Anti-VEGFA Therapy Reduces Tumor Growth and Extends Survival in a Murine Model of Ovarian Granulosa Cell Tumor

Abstract

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.

The molecular mechanism of ovarian granulosa cell tumors

“…New treatment strategies need to be explored. The employment of anti-VEGFA antibody in mouse model successfully slowed the tumor development through inhibiting the tumor cell proliferation [ 96 ]. Other studies also demonstrated anti-VEGF (or VEGFR) had conspicuous function in inhibiting GCT development [ 97 , 98 ].…”

Mitochondrial membrane depolarization enhances TRAIL-induced cell death in adult human granulosa tumor cells, KGN, through inhibition of BIRC5

“…Such findings suggest the development of new therapeutic strategies targeting Δψ m to more specifically treat aGCTs, in comparison to EOCs. Although there is limited clinical data focused solely on aGCTs, others have also described glycolytic signatures [ 32 ], with promising initial studies in mural models of GCTs [ 33 ], however the GCT field remains sparse, in comparison to EOCs. The availability of the KGN cell line to model aGCTs in vitro provides an important opportunity to characterize new basic research strategies, such as deciphering the role played by mitochondria as a hub of cellular signaling in response to cytotoxic treatment, independent of small clinical cohorts.…”

The impact of microRNA expression on cellular proliferation

“…It has been reported that over-expression of SLC25A37 causes cancer-related fatigue in patients with non-metastatic prostate cancer during external beam radiation therapy (Hsiao et al 2013). It is important to note that although we showed that over-expression of miR-22 leads to decreased expression of MXI1 and SLC25A37 , we did not perform the same functional study on the expression of the remaining 37 (potential target) genes, some of which are supported by previous studies such as the reduction of tumor cell proliferation when Vascular Endothelial Growth Factor A ( VEGFA ) was targeted in mouse model with ovarian granulosa cell tumor (Tsoi et al 2013). Additional studies of miR-22 and its target genes in cancers and other pathological contexts are warranted.…”