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

目的：本研究旨在测定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/VEGF）的相对活性，（VEGF/VPF）和白细胞介素-8（IL-8）在调节膀胱移行细胞癌（TCC）的致瘤性和转移过程中的作用。我们根据bFGF的表达水平选择特异性表达克隆，VEGF或IL-8在高致瘤性和高转移性人TCC细胞系253 JB-1中的作用我们评估了特异性表达克隆原位移植后的过渡性致瘤性和自发性淋巴结转移的产生。结果：在体外培养条件下，特异性表达最高和最低的克隆均能稳定表达特异性总RNA，而特异性总RNA表达最低的克隆则能稳定表达特异性总RNA，特异性总RNA表达最高的克隆能稳定表达特异性总RNA，特异性总RNA表达最低的克隆能稳定表达特异性总RNA，特异性总RNA表达最低的克隆能稳定表达特异性总RNA ...更多信息 NA和蛋白质。植入无胸腺裸鼠膀胱后，bFGF和IL-8表达最高的克隆细胞仅在早期获得致瘤性增加。此外，与亲本253 JB-V细胞系相比，最低bFGF表达克隆和最低IL-8表达克隆的致瘤性在所有阶段均受到一致抑制。bFGF和IL-8表达最高的克隆细胞在早期获得相对转移。此外，与亲本253 JB-V细胞系相比，最低IL-8表达克隆的转移相对受到抑制。VEGF特异性表达克隆的成瘤性和转移性与亲本253 JB-V细胞系无显著差异，在肿瘤中，各高表达克隆的特异性mRNA表达和新生血管数均显著高于亲本253 JB-V细胞系，而各低表达克隆的特异性mRNA表达和新生血管数仅在早期显著低于亲本253 JB-V细胞系。但在4周内，特异性表达克隆的肿瘤内新生血管和肿瘤内bFGF、VEGF和IL-8的表达水平逐渐被调节至与亲本253 JB-V细胞系相同的表达水平。这些发现表明bFGF的表达调节血管生成，在裸鼠膀胱内生长的人膀胱移行细胞癌的致瘤性，特别是肿瘤进展的早期阶段。因此，本研究为靶向血管生成通路（如bFGF）治疗膀胱移行细胞癌提供了新的、有效的、有前途的治疗方法，在膀胱移行细胞癌肿瘤进展的早期阶段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