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)和白介素8(IL-8)在调节膀胱移行细胞癌(TCC)发生和转移过程中的相对活性。我们对特定表达克隆原位移植后的肿瘤发生和自发性淋巴结转移的产生进行了过渡性评估。结果：在体外，特异性表达最高和最低的克隆均能稳定表达特异性总R-…更多的NA和蛋白质。移植到裸鼠膀胱中后，bFGF和IL-8表达最高的克隆细胞仅在早期获得了更高的致瘤性。此外，与亲本253JB-V细胞系相比，表达最低bFGF和最低IL-8的克隆的致瘤性在所有阶段都受到持续抑制。BFGF-和IL-8表达最高的克隆细胞在早期相对获得转移。此外，与亲本253JB-V细胞系相比，IL-8表达最低的克隆的转移受到相对抑制。与亲本253JB-V细胞相比，各高表达克隆的成瘤性和转移性差异无统计学意义，各高表达克隆均显著增强肿瘤细胞的特异性mRNA表达和新生血管，低表达克隆仅在早期显著降低特异性mRNA表达和新生血管。而在4周内，特异性表达克隆的肿瘤内新生血管和bFGF、VEGF、IL-8的表达水平逐渐被调节到与亲代253JB-V细胞相同的表达水平。结论：bFGF的表达调控裸鼠膀胱癌的血管生成和致瘤性，尤其是在肿瘤进展的早期阶段。因此，本研究为血管生成通路的靶向治疗在膀胱移行细胞癌的早期进展中提供了一种新的、有效的、有希望的治疗方法，具有显著的抗肿瘤作用。较少

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