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.
Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas 78712, USA.
Stephen D
SD
Hursting
Susan N
SN
Perkins
Jackie A
JA
Lavigne
Linda
L
Beltran
Diana C
DC
Haines
Heather L
HL
Hill
W Gregory
WG
Alvord
J Carl
JC
Barrett
John
J
DiGiovanni
D000814:Aniline Compounds / Q000633:toxicity; D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002417:Cattle; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D053555:Keratin-5 / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010212:Papilloma / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
D000814:Aniline Compounds; D053555:Keratin-5; C013453:cresidine; D007334:Insulin-Like Growth Factor I