Effect of reproductive hormones on ovarian epithelial tumors: II. Effect on angiogenic activity.
Menstrual cycle activity predisposes to ovarian epithelial tumors based on numerous epidemiological studies. We showed that the hormones involved in menstrual cycle regulation modulate cell cycle activity in these tumors in an accompanying paper. We investigated whether such hormones could also influence angiogenesis, an important determinant of tumor progression, in the same tumors. Treatment with progesterone (P4) stimulated VEGF protein secretion in 4 of 5 ovarian carcinoma cell lines examined. Northern blot analyses performed in MCV50 cells showed that this effect was accompanied by increased VEGF mRNA levels. P4 also stimulated VEGF promoter activity in these cells. Estradiol (E2) showed a similar, but substantially smaller effect on VEGF secretion which was additive to that of P4. Conditioned medium from P4-treated cells strongly stimulated angiogenesis on chicken chorio-allantoic membranes. Incubating the conditioned medium with a neutralizing anti-VEGF antibody, but not with non-specific immunoglobulins abolished this effect. Angiogenic activity was not altered by treatment of the membranes with P4 directly. We conclude that P4 can stimulate angiogenic activity via induction of VEGF secretion in some ovarian epithelial tumors. Therapeutic use of progestins may be most effective when administered in combination with an anti-angiogenic agent, at least against a subset of ovarian carcinomas.
Chen
Chen
C
Deportment of Pathology USC/Norris Comprehensive Concer Center, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
Petitclerc
Eric
E
Zhou
Hong
H
Brooks
Peter C
PC
Sun
Tong
T
Yu
Mimi C
MC
Zheng
Wenxin
W
Dubeau
Louis
L
D000482:Allantois / Q000737:chemistry; D000818:Animals; D015152:Blotting, Northern; D002642:Chick Embryo; D002823:Chorion / Q000737:chemistry; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000098:blood supply*; D011374:Progesterone / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements; D014162:Transfection; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011374:Progesterone; D004958:Estradiol; D008156:Luciferases