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Gene expression profiling of human mesothelioma cell lines derived from pleural effusions

ABSTRACT: Malignant pleural mesothelioma (MPM) is an asbestos-related lethal malignancy refractory to conventional therapies. Since its symptoms are not specific, MPM can be easily confused with other chest diseases, especially metastatic lung adenocarcinomas (ADCA), and diagnosis is often established late when the disease is at an advanced stage. Classically, a reliable diagnosis requires histological analysis of multiple pleural biopsies. However, there is still no absolute marker for MPM. Thus, with the aim of identifying novel markers with higher specificity and sensitivity, gene expression profiling studies have been conducted using tumor specimens. Because of the cell heterogeneity of tumor samples, we decided to apply counterflow centrifugal elutriation to isolate cancer cells from pleural effusions, which are a common feature of MPM and ADCA. We profiled a total of 54 biological samples corresponding to triplicates of 13 MPM and 4 ADCA as well as the SV40-immortalized cell line MeT-5A. Our microarray results confirmed some of the existing markers which are currently used to distinguish MPM from ADCA by immunostaining of pleural biopsies and which have also been proposed for use in a PCR-based assay. Of particular interest, we also identified novel cellular markers (including predominantly COL3A1, OSAP, OCIAD2, XAGE1), which we validated by real time RT-PCR, and novel soluble markers, such as osteonectin and galectin-3, whose clinical utility as molecular targets remains to be determined. Keywords: cell type comparison three-condition experiment: ADCA vs MPM vs Met5A cells 13 MPM, 4 ADCA and Met5A were independantly grown and harvested 3 biological replicates per cell line, one replicate per array

ORGANISM(S): Homo sapiens

SUBMITTER: Gueugnon Fabien

PROVIDER: S-ECPF-GEOD-17310 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:BackgroundPatients with malignant mesothelioma have a poor prognosis and only 40% respond to first line treatment; a combination of pemetrexed and cisplatin or carboplatin. We used primary malignant mesothelioma cells and an ex vivo chemosensitivity assay with future purpose to predict best choice of treatment. The clinical outcome of these patients might be predicted by measuring drug sensitivity.MethodsPleural effusions containing primary malignant mesothelioma cells were received from the diagnostic routine. We characterized and tested the chemosensitivity of 18 malignant samples and four benign samples from 16 different patients with pleural effusions. Cells were seeded in a 384-well plate for a robotized ex vivo testing of drug sensitivity to 32 different drugs. The primary cells were further characterized by immunocytochemistry to evaluate the proportion of malignant cells and to study the RRM1 and ERCC1 reactivity, two proteins associated with drug resistance.ResultsWe observed great individual variability in the drug sensitivity. Primary cell isolates were affected by between one and ten drugs, and resistant to the remaining tested drugs. Actinomycin D and daunorubicin were the two drugs effective in most cases. Adjusting efficiency of individual drugs for varying proportion of tumor cells and to the average effect on benign cells correlated with effect of pemetrexed, cisplatin and survival time. General drug sensitivity, proportion of malignant cells and reactivity to RRM1 correlated to each other and to survival time of the patients.ConclusionsThe proportion of malignant cells and RRM1 reactivity in the pleural effusions correlate to drug sensitivity and survival time. The variability in response to the commonly used chemotherapies emphasizes the need for tests that indicate best individual choice of cytotoxic drugs. The efficiency of the obtained results should preferably be corrected for admixture of benign cells and effects of given drugs on benign cells.

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Gene expression profiling of human mesothelioma cell lines derived from pleural effusions

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