Distinct molecular signature of recurrent ovarian tumor cells isolated from the ascites of advanced-stage serous ovarian cancer patients

Seventypercent of ovarian cancer patientsdiedue toconsecutive episodesof recurrences resulting from the re-growth of ovarian tumor cells resistant to conventional chemotherapies. In an effort to identify chemoresistance mechanisms, we compared the expression of genes in tumor cells isolated from the ascites of advanced-stage serous ovarian cancer patients prior to (chemonaive,CN) andafter chemotherapy treatments (chemoresistant/recurrent, CR). A novel, recently publishedmethodwas used for the isolation of tumor cells from the ascites of CN and CR patients. Illumina HT-12 platform was used to assess the differential expressionof genes (DEGs) between the isolated tumor cells from the ascites ofCNandCRpatients. The identification of DEGswas achieved by comparing the genetic signatures of CN versusCR samples by amean expression ratio (fold change) of 2 and P < 0.05. Validation of selected genes was performed by quantitative Real Time Polymerase Chain Reaction (qRT-PCR). The dominant canonical pathways in the CR versus CN tumor cells were determined by Ingenuity Pathway Analysis. Gene expression analysis revealed differential expression of 414 genes, with 179 genes up regulated and 235 down regulated in theCR group. There were significant differences in gene expressions encoding for proteins involved with cancer stem cells, cell-cell adhesion, embryonic development, tumor suppression, immune surveillance, retinoic acid and energymetabolism in tumor cells isolated from CR compared to CN patients. Pathway analysis revealed that changes in cell cycle pathways, prominently those involved with mitosis and polo-like kinase (PLK1), G2/M DNA damage and proteins linked with cell cycle checkpoint regulation associated with chemoresistance. This preliminary molecular profiling, on a small number of patient samples, suggests an important discrimination of genes in the isolated tumor cells derived from the ascites of CN andCRpatients. This type of study on a larger cohort of samples may have important clinical implications for the development of therapeutic strategies to overcome chemoresistance and associated recurrences in ovarian cancer patients.