Urinary bladder cancer is the fifth most common cancer in men in Western society, and its incidence in the U.S. is more than 50,000 cases each year. Exposure to a variety of chemicals either as an occupational hazard or as a result of cigarette smoking is the leading cause of bladder cancer in the Western world. Epidemiologic and experimental animal studies have established that urinary tract infection is also a significant risk factor for the development of bladder cancer. Although the risk is most significantly associated with chronic infection, it also increases with the number of episodes of acute cystitis, and multiplies with cigarette smoking. To test the effect of persistent inflammation on bladder carcinogenesis, we repeatedly instilled heat-killed E. coli (KEC) into the heterotopically transplanted rat urinary bladders (HTB) in which carcinogenesis was initiated by a single small dose of N-methyl-N-nitrosourea (MNU). The rats treated with KEC had a striking increase in the number of tumors whether the treatment was begun immediately or as long as 18 weeks after MNU treatment, whereas hardly any tumors developed in the controls receiving MNU alone or KEC alone. To account for the KEC action, we propose the following hypothesis: """"""""KEC (or its endotoxin lipopolysaccharide [LPS]) enhances MNU-initiated rat bladder carcinogenesis by two mechanisms; first by inducing irreversible genetic changes in MNU-initiated urothelial (bladder epithelial) cells mediated by reactive oxygen intermediates (ROI), notably H2O2, which are generated by activated inflammatory cells recruited to the urothelium, and second, by bestowing on these cells selective growth advantage because of their acquired sensitivity to growth stimulation by cytokines. Whereas DNA modifications induced by MNU or KEC alone is insufficient, when combined, they are highly effective in inducing tumors."""""""" The specific aims to test the hypothesis are: l. To demonstrate that oxidative stress induced by activated polymorphonuclear leukocytes or H2O2 and subsequent exposure to cytokines notably interleukin-6 (IL-6) will convert MNU-initiated MYP3 cells, a near-diploid-nontumorigenic rat urothelial cell line, to tumorigenic. 2. To determine the mechanism of cytokine (IL-6) action whether it is paracrine or autocrine or both, in response to LPS stimulation. 3. To demonstrate whether instillation of H2O2 and a cytokine, notably IL- 6, promotes the MNU-initiated bladder carcinogenesis in vivo. These experiments will be conducted initially with in vitro cell culture system and later with the heterotopically transplanted rat bladder established in syngeneic rats. Our hypothesis, when proven, should support the view that repeated or chronic urinary tract infection is a potent risk factor, especially among smokers, for the development of bladder cancer. The information generated from this investigation should be useful in establishing strategies to intervene neoplasia not only of the urinary bladder but of other organs.
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