Tumorigenic Conversion of a Rat Urothelial Cell Line by Human Polymorphonuclear Leukocytes Activated by Lipopolysaccharide

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Abstract
Chronic inflammation is a significant risk factor for the development of urinary bladder cancer. We have shown that inflammation induced by killed Escherichia coli and also by its lipopolysaccharide (LPS) strikingly enhances N‐methyl‐N‐nitrosourea (MNU)‐initiated rat bladder carcinogenesis. Aspirates from the bladder lumen contained a large quantity of hydrogen peroxide (H2O2) and several cytokines. In this study, we tested the hypothesis that reactive oxygen intermediates (ROI) released from activated polymorphonuclear leukocytes (PMN) are involved in inflammation‐associated bladder carcinogenesis. Using an immortalized nontumorigenic rat urothelial cell line, MYP3, we examined the effect of LPS‐activated PMN on malignant transformation. MYP3 cells pretreated with or without MNU were exposed daily to LPS‐activated PMN for one week and were then tested for growth in soft agar. In contrast to no colony formation by the parental cells, a varying number of colonies developed from cells treated with LPS‐activated PMN. Although combined treatment with MNU and PMN was most effective (P < 0.01), cells treated with LPS‐activated PMN alone also formed a small number of colonies. Addition of catalase, which decomposes H2O2, and/or an antioxidant, α‐tocopherol, reduced the number of colonies induced by LPS‐activated PMN (P<0.05). Cells derived from colonies were tumorigenic in athymic nude mice. However, tumorigenicity in mice was greater with cells treated with both MNU and PMN than with cells treated with PMN alone. Our results suggest that ROI released from LPS‐activated PMN may be one of the mechanisms involved in the carcinogenesis associated with active urinary tract infection.

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