Okamoto M, Kawai K, Reznikoff C A, Oyasu R
Department of Pathology, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Cancer Res. 1996 Oct 15;56(20):4649-53.
Chronic infection/inflammation of the urinary tract is a significant risk factor for the development of bladder cancer. The present study examined the hypothesis that hydrogen peroxide (H202) and cytokines released during inflammation are involved in the enhancement of bladder carcinogenesis. Using growth in soft agar and tumorigenicity in athymic nude mice as indices of transformation, we examined the effect of H202 and cytokines on the enhancement of N-methyl-N-nitrosourea (MNU)-initiated transformation of MYP3 cells, an anchorage-dependent nontumorigenic rat bladder epithelial cell line. MYP3 cells pretreated with or without MNU were exposed to H202 (0.001 to 0.1 mM) daily for 1 week in monolayer culture and were then tested for growth in soft agar. A marked increase in colony numbers was observed in the cells that were MNU-initiated and exposed to H202 (P < 0.01). Furthermore, H202 exposure alone at 0.01 mM or 0.1 mM caused colony formation in soft agar. The transformants induced by MNU plus H202 or H202 alone formed high-grade transitional cell carcinomas when injected into nude mice. The growth of these transformants was stimulated by several cytokines (interleukin 1alpha, interleukin 6, and tumor necrosis factor-alpha) better than the parental cells both on a plastic surface and in soft agar. Our results indicate that H202 causes genetic change(s) to induce tumorigenic conversion in urothelial cells and that the transformants are stimulated to grow because of their selective response to several cytokines. We suggest that these mechanisms may be involved in the in vivo carcinogenesis associated with chronic urinary tract infection.
慢性泌尿系统感染/炎症是膀胱癌发生的一个重要危险因素。本研究检验了这样一个假设，即炎症过程中释放的过氧化氢（H2O2）和细胞因子参与了膀胱癌发生的增强过程。以软琼脂中的生长和无胸腺裸鼠中的致瘤性作为转化指标，我们研究了H2O2和细胞因子对N-甲基-N-亚硝基脲（MNU）启动的MYP3细胞转化增强的影响，MYP3细胞是一种依赖贴壁生长的非致瘤性大鼠膀胱上皮细胞系。在单层培养中，将经或未经MNU预处理的MYP3细胞每天暴露于H2O2（0.001至0.1 mM）中1周，然后检测其在软琼脂中的生长情况。在经MNU启动并暴露于H2O2的细胞中观察到集落数量显著增加（P < 0.01）。此外，单独暴露于0.01 mM或0.1 mM的H2O2会导致在软琼脂中形成集落。当将MNU加H2O2或单独H2O2诱导的转化体注射到裸鼠中时，会形成高级别移行细胞癌。在塑料表面和软琼脂中，几种细胞因子（白细胞介素1α、白细胞介素6和肿瘤坏死因子-α）对这些转化体生长的刺激作用优于亲本细胞。我们的结果表明，H2O2会引起基因变化，从而诱导尿路上皮细胞发生致瘤性转化，并且转化体因其对几种细胞因子的选择性反应而被刺激生长。我们认为这些机制可能参与了与慢性泌尿系统感染相关的体内致癌过程。
