Epithelial ovarian cancer (EOC) is the ninth most common cancer diagnosed in Australian women, but the fifth most common cause of cancer related death. One of the pathways involved in EOC is the Wnt signalling pathway, a key developmental pathway which is often dysregulated in cancer and is thought to play a role in epithelial to mesenchymal transition (EMT) and metastasis.
In this study we investigated the expression of the Wnt ligand, Wnt-5a in a large cohort of 721 patients with benign, borderline and EOC disease. Wnt-5a expression was significantly higher in EOC compared to benign and borderline patients (p<0.0001). Patients with high Wnt-5a expression had a shorter relapse-free and disease-specific survival compared to patients with low or absent Wnt-5a. There was no difference in Wnt-5a expression amongst the histological subtypes of EOC (serous, endometrioid, mucinous and clear cell).
Wnt-5a expression was correlated with clinico-pathological parameters of EOC; positive correlation was found between Wnt-5a and tumour marker CA-125 (p=0.01). Wnt-5a expression was also significantly associated with patient age (p<0.0001), ascites (p<0.0001), residual disease (p<0.0001) and advanced FIGO stage (p=0.0075). In addition, there was a significant negative correlation between Wnt-5a and sFRP4 expression, an antagonist of the Wnt signalling pathway (p<0.0001).
This study demonstrated for the first time an association between Wnt-5a, sFRP4 and aggressive ovarian cancer. We are currently undertaking a series of in vitro studies investigating the effects of Wnt-5a modulation in the serous ovarian cancer cell line OVCAR3 and the normal ovarian surface cell line HOSE 6.3. Preliminary results using siRNA against Wnt-5a and recombinant Wnt-5a indicate that modulation of this Wnt ligand can effect downstream Wnt signalling and EMT.
In conclusion, we have shown in a large patient cohort that Wnt-5a plays an oncogenic role and is a predictor of poor survival for EOC patients.