This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schumacher, J. J. Articles by Ramakrishnan, S. Search for Related Content PubMed PubMed Citation Articles by Schumacher, J. J. Articles by Ramakrishnan, S.

Modulation of Angiogenic Phenotype Alters Tumorigenicity in Rat Ovarian Epithelial Cells

Departments of ¹ Pharmacology, ² Biochemistry, Molecular Biology, and Biophysics, and ³ Obstetrics and Gynaecology, University of Minnesota, Minneapolis, Minnesota and ⁴ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Sundaram Ramakrishnan, University of Minnesota, 6-120 Jackson Hall, 321 Church Street Southeast, Minneapolis, MN 55445. Phone: 612-626-6461; Fax: 612-625-8408; E-mail: sunda001{at}tc.umn.edu.

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. [Cancer Res 2007;67(8):3683–90]

This article has been cited by other articles:

				W. Yan, B. Bentley, and R. Shao Distinct Angiogenic Mediators Are Required for Basic Fibroblast Growth Factor- and Vascular Endothelial Growth Factor-induced Angiogenesis: The Role of Cytoplasmic Tyrosine Kinase c-Abl in Tumor Angiogenesis Mol. Biol. Cell, May 1, 2008; 19(5): 2278 - 2288. [Abstract] [Full Text] [PDF]

				D. Belotti, C. Calcagno, A. Garofalo, D. Caronia, E. Riccardi, R. Giavazzi, and G. Taraboletti Vascular Endothelial Growth Factor Stimulates Organ-Specific Host Matrix Metalloproteinase-9 Expression and Ovarian Cancer Invasion Mol. Cancer Res., April 1, 2008; 6(4): 525 - 534. [Abstract] [Full Text] [PDF]