Expression of vascular endothelial growth factor in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis

Vascular endothelial growth factor (VEGF) and basic fibroblast growth facto r (bFGF) are proteins implicated in tumor-associated microvascular angiogen esis. Expressions of VEGF and bFGF in various stages of chemical-induced ra t bladder carcinogenesis were immunohistochemically investigated. Thirty-tw o male 6-week-old Wistar rats were given drinking water containing 0.05% N- butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 20 weeks. VEGF and bFGF were not detected in the normal bladder epithelium. In simple hyperplasia, inten sive expression of VEGF was observed in a few epithelial cells, and the exp ression of epithelial VEGF became more pronounced in papillary or nodular ( PN) hyperplasia and papilloma. In carcinoma, heterogeneous expression of VE GF was observed in focal tumor cells, intensely expressed in the invading t umor cells. Ultrastructurally, carcinoma cells showed VEGF immunoreactivity in the cytoplasmic matrix and some rough endoplasmic reticulum, and VEGF-p ositive and -negative carcinoma cells were also clearly defined. High level s of VEGF mRNA were observed in the carcinoma. However, bFGF was not detect ed in the epithelium throughout the carcinogenesis. Increased microvessel c ounts appeared at simple hyperplasia and became more pronounced in PN hyper plasia, papilloma, and carcinoma (F-test; P < 0.05). In the carcinoma, the microvessel counts of the VEGF-expressing tumor areas were significantly hi gher than that of the non-VEGF-expressing tumor areas (U-test; P < 0.05). T he present study suggests that upregulation of epithelial VEGF may begin at a quite early stage in BBN-induced rat bladder carcinogenesis, but bFGF ma y not be involved.