Functional significance of VEGFR-2 on ovarian cancer cells.
Vascular endothelial growth factor receptor (VEGFR) has recently been discovered on ovarian cancer cells, but its functional significance is unknown and is the focus of this study. By protein analysis, A2780-par and HeyA8 ovarian cancer cell lines expressed VEGFR-1 and HeyA8 A2774, and SKOV3ip1 expressed VEGFR-2. By in situ hybridization (ISH), 85% of human ovarian cancer specimens showed moderate to high VEGFR-2 expression, whereas only 15% showed moderate to high VEGFR-1 expression. By immunofluorescence, little or no VEGFR-2 was detected in normal ovarian surface epithelial cells, whereas expression was detected in 75% of invasive ovarian cancer specimens. To differentiate between the effects of tumor versus host expression of VEGFR, nude mice were injected with SKOV3ip1 cells and treated with either human VEGFR-2 specific antibody (1121B), murine VEGFR-2 specific antibody (DC101) or the combination. Treatment with 1121B reduced SKOV3ip1 cell migration by 68% (p < 0.01) and invasion by 72% (p < 0.01), but exposure to VEGFR-1 antibody had no effect. Treatment with 1121B effectively blocked VEGF-induced phosphorylation of p130Cas. In vivo treatment with either DC101 or 1121B significantly reduced tumor growth alone and in combination in the SKOV3ip1 and A2774 models. Decreased tumor burden after treatment with DC101 or 1121B correlated with increased tumor cell apoptosis, decreased proliferative index, and decreased microvessel density. These effects were significantly greater in the combination group (p < 0.001). We show functionally active VEGFR-2 is present on most ovarian cancer cells. The observed anti-tumor activity of VEGF-targeted therapies may be mediated by both anti-angiogenic and direct anti-tumor effects.
Spannuth
Whitney A
WA
Department of Gynecologic Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA.
Nick
Alpa M
AM
Jennings
Nicholas B
NB
Armaiz-Pena
Guillermo N
GN
Mangala
Lingegowda S
LS
Danes
Christopher G
CG
Lin
Yvonne G
YG
Merritt
William M
WM
Thaker
Premal H
PH
Kamat
Aparna A
AA
Han
Liz Y
LY
Tonra
James R
JR
Coleman
Robert L
RL
Ellis
Lee M
LM
Sood
Anil K
AK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D049109:Cell Proliferation; D050719:Crk-Associated Substrate Protein / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000473:pathology* / Q000628:therapy; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D050719:Crk-Associated Substrate Protein; D040301:Vascular Endothelial Growth Factor Receptor-2