This project focuses on two members of the vascular endothelial growth factor (VEGF) family, i.e. VEGF and VEGF-D. Using a one-vector VEGF-Tet system, we showed that the switching on and off of VEGF has striking effects on tumor growth. Carcinoma cells lacking VEGF did not grow at all as xenografts in nude mice, whereas VEGF overexpressing cells showed marked growth advantage over the control, especially at the pre- vascular stage of tumor development. Based on these findings, VEGF appears to stimulate early tumor cell growth by a mechanism unrelated to its endothelial mitogenic effect. The present emphasis is on the growth enhancing effects of VEGF at the pre-vascular stage of tumor development. Our observation of greatly increased production of nitric oxide in the VEGF-overexpressing tumors, resulting in vasolidation, may partly explain the pre-vascular growth enhancing effects. To better understand the role of VEGF in mammary tumor development and progression, transgenic (MMTV/VEGF) and conditional knockout (MMTV/Cre- VEGF/Lox and WAP/MMTV-VEGF/Lox) approaches are employed as collaborative efforts. VEGF-D was recently discovered as a c-fos- induced gene in mouse fibroblasts. In contrast to VEGF, VEGF-B and -C, VEGF-D was not expressed in human breast carcinomas. In normal breast tissues, VEGF-D co-localized with a-actin in vascular smooth muscle cells and ductal myoepithelial cells. VEGF-D, like VEGF, is a ligand for the endothelial signaling VEGF receptor-2. We are testing the hypothesis that the vascular smooth muscle cell VEGF-D is anchored to the inactive VEGF-receptor-2 in order to maintain endothelial quiescence. - angiogenesis, Apoptosis, Breast, Cancer, NOS, - Human Tissues, Fluids, Cells, etc.
| Buck, T B; Hall, A L; Sinha, C C et al. (2000) cis-hydroxyproline stimulates the growth of rat mammary carcinoma cells. In Vivo 14:11-Jul |
| Schoeffner, D J; Thorgeirsson, U P (2000) Susceptibility of nonhuman primates to carcinogens of human relevance. In Vivo 14:149-56 |
| Harris, S R; Panaro, N J; Thorgeirsson, U P (2000) Oxidative stress contributes to the anti-proliferative effects of flavone acetic acid on endothelial cells. Anticancer Res 20:2249-54 |
| Panaro, N J; Popescu, N C; Harris, S R et al. (1999) Flavone acetic acid induces a G2/M cell cycle arrest in mammary carcinoma cells. Br J Cancer 80:1905-11 |
