Angiogenic Factors Regulate Tumorigenicity and Metastasis of Human Transitional Cell Carcinoma in the Urinary Bladder

目的：探讨碱性成纤维细胞生长因子（bFGF）、血管内皮生长因子/血管通透性因子（VEGF/VPF）和白细胞介素-8 （IL-8）在膀胱移行细胞癌（TCC）致瘤性和转移过程中的相对活性。实验设计：根据高致瘤性、高转移性人TCC细胞系253JB-V中bFGF、VEGF或IL-8 m的表达水平选择特异性表达克隆。我们评估了特异性表达克隆原位植入后的过渡性肿瘤发生和自发淋巴结转移的产生。为了评估血管生成的过渡性变化和血管生成因子的表达，我们检测了肿瘤内新生血管和血管生成因子mRNA的表达。结果：体外最高和最低特异性表达克隆均能稳定表达特异性总rna、更多NA和蛋白。植入胸腺裸鼠膀胱后，最高bFGF-和最高il -8表达的克隆细胞仅在早期获得更高的致瘤性。此外，与亲本253JB-V细胞系相比，最低bFGF-和最低il -8表达的克隆在所有阶段的致瘤性均被一致抑制。bFGF-和il -8表达最高的克隆细胞相对较早获得转移。此外，il -8表达最低的克隆与亲本253JB-V细胞系相比，转移受到相对抑制。然而，VEGF特异性表达克隆的致瘤性和转移性与亲本253JB-V细胞系无显著差异。在肿瘤中，与亲本253JB-V细胞系相比，每一个最高表达克隆均显著增加了特异性mRNA表达和新生血管，而每一个最低表达克隆仅在早期显著降低了特异性mRNA表达和新生血管。而特异性表达克隆的肿瘤内新生血管及肿瘤内bFGF、VEGF、IL-8的表达水平在4周内逐渐调节至与亲代253JB-V细胞系相同的表达水平。结论：上述结果提示bFGF的表达可调节裸小鼠膀胱中生长的人TCC的血管生成和致瘤性，特别是在肿瘤进展的早期。因此，本研究提供了证据，证明以bFGF等血管生成途径为靶点的治疗在膀胱TCC肿瘤进展早期是一种新颖、有效、有前景的治疗方法，具有显著的抗肿瘤作用。少

Purpose : This study was designed to determine the relative activity of basic fibroblast growth factor (bFGF), vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), and interleukin-8 (IL-8) in the process of regulating tumorigenicity and metastasis of transitional cell carcinoma (TCC) of the urinary bladder.Experimental Design : We selected the specific expression clones as indicated to the expression level of bFGF, VEGF or IL-8 m highly tumorigenic and highly metastatic human TCC cell line 253JB-V. We evaluated transitionally tumorigemcily and production of spontanous lymph node metastases after orthotopic implantation of the specific expression clones. To assess the transitional changes of angiogenesis and the expression of angiogenic factors, intratumor neovascularization and mRNA expression of angiogenic factors were determined in the tumors.Results : In vitro, the highest and lowest specific expression clones demonstrated stable expression of specific total R … More NA and protein. Following implantation into the bladders of athymic nude mice, the highest bFGF- and the highest IL-8-expressing clone cells acquired increased tumorigenicity in only early stage. Moreover, the tumorigenicity of the lowest bFGF- and the lowest IL-8-expressing clone were consistently inhibited through all stages compared to parental 253JB-V cell lines. The highest bFGF- and the highest IL-8-expressing clone cells relatively acquired matastasis in earlier stage. Moreover, the metastasis of the lowest IL-8-expressing clone was relatively inhibited compared to parental 253JB-V cell lines. However, the tumorigenicity and metastasis of the specific expression clones of VEGF were not significantly different from that of parental 253JB-V cell lines.In the tumors, each highest expressing clone significantly increased the specific mRNA expression and neovascularity, and each lowest expressing clone significantly decreased specific mRNA expression and neovascularity in only early stage compared to parental 253JB-V cell lines. However, the intratumor neovascularity and the expression level or bFGF, VEGF and IL-8 in the tumor of the specific expression clones were gradually regulated to the same expression level as parental 253JB-V cell lines within 4 weeks.Conclusions : These findings indicate that the expression of bFGF regulates angiogenesis, tumorigenicity especially in early stage of tumor progression of human TCC growing in the urinary bladder of athymic nude mice. Thereore, this study provided tha evidence that the therapy targeting angiogenesis pathways such as bFGF represents a novel, effective, and promising therapy with significant anti-tumoral effect, in the early stage of tumor progression of TCC in the urinary bladder. Less