Expression of vascular endothelial growth factor and its receptors during lung carcinogenesis by N-nitrosobis(2-hydroxypropyl)amine in rats

The expression of vascular endothelial growth factor (VEGF) and its recepto rs (VEGFRs), VEGFR-1/Flt-1 and VEGFR-2/Flk-1, was investigated by immunohis tochemical and northern blot analysis during lung carcinogenesis by N-nitro sobis(2-hydroxypropyl)amine (BHP) in male Wistar rats. After BHP was given in the drinking water for 12 wk, the rats were maintained without further t reatment until they were killed at 20-28 wk. Immunohistochemical studies re vealed VEGF expression in almost all malignancies, the reaction being stron gly positive in most adenocarcinomas (15 of 18; 83.3%) and squamous cell ca rcinomas (four of five; 80.0%), but less so in a total of 120 adenomas and 136 alveolar hyperplasias. In addition, VEGF mRNA and VEGFR mRNAs were foun d to be overexpressed in most adenocarcinomas and squamous cell carcinomas as well as in one to three of the five adenomas tested. The results indicat ed that VEGF and VEGFRs play important roles in the acquisition of malignan t potential by preneoplastic lung lesions induced by BHP in rats. Moreover, overexpression of VEGF was related to upregulation of VEGFR-1/Flt-1 and VE GFR-2/Flk-1 expression in malignant and premalignant lung lesions. (C) 1999 Wiley-Liss, Inc.