Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic

Serous epithelial ovarian cancer (EOC) patients often succumb to aggressive metastatic disease, yet little is usually known about the behavior and genetics of ovarian cancer metastasis. lethal cisplatin concentrations. These observations suggest that at least two of the miRNAs, miR-146a and miR-150, up-regulated in omental lesions, stimulate survival and increase drug tolerance. Our observations suggest that cancer cells in omental tumors express key miRNAs differently than primary tumors, and that at least some of these microRNAs may be crucial regulators of the emergence of drug resistant disease. Introduction Serous Epithelial MKK6 Ovarian Cancer (EOC) is usually an aggressive disease for which there are few effective biomarkers and therapies. EOC is usually often diagnosed after tumor cells have disseminated within the peritoneal cavity [1]. Despite the fact that metastases account for the majority of disease-related deaths, ovarian cancer metastasis remains poorly comprehended [1]. The purpose of this study was to identify features that may be important to establish metastases and to determine how these factors may affect chemotherapy responses. Advanced metastatic disease remains GNE-900 supplier a daunting challenge to treat, most often leading to recurrent, drug resistant tumors. Metastases can be enriched for a distinct mutational spectrum compared to primary tumors [2], [3], [4]. Comparing primary and metastatic tumors has generated important insights into disease progression in both animal models [5] and in patients [2]. To improve treatment of metastatic disease, it is usually vital to understand the genes and pathways emerging in metastases that may not be present in primary GNE-900 supplier tumors. Although metastatic potential can be predicted based on the primary tumor [6], [7], this observation is usually not mutually unique with the possibility that key features emerge in metastases that are not observed in primary tumors. For example, the new microenvironment can induce significant phenotypic changes to cancer cells, including changes to metabolic activity in the omentum [8], and increased drug resistance [9]. Previous mRNA manifestation studies examining matched up ovarian primary and metastatic tumors from the same patient, support a primary tumor predisposition model [6], [10], [11], [12]. mRNA manifestation data using early generation microarrays suggest there are few significant manifestation differences between omental lesions and primary tumors [13], [14], [15], however, numerous studies have described differential manifestation of key regulatory factors between primary tumors and metastases, including E-cadherin [16], MMPs [17], [18] and integrins [19]. To address this apparent discrepancy and to gain new insights into the state of cancer cells in metastases, we profiled miRNA manifestation in matched up pairs of primary serous epithelial ovarian (EOC) tumors and omental lesions. miRNA manifestation profiling identifies miR-150 and miR-146a to be up-regulated in omental metastases. We find that miR-150 and miR-146a promote spheroid formation and increase the fraction of residual surviving cells after cisplatin exposure. These observations suggest that higher manifestation of miR-146a and miR-150 in omental lesions may lead to more aggressive, chemoresistant disease. Results We identified 9 Stage IIIC serous epithelial ovarian cancer patients with pairs of primary and omental metastatic tumor specimens (Physique H1, Table H1). All patients were post-menopausal (>55 years aged at time of diagnosis) and had metastatic disease in the omentum. We assessed miRNA manifestation using Taqman qPCR array cards in the 9 pairs of tumors. Each tumor had >70% cancer cells, and good RNA quality (Agilent Bioanalyzer RIN>5). Our focus is usually to understand the changes manifesting during disease progression, and therefore we have focused on comparing the metastases to the primary tumors and did not consider normal ovarian epithelial cells. Identification of miRNAs differentially GNE-900 supplier expressed between primary and metastatic tumors We assessed 377 miRNAs using ABI Taqman qPCR arrays, specific for mature miRNAs [20], in 9 matched up primary and metastatic human tumors. 180 miRNAs GNE-900 supplier are expressed, in at least two tumors, with no global up- or down-regulation of these miRNAs between the primary and metastatic tumors. Physique 1A summarizes the miRNAs with large recurring manifestation. GNE-900 supplier