Role of tumor-associated macrophage in tumor invasion and inhibition of tumor invasion in urothelial cancers

（导读）我们曾报道肿瘤组织中肿瘤相关巨噬细胞（tumor-associated macrophage， TAM）的密度与膀胱癌患者的预后有良好的相关性。我们还观察到胸苷磷酸化酶（TP）的表达在浸润性膀胱癌中明显高于浅表性膀胱癌，TP是一种有效的血管生成因子。因此，我们分析哪些因素对膀胱癌的肿瘤侵袭最重要。（材料与方法）对72例膀胱癌患者组织标本进行实时荧光定量PCR（ABI PRISM 7900HT, Applied Biosystems Japan Ltd）分析，其中浸润性癌34例，浅表性癌38例。我们分析了72例标本中MMP-1、MMP-2、MMP-7、MMP-9、MMP-14、TIMP-2、uPA、PAI-1、TS、DPD、TP、VEGF等肿瘤侵袭相关因子的表达情况。以GAPDH表达归一化表达水平。研究还探讨了这些因素之间的相关性。（结果）Real-time PCR分析显示，侵袭性癌组织中MMP-2、MMP-9、TIMP-2、uPA、TP的表达明显高于浅表性癌组织。其中奇数比最高的TP似乎对膀胱癌的肿瘤侵袭最为重要。TP表达与MMP-1、MMP-7、MMP-9、TIMP-2、uPA、PAI-1、DPD、VEGF表达显著相关。然后，我们研究了TP酶促反应产物2-脱氧-d核糖对这些因子在体外表达的影响。结果表明，在酸性条件下，2-脱氧-d核糖诱导MMP-2、MMP-9、uPA的表达。（结论）MMP-2、MMP-9、uPA和TP在膀胱癌的侵袭过程中起重要作用。TP在膀胱癌中可能通过诱导其他侵袭相关因子如MMP-2、MMP-9、uPA促进肿瘤侵袭。

(Introduction) we previously reported that the density of tumor-associated macrophage (TAM) in tumor tissue was well correlated with prognosis of bladder cancer patients. We also observed that the expression of thymidine phosphorylase (TP), one of the potent angiogenic factors, is significantly higher in invasive bladder cancers than that in superficial bladder cancers. Therefore we analyzed which factor was most important for the tumor invasion of bladder cancers. (Materials and Methods) Tissue specimens from 72 patients with bladder cancer, including 34 invasive cancers and 38 superficial cancers were analyzed for the expression by quantitative real-time PCR(ABI PRISM 7900HT, Applied Biosystems Japan Ltd). We analyzed the expression of various factors related with tumor invasion, such as MMP-1, MMP-2, MMP-7, MMP-9, MMP-14, TIMP-2, uPA, PAI-1, TS, DPD, TP, VEGF in 72 specimens. The expression level was normalized by GAPDH expression. Correlation among these factors was also investigated in the study. (Results) Real-time PCR analysis revealed that the expression of MMP-2, MMP-9, TIMP-2, uPA, TP was significantly higher in invasive cancers that in superficial cancers. Among them, TP with the highest odd-ratio seems to be most important for tumor invasion of bladder cancer. Furthermore, TP expression was significantly correlated with expression of MMP-1, MMP-7, MMP-9, TIMP-2, uPA, PAI-1, DPD, VEGF. We then investigated the effect of 2-deoxy-D-ribose, a product of TP enzymatic reaction on expression of these factors in vitro. The results showed that 2-deoxy-D-ribose induced expression of MMP-2, MMP-9, uPA in the acidic condition. (Conclusion) Our results suggest that MMP-2, MMP-9, uPA and TP plays important roles in tumor invasion of bladder cancer. TP may promote tumor invasion by induction of other invasion related factors, such as MMP-2, MMP-9, uPA in bladder cancers.