Tumorigenic conversion of a rat urothelial cell line by human polymorphonuclear leukocytes activated by lipopolysaccharide

Chronic inflammation is a significant risk factor for the development of ur inary bladder cancer. We have shown that inflammation induced by killed Esc herichia coli and also by its lipopolysaccharide (LPS) strikingly enhances N-methyl-N-nitrosourea (MNU)-initiated rat bladder carcinogenesis. Aspirate s from the bladder lumen contained a large quantity of hydrogen peroxide (H 2O2) and several cytokines, In this study, we tested the hypothesis that re active oxygen intermediates (ROI) released from activated polymorphonuclear leukocytes (PMN) are involved in inflammation-associated bladder carcinoge nesis. Using an immortalized nontumorigenic rat urothelial cell line, MYP3, we examined the effect of LPS-activated PMN on malignant transformation. M YP3 cells pretreated with or without MNU were exposed daily to LPS-activate d PMN for one week and were then tested for growth in soft agar, In contras t rep no colony formation by the parental cells, a varying number of coloni es developed from cells treated with LPS-activated PMN. Although combined t reatment with MNU and PMN was most effective (P<0.01), cells treated with L PS-activated PMN alone also formed a small number of colonies. Addition of catalase, which decomposes H2O2, and/or an antioxidant, alpha-tocopherol, r educed the number of; colonies induced by LPS-activated PMN (P<0.05). Cells derived from colonies were tumorigenic in athymic nude mice. However, tumo rigenicity in mice was greater with cells treated with both MNU and PMN tha n 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 carcino genesis associated with active urinary tract infection.