Gene expression profiling of primary cultures of ovarian epithelial cells identifies novel molecular classifiers of ovarian cancer

Abstract

In order to elucidate the biological variance between normal ovarian surface epithelial (NOSE) and epithelial ovarian cancer (EOC) cells, and to build a molecular classifier to discover new markers distinguishing these cells, we analysed gene expression patterns of 65 primary cultures of these tissues by oligonucleotide microarray. Unsupervised clustering highlights three subgroups of tumours: low malignant potential tumours, invasive solid tumours and tumour cells derived from ascites. We selected 18 genes with expression profiles that enable the distinction of NOSE from these three groups of EOC with 92% accuracy. Validation using an independent published data set derived from tissues or primary cultures confirmed a high accuracy (87 -96%). The distinctive expression pattern of a subset of genes was validated by quantitative reverse transcription -PCR. An ovarian-specific tissue array representing tissues from NOSE and EOC samples of various subtypes and grades was used to further assess the protein expression patterns of two differentially expressed genes (Msln and BMP-2) by immunohistochemistry. This study highlights the relevance of using primary cultures of epithelial ovarian cells as a model system for gene profiling studies and demonstrates that the statistical analysis of gene expression profiling is a useful approach for selecting novel molecular tumour markers.

Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth

“…We and others have recently shown BMP signaling to be active in and regulate ovarian cancer cells as well. It has previously been shown that BMP ligands and signaling is increased in ovarian cancer cells in comparison to normal ovarian cells [46; 47]. Similar to previous studies, here we show that BMP ligands and receptors are overexpressed in more than 50% of ovarian cancer tumors and ovarian cancer cell lines (Figure 1, Supplementary Figure 1) and is endogenously active in ovarian cancer cell lines (Figure 2).…”

Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2

“…Supporting a role for BMP2 pathway activation in ovarian cancer, compared with normal ovarian surface epithelium, BMP2 is upregulated in ovarian cancer cells (25) whereas the BMP antagonist Chordin is down-regulated (26). Importantly, increased BMP2 expression in ovarian tumors is correlated with poor patient prognosis (27).…”

Human ovarian carcinoma–associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production

“…BMP4 has also been reported to drive tumorigenesis of ovarian cancer cells via the regulation of the proto-oncogene ID3 (40). BMP2 has been reported to be specifically upregulated in ovarian cancer cells as compared with normal ovarian surface epithelium (41). BMP2 also appears to have prognostic significance in ovarian cancer patients; BMP2 expression in tumor tissues from ovarian cancer patients has been shown to be inversely correlated with patient survival (34).…”