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Anti-VEGFA Therapy Reduces Tumor Growth and Extends Survival in a Murine Model of Ovarian Granulosa Cell Tumor12
Although angiogenesis has been proposed as a therapeutic target for the treatment of ovarian granulosa cell tumor (GCT), its potential has not been evaluated in controlled studies. To do so, we used the Pten tm1Hwu/tm1Hwu ; Ctnnb1 tm1Mmt/+ ; Amhr2 tm3(cre)Bhr/+ ( PCA ) mouse model, which develops GC...
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Published in: | Translational oncology 2013-06, Vol.6 (3), p.226-233 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
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Summary: | Although angiogenesis has been proposed as a therapeutic target for the treatment of ovarian granulosa cell tumor (GCT), its potential has not been evaluated in controlled studies. To do so, we used the
Pten
tm1Hwu/tm1Hwu
;
Ctnnb1
tm1Mmt/+
;
Amhr2
tm3(cre)Bhr/+
(
PCA
) mouse model, which develops GCTs that mimic the advanced disease in women. A monoclonal anti-vascular endothelial growth factor A (VEGFA) antibody was administered weekly to
PCA
mice beginning at 3 weeks of age. By 6 weeks of age, anti-VEGFA therapy significantly decreased tumor weights relative to controls (
P
< .05) and increased survival, with all treated animals but none of the controls surviving to 8 weeks of age. Analyses of
PCA
tumors showed that anti-VEGFA treatment resulted in significant decreases in tumor cell proliferation and microvessel density relative to controls (
P
< .05). However, treatment did not have a significant effect on apoptosis or tumor necrosis. The VEGFA receptor 2 (VEGFR2) signaling effector p44/p42 mitogen-activated protein kinase (MAPK), whose activity is associated with cell proliferation, was significantly less phosphorylated (i.e., activated) in tumors from the treated group (
P
< .05). Conversely, no significant difference was found in the activation of protein kinase B, a VEGFR2 signaling effector associated with cell survival. Together, these results suggest that anti-VEGFA therapy is effective at inhibiting GCT growth in the
PCA
model and acts by reducing microvascular density and cell proliferation through inhibition of the VEGFR2-MAPK pathway. Findings from this preclinical model therefore support the investigation of targeting VEGFA for the adjuvant treatment of GCT in women. |
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ISSN: | 1936-5233 |