Molecular Studies on Pathogenesis, Prognostic Factors, and New Treatment Options for Ovarian Granulosa Cell Tumors

Granulosa cell tumor (GCT) is the second most common subtype of ovarian cancer, representing 5% of all ovarian malignancies. GCTs are characterized by an indolent course of disease, with a 5-year survival rate of over 90%. However, recurrences occur in 20-30% of patients, also those with early-stage disease, leading to increased mortality. The pathogenesis and factors affecting prognosis of GCTs are largely unknown. Further, the treatment of advanced or recurrent GCT is difficult underscoring the need for biologically targeted treatments for aggressive GCTs. The molecular mechanisms leading to GCT formation are likely to include regulators of granulosa cell proliferation and apoptosis. We studied granulosa cell regulators and tumor angiogenesis in GCTs utilizing tumor tissue and serum samples, and cell culture assays. The objectives of this study were to find new molecular prognostic factors and to identify targets for future biological treatments for GCT. GCTs express Anti-Müllerian Hormone (AMH) and knockout mouse models suggest that AMH acts as a growth inhibitor in GCT pathogenesis. We found that GCTs expressed AMH receptors, with the AMH type II receptor (AMHRII) being characteristic of GCTs. AMH expression was decreased in large GCTs, and recombinant AMH inhibited growth of GCT cells in vitro. The results support the premise that AMH acts as a growth inhibitor in GCTs, and AMH and AMHRII emerge as targets for treatment of GCT. Vascular Endothelial Growth Factor-A (VEGF) is a key factor in tumor angiogenesis that has been successfully targeted in cancer treatment. We found that VEGF and its functional receptor VEGFR-2 are highly expressed in GCTs; VEGFR-2 was also expressed in the active, phosphorylated form. GCTs produced significant amounts of VEGF that could also be detected in the serum of GCT patients. In cell culture assays, the inhibition of VEGF by soluble anti-VEGF antibody (bevacizumab) inhibited growth and induced apoptosis of GCT cells. These results indicate a pro-tumorigenic role of VEGF in GCTs and encourage targeting VEGF and VEGFR-2 in the treatment of GCTs. Transcription factor GATA4 associates with GCT pathogenesis and prognosis. We found that high tumor GATA4 expression was an independent prognostic factor for GCT recurrence. GATA4 was also prognostic of shorter disease-specific survival along with higher tumor stage (II-III) and nuclear atypia. These results suggest that GATA4 can be used as a new prognostic marker for GCT. Human Epidermal Growth Factor Receptor 2 (HER2) is a known oncogene and a target for treatment in breast and gastric cancer. We found that high expression of HER2 delineated an aggressive subset of GCTs and HER2 is thus a potential target for treatment also in this disease.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2012

Author dc:creator

• Färkkilä, Anniina

• lääketiede

Statement dc:rights

• Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
• This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited.
• Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden.

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/37248

OAI record oai:identifier

https://helda.helsinki.fi/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Ahelda.helsinki.fi%3A10138%2F37248