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

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(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.