Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are highly expressed in ovarian granulosa cell tumors.
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.
Pediatric Research Center, Children's Hospital Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Central Hospital, PO Box 20, 00014 Helsinki, Finland.
Anniina
A
Färkkilä
Mikko
M
Anttonen
Jurate
J
Pociuviene
Arto
A
Leminen
Ralf
R
Butzow
Markku
M
Heikinheimo
Leila
L
Unkila-Kallio
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006106:Granulosa Cell Tumor / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000378:metabolism; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2