Expression of angiogenesis-related genes regulates different steps in the process of tumor growth and metastasis in human urothelial cell carcinoma of the urinary bladder.

OBJECTIVE This study was designed to determine the relative activity of angiogenesis-related genes in the regulation of tumorigenicity and subsequent metastases of urothelial cell carcinomas (UC) of the urinary bladder. METHODS We selected the clones with the highest and lowest expression level of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF)/vascular permeability factor or interleukin-8 (IL-8) in the highly tumorigenic and metastatic human UC cell line 253J B-V. Tumorigenicity and production of spontaneous lymph node metastases were evaluated 1, 2, 4, 8 and 12 weeks after orthotopic implantation of each specific expression clone into the urinary bladder of athymic nude mice. Moreover, the transitional changes in the expression of angiogenesis-related genes and neovascularization were determined in tumors and metastases. RESULTS At the early stage of tumor growth following orthotopic implantation, tumorigenicity and metastases were significantly increased in the clones with the highest expression of bFGF and IL-8, while they were significantly inhibited in the clones with the lowest expression of bFGF and IL-8 compared to parental 253J B-V. In the tumors, specific expression of angiogenesis-related genes and intratumor neovascularity of each clone were gradually regulated to the same level as parental 253J B-V. In metastasized tumors of the highest and lowest IL-8-expressing clones, IL-8 expression was consistently high and low, respectively. CONCLUSIONS These findings indicate that at the early stage of tumor growth, bFGF and IL-8 expression play important roles in the regulation of angiogenesis, tumorigenicity and subsequent metastases of human bladder cancer.