Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model.
Ovarian cancer is the most lethal gynecological malignancy and the fifth most common cause of cancer in women. It is characterized by diffuse peritoneal carcinomatosis and often by large volumes of i.p. ascites. Because vascular endothelial growth factor (VEGF), also known as vascular permeability factor, increases vascular permeability and stimulates endothelial cell growth, its role in ovarian cancer has been evaluated in a number of studies. However, questions remain regarding the ability of VEGF alone to cause ascites formation and the ability of VEGF blockade to inhibit the growth of disseminated cancer. We have used retroviral technology to create cell populations that overproduce VEGF and report that enforced expression of VEGF by ovarian carcinoma cells dramatically reduces the time to onset of ascites formation. In fact, even tumor-free peritoneal overexpression of VEGF, created by using adenoviral vectors, is sufficient to cause ascites to accumulate. We have found that systemic administration of the VEGF-Trap, a recently described high-affinity soluble decoy receptor for VEGF, prevents ascites accumulation and also inhibits the growth of disseminated cancer. Remarkably, much as is observed in s.c. tumor models, VEGF blockade results in dramatic remodeling of the blood vessels in disseminated ovarian carcinoma. The potent effects of the VEGF-Trap in reducing both ascites and tumor burden suggest that it will be of value in a regimen for treatment of women with ovarian cancer and ascites.
Byrne
Annette T
AT
Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California 94143, USA.
Ross
Leorah
L
Holash
Joceyln
J
Nakanishi
Mikiye
M
Hu
Limin
L
Hofmann
Judith I
JI
Yancopoulos
George D
GD
Jaffe
Robert B
RB
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D001201:Ascites / Q000517:prevention & control*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; C475927:VEGF-Trap fusion protein, recombinant; D040262:Receptors, Vascular Endothelial Growth Factor