Expression of vascular endothelial growth factor (VEGF) and specific receptors (Flt-1 and Flk-1) in rat tongue carcinogenesis induced by 4-nitroquinofine 1-oxide

Tongue carcinoma is one of the most common malignant neoplasms in the oral cavity. To assess the role for angiogenesis in carcinogenesis of tongue carcinoma, we performed qualitative and quantitative analyses of vascular endothelial growth factor (VEGF) and two forms of the specific receptors (VEGFRs), Flt-1 and Flk-1, in rat tongue squamous cell carcinoma induced by 4-nitroquinoline 1-oxide. In situ hybridization and immunohistochemistry revealed the colocalization of VEGF and VEGFRs mRNA signals and protein immunoreactivities, respectively in the cytoplasm of the normal epithelial cells, dysplastic cells, cancer cells, and vascular endothelial cells. Both the labeling indices of VEGF and VEGFRs in immunostained sections and the immunoreactive intensities on immunoblots for VEGF and VEGFRs disclosed a duration-dependent increase along with disease progression. An increase in the VEGF labeling index positively correlated with increases in the Ki-67 labeling index and blood vessel density. The present results suggest that angiogenesis is necessary for carcinogenesis, and that VEGF has relevance to the pathomechanism of tongue carcinoma via paracrine and autocrine mechanisms.