Vascular endothelial growth factor (
VEGF) expression correlates with microvessel density, stage, malignant
ascites,
metastasis, and survival in
ovarian cancer. By transducing VEGF165 into a nontumorigenic rat ovarian surface epithelial cell line (ROSE199), we investigated the direct effect of an angiogenic phenotype on
tumor development. The neu oncogene, which is overexpressed in >30% of
ovarian cancers, was used in comparison. Neu-transfected ROSE199 cells showed phenotypic characteristics of transformation in vitro with an abundance of focus-forming units in monolayer cultures and anchorage-independent growth in soft
agar. In contrast,
VEGF-secreting ROSE199 cells (VR) retained normal morphology and in vitro growth characteristics (e.g., proliferation rate) compared with parental ROSE199 cells. Interestingly, injection of VR cells into athymic mice formed malignant
ascites in 100% of the animals when injected into the peritoneum and developed vascularized
tumors in 85% of the mice when injected s.c. Furthermore, blocking
VEGF-mediated signaling by the Flk-1/KDR receptor
kinase inhibitor
SU5416 significantly inhibited the growth of VR
tumors. To validate that the proangiogenic switch is responsible for
tumor development, the angiogenic phenotype was balanced by the inducible coexpression of
endostatin under the control of Tet-activated promoter. Coexpression of
endostatin along with
VEGF reversed the tumorigenic phenotype of VR cells. These studies show that alterations in the angiogenic characteristics of ovarian surface epithelium may play an important role in the etiology of
ovarian cancer, and that inhibition of angiogenesis can be effective in the treatment of
epithelial ovarian cancer.