Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are highly expressed in ovarian granulosa cell tumors

Abstract

Objective: Ovarian granulosa cell tumors (GCTs) are hormonally active sex cord stromal tumors accounting for 3-5% of all ovarian cancers. These tumors are generally diagnosed at an early stage but there is a high risk of recurrence, associated with high mortality. Treatment of recurrent GCTs is difficult, and biologically targeted treatment modalities are lacking. GCTs are highly vascularized, and angiogenic factors most probably play a role in their pathology. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, but in GCTs, the role of VEGF and its receptors VEGFR-1 (FLT1) and VEGFR-2 (KDR) remains largely unknown. Our objective is to study the expression of VEGF and its receptors in human GCTs. Methods: We analyzed GCTs from 106 patients for the expressions of VEGF and its receptors utilizing tumor tissue microarray, tumor mRNA, and patient serum samples. Results: We found that VEGF and its main biologically active receptor VEGFR-2 were highly expressed in primary and recurrent GCTs, when compared with normal granulosa-lutein cells. The expression of VEGF correlated positively to tumor microvessel density and to VEGFR-2 expression at the protein (P!0.05) and mRNA (P!0.05) levels. In contrast to VEGFR-2, the expression of VEGFR-1 was weak. Tumor VEGF protein expression was not prognostic for recurrence, however, we found high levels of circulating VEGF in the serum of patients with primary GCT. Conclusions:The results suggest an important role of VEGF and VEGFR-2 in GCT pathology and support the possibility of applying novel VEGF-or VEGFR-2-targeted treatments to patients with GCT.

Anti-Müllerian hormone inhibits growth of AMH type II receptor-positive human ovarian granulosa cell tumor cells by activating apoptosis

“…7,29,37,38 The latter were verified to possess the c.402C-G (p.C134W) mutation in FOXL2 5 and the mutation frequency of 95% corresponds to other published GCT series. [2][3][4] All histological diagnoses were carefully reevaluated, 29 patient charts were reviewed to obtain clinical data and recurrences were updated as of September 2009.…”

“…AMHRII mRNA or protein expression did not correlate with any analyzed clinicopathological parameters of the primary tumors, ie, age and menopause status of the patient at diagnosis, clinical stage, size of the tumor, tumor subtype, nuclear atypia, mitotic index, and risk of recurrence. 7,29 We also employed Kaplan-Meier analysis on the 79 primary GCTs for the correlation of AMHRII expression and recurrence-free survival, and found similar recurrence probability in tumors with high or low expression of AMHRII (data not shown), in contrast to earlier findings in ovarian cancer. 19 Figure 1 mRNA expression of AMH, AMHRII, ALK2, ALK3, ALK6, Smad1, and Smad5 in GCTs.…”

“…52 Accordingly, several previous studies utilizing human GCT tissue series (reviewed in Fuller and Chu 53 ) have focused on genes and factors involved in the normal granulosa cell function. 5,7,29,54 We now describe the expression patterns of the AMH-signaling pathway components in GCT in detail and show evidence for AMH being a growth inhibitor for GCT. Previously, AMHRII positivity and AMH responsiveness have been reported in ovarian cancers originating from the Müllerian duct derivatives.…”

“…[2][3][4] All histological diagnoses were carefully reevaluated, 29 patient charts were reviewed to obtain clinical data and recurrences were updated as of September 2009. 7 For the tumor size, a cutoff of tumor diameter 10 cm was chosen based on earlier GCT studies. [39][40][41] For controls, we utilized three normal ovarian tissue samples from three pre-menopausal women operated upon for cervical cancer.…”

“…6 GCT often presents in an early stage (Ia), and the overall prognosis is favorable. However, recurrences occur in up to 25% of patients, 7,8 presenting even decades after primary diagnosis, and mortality in recurrent disease is high. 9 The poor prognosis of recurrent GCTs or those primarily presenting in an advanced stage has warranted the search for new biologically targeted treatment modalities.…”