Taylor John A, Kuchel George A, Hegde Poornima, Voznesensky Olga S, Claffey Kevin, Tsimikas John, Leng Lin, Bucala Richard, Pilbeam Carol
Division of Urology, University of Connecticut Health Center, Farmington, CT, USA.
BMC Cancer. 2007 Jul 24;7:135. doi: 10.1186/1471-2407-7-135.
Inflammatory cytokines may promote tumorigenesis. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with regulatory properties over tumor suppressor proteins involved in bladder cancer. We studied the development of bladder cancer in wild type (WT) and MIF knockout (KO) mice given N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), a known carcinogen, to determine the role of MIF in bladder cancer initiation and progression.
5-month old male C57Bl/6 MIF WT and KO mice were treated with and without BBN. Animals were sacrificed at intervals up to 23 weeks of treatment. Bladder tumor stage and grade were evaluated by H&E. Immunohistochemical (IHC) analysis was performed for MIF and platelet/endothelial cell adhesion molecule 1 (PECAM-1), a measure of vascularization. MIF mRNA was analyzed by quantitative real-time polymerase chain reaction.
Poorly differentiated carcinoma developed in all BBN treated mice by week 20. MIF WT animals developed T2 disease, while KO animals developed only T1 disease. MIF IHC revealed predominantly urothelial cytoplasmic staining in the WT control animals and a shift toward nuclear staining in WT BBN treated animals. MIF mRNA levels were 3-fold higher in BBN treated animals relative to controls when invasive cancer was present. PECAM-1 staining revealed significantly more stromal vessels in the tumors in WT animals when compared to KOs.
Muscle invasive bladder cancer with increased stromal vascularity was associated with increased MIF mRNA levels and nuclear redistribution. Consistently lower stage tumors were seen in MIF KO compared to WT mice. These data suggest that MIF may play a role in the progression to invasive bladder cancer.
炎性细胞因子可能促进肿瘤发生。巨噬细胞移动抑制因子（MIF）是一种促炎细胞因子，对膀胱癌中涉及的肿瘤抑制蛋白具有调节特性。我们研究了给予已知致癌物N-丁基-N-（4-羟丁基）亚硝胺（BBN）的野生型（WT）和MIF基因敲除（KO）小鼠膀胱癌的发生情况，以确定MIF在膀胱癌起始和进展中的作用。
对5月龄雄性C57Bl/6 MIF WT和KO小鼠进行BBN处理或不处理。在长达23周的治疗期间定期处死动物。通过苏木精和伊红染色（H&E）评估膀胱肿瘤的分期和分级。对MIF和血小板/内皮细胞黏附分子1（PECAM-1，一种血管生成指标）进行免疫组织化学（IHC）分析。通过定量实时聚合酶链反应分析MIF mRNA。
到第20周时，所有接受BBN处理的小鼠均发生了低分化癌。MIF WT动物发生了T2期疾病，而KO动物仅发生了T1期疾病。MIF IHC显示，WT对照动物中主要为尿路上皮细胞质染色，而WT BBN处理动物中则向核染色转变。当存在浸润性癌时，BBN处理动物中的MIF mRNA水平相对于对照高3倍。与KO小鼠相比，WT动物肿瘤中的PECAM-1染色显示基质血管明显更多。
具有增加的基质血管生成的肌层浸润性膀胱癌与MIF mRNA水平升高和核重新分布相关。与WT小鼠相比，MIF KO小鼠中观察到的肿瘤分期始终较低。这些数据表明MIF可能在浸润性膀胱癌的进展中起作用。
