PO-138 Hedgehog signalling pathway activity in high-grade serous ovarian carcinoma

Abstract

IntroductionHigh-grade serous (ovarian) carcinoma (HGSC) is the most lethal gynaecological malignancy with a 5 year survival rate of approximately 30%. This is caused by the fact that most tumours are detected at late stage of disease and due to limited therapeutic options. Knowledge on the cellular origin of HGSC may be of help in developing targeted therapies. These therapies interfere with signalling transduction pathways (STP), which are chains of biochemical events controlling gene expression. One such STP is the hedgehog (HH) pathway. Previous research yielded contradictory results on HH activity in HGSC, possibly due to the erroneous interpretation of separate pathway components as a marker for functional pathway activity.As most HGSC are thought to arise from Fallopian tube epithelium, the aim of our study was to determine the functional HH activity in normal oviduct epithelium, HGSC and Fallopian tube stem cells (FTSC), in order to provide new insights in the HGSC cell type of origin and the potential use of HH targeted therapies. Additionally, we studied the activity of other STP.Material and methodsThis study used a novel computational diagnostic approach; signal transduction pathway activation analysis (STA-analysis), enabling quantitative measurements of the functional pathway activity based on inferring mRNA levels of specific target genes. STA-analysis was based on publicly available Affymetrix data (GSE69428 and GSE69453) containing microdissected HGSC (n=10), paired normal oviduct epithelium (n=10) and cultured FTSC (n=2).Results and discussionsDespite the fact that samples showed some RNA degradation we demonstrated an up-regulation of HH pathway activity in HGSC (p=0.001) and FTSC (p<0.05) compared to normal oviduct epithelium. The majority of HGSC were considered HH-active. HH activity in HGSC and FTSC were comparable, supporting the hypothesis of FTSC as the cell type of origin of HGSC. This is in agreement with earlier findings of Fallopian tube stem-like cells in cancerous lesions in the distal fimbriae. It is thought that the HH pathway is frequently reactivated in an oncogenic manner in HGSC, while inactive in the normal adult oviduct epithelium.ConclusionOur model showed significant up-regulation of the functional HH activity in HGSC and FTSC compared to normal oviduct epithelium, suggesting the HH STP has a tumour-promoting role in most HGSC. This subset of HH-active HGSC might be of interest for HH targeted therapies.