.IGF‐1 TG mice). Indomethacin was also tested to determine if the cyclooxygenase (COX) pathway is a target for bladder cancer prevention in this model. Thirty‐three female BK5.IGF‐1 TG mice and 29 female nontransgenic littermates were randomized to the following treatments: (1) AIN‐76A diet; (2) AIN‐76A diet with 0.5% p‐cresidine; or (3) AIN‐76A diet with 0.5% p‐cresidine + 0.00075% indomethacin. BK5.IGF‐1 TG mice, with twofold greater total serum IGF‐1 than nontransgenic mice, exhibited greatly increased susceptibility to p‐cresidine‐induced bladder tumors compared to nontransgenic mice. The most common type of bladder tumor in the BK5.IGF‐1 TG mice was transitional cell carcinoma, which is the predominant type of bladder cancer observed in developed countries. Indomethacin inhibition of bladder tumor development in BK5.IGF‐1 TG mice was not statistically significant. These results present further evidence for the role of IGF‐1 in bladder cancer progression. In addition, these transgenic mice provide a useful model for studying the role of the IGF‐1 pathway in bladder carcinogenesis and its prevention. © 2009 Wiley‐Liss, Inc.