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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Characterization and drug sensitivity profiling of primary malignant mesothelioma cells from pleural effusions

Authors: Adam Szulkin, Rita Ötvös, Carl-Olof Hillerdal, Aytekin Celep, Eviane Yousef-Fadhel, Henriette Skribek, Anders Hjerpe, László Székely, Katalin Dobra

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

Patients 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.

Methods

Pleural 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.

Results

We 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.

Conclusions

The 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.
Appendix
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Literature
1.
Wagner JC, Sleggs CA, Marchand P: Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br J Ind Med. 1960, 17: 260-271.PubMedPubMedCentral
2.
Suzuki Y: Pathology of human malignant mesothelioma–preliminary analysis of 1,517 mesothelioma cases. Ind Health. 2001, 39 (2): 183-185. 10.2486/indhealth.39.183.CrossRefPubMed
3.
Antman K, Shemin R, Ryan L, Klegar K, Osteen R, Herman T, Lederman G, Corson J: Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women’s Hospital experience over two decades, 1965-1985. J Clin Oncol. 1988, 6 (1): 147-153.PubMed
4.
Porcel JM, Light RW: Diagnostic approach to pleural effusion in adults. Am Fam Physician. 2006, 73 (7): 1211-1220.PubMed
5.
Abakay A, Abakay O, Tanrikulu AC, Sezgi C, Sen H, Kaya H, Kucukoner M, Kaplan MA, Celik Y, Senyigit A: Effects of treatment regimens on survival in patients with malignant pleural mesothelioma. Eur Rev Med Pharmacol Sci. 2013, 17 (1): 19-24.PubMed
6.
Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Paoleti P: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003, 21 (14): 2636-2644. 10.1200/JCO.2003.11.136.CrossRefPubMed
7.
Nowak AK: Chemotherapy for malignant pleural mesothelioma: a review of current management and a look to the future. Ann Cardiothorac Surg. 2012, 1 (4): 508-515.PubMedPubMedCentral
8.
Blayney JK, Ceresoli GL, Castagneto B, O'Brien ME, Hasan B, Sylvester R, Rudd R, Steele J, Busacca S, Porta C, Fennell DA: Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma. Eur J Cancer. 2012, 48 (16): 2983-2992. 10.1016/j.ejca.2012.05.018.CrossRefPubMed
9.
Rabik CA, Dolan ME: Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 2007, 33 (1): 9-23. 10.1016/j.ctrv.2006.09.006.CrossRefPubMed
10.
Wang J, Lohman GJ, Stubbe J: Enhanced subunit interactions with gemcitabine-5′-diphosphate inhibit ribonucleotide reductases. Proc Natl Acad Sci U S A. 2007, 104 (36): 14324-14329. 10.1073/pnas.0706803104.CrossRefPubMedPubMedCentral
11.
Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Soria JC: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006, 355 (10): 983-991. 10.1056/NEJMoa060570.CrossRefPubMed
12.
Reynolds C, Obasaju C, Schell MJ, Li X, Zheng Z, Boulware D, Caton JR, Demarco LC, O'Rourke MA, Shaw Wright G, Bepler G: Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. J Clin Oncol. 2009, 27 (34): 5808-5815. 10.1200/JCO.2009.21.9766.CrossRefPubMedPubMedCentral
13.
Zimling ZG, Sorensen JB, Gerds TA, Bech C, Andersen CB, Santoni-Rugiu E: Low ERCC1 expression in malignant pleural mesotheliomas treated with cisplatin and vinorelbine predicts prolonged progression-free survival. J Thorac Oncol. 2012, 7 (1): 249-256. 10.1097/JTO.0b013e318233d6a9.CrossRefPubMed
14.
Ting S, Mairinger FD, Hager T, Welter S, Eberhardt WE, Wohlschlaeger J, Schmid KW, Christoph DC: ERCC1, MLH1, MSH2, MSH6, and betaIII-tubulin: resistance proteins associated with response and outcome to platinum-based chemotherapy in malignant pleural mesothelioma. Clin Lung Cancer. 2013, 14 (5): 558-567. 10.1016/j.cllc.2013.04.013. e553CrossRefPubMed
15.
Zimling ZG, Sorensen JB, Gerds TA, Bech C, Andersen CB, Santoni-Rugiu E: A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma. Cancer Chemother Pharmacol. 2012, 70 (5): 743-754. 10.1007/s00280-012-1965-0.CrossRefPubMed
16.
Szulkin A, Nilsonne G, Mundt F, Wasik AM, Souri P, Hjerpe A, Dobra K: Variation in drug sensitivity of malignant mesothelioma cell lines with substantial effects of selenite and bortezomib, highlights need for individualized therapy. PLoS One. 2013, 8 (6): e65903-10.1371/journal.pone.0065903.CrossRefPubMedPubMedCentral
17.
Besse B, Olaussen KA, Soria JC: ERCC1 and RRM1: ready for prime time?. J Clin Oncol. 2013, 31 (8): 1050-1060. 10.1200/JCO.2012.43.0900.CrossRefPubMed
18.
Mundt F, Nilsonne G, Arslan S, Csuros K, Hillerdal G, Yildirim H, Metintas M, Dobra K, Hjerpe A: Hyaluronan and N-ERC/mesothelin as key biomarkers in a specific two-step model to predict pleural malignant mesothelioma. PLoS One. 2013, 8 (8): e72030-10.1371/journal.pone.0072030.CrossRefPubMedPubMedCentral
19.
Creaney J, Sneddon S, Dick IM, Dare H, Boudville N, Musk AW, Skates SJ, Robinson BW: Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum. Dis Markers. 2013, 35 (2): 119-127.CrossRefPubMedPubMedCentral
20.
Creaney J, Dick IM, Segal A, Musk AW, Robinson BW: Pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma. Lung Cancer. 2013, 82 (3): 491-498. 10.1016/j.lungcan.2013.09.016.CrossRefPubMed
21.
Thylen A, Hjerpe A, Martensson G: Hyaluronan content in pleural fluid as a prognostic factor in patients with malignant pleural mesothelioma. Cancer. 2001, 92 (5): 1224-1230. 10.1002/1097-0142(20010901)92:5<1224::AID-CNCR1441>3.0.CO;2-U.CrossRefPubMed
22.
Toole BP: Hyaluronan promotes the malignant phenotype. Glycobiology. 2002, 12 (3): 37R-42R. 10.1093/glycob/12.3.37R.CrossRefPubMed
23.
Liu Z, Dobra K, Hauzenberger D, Klominek J: Expression of hyaluronan synthases and hyaluronan in malignant mesothelioma cells. Anticancer Res. 2004, 24 (2B): 599-603.PubMed
24.
Asplund T, Heldin P: Hyaluronan receptors are expressed on human malignant mesothelioma cells but not on normal mesothelial cells. Cancer Res. 1994, 54 (16): 4516-4523.PubMed
25.
Hassan R, Ho M: Mesothelin targeted cancer immunotherapy. Eur J Cancer. 2008, 44 (1): 46-53. 10.1016/j.ejca.2007.08.028.CrossRefPubMed
26.
Chang K, Pastan I, Willingham MC: Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium. Int J Cancer. 1992, 50 (3): 373-381. 10.1002/ijc.2910500308.CrossRefPubMed
27.
Hassan R, Bera T, Pastan I: Mesothelin: a new target for immunotherapy. Clin Cancer Res. 2004, 10 (12 Pt 1): 3937-3942.CrossRefPubMed
28.
Hjerpe A: Liquid-chromatographic determination of hyaluronic acid in pleural and ascitic fluids. Clin Chem. 1986, 32 (6): 952-956.PubMed
29.
Dejmek A, Hjerpe A: The combination of CEA, EMA, and BerEp4 and hyaluronan analysis specifically identifies 79% of all histologically verified mesotheliomas causing an effusion. Diagn Cytopathol. 2005, 32 (3): 160-166. 10.1002/dc.20202.CrossRefPubMed
30.
Flores-Staino C, Darai-Ramqvist E, Dobra K, Hjerpe A: Adaptation of a commercial fluorescent in situ hybridization test to the diagnosis of malignant cells in effusions. Lung Cancer. 2010, 68 (1): 39-43. 10.1016/j.lungcan.2009.05.004.CrossRefPubMed
31.
Segal A, Sterrett GF, Frost FA, Shilkin KB, Olsen NJ, Musk AW, Nowak AK, Robinson BW, Creaney J: A diagnosis of malignant pleural mesothelioma can be made by effusion cytology: results of a 20 year audit. Pathology. 2013, 45 (1): 44-48. 10.1097/PAT.0b013e32835bc848.CrossRefPubMed
32.
Klominek J, Robert KH, Hjerpe A, Wickstrom B, Gahrton G: Serum-dependent growth patterns of two, newly established human mesothelioma cell lines. Cancer Res. 1989, 49 (21): 6118-6122.PubMed
33.
Schmitter D, Lauber B, Fagg B, Stahel RA: Hematopoietic growth factors secreted by seven human pleural mesothelioma cell lines: interleukin-6 production as a common feature. Int J Cancer. 1992, 51 (2): 296-301. 10.1002/ijc.2910510220.CrossRefPubMed
34.
Pelin-Enlund K, Husgafvel-Pursiainen K, Tammilehto L, Klockars M, Jantunen K, Gerwin BI, Harris CC, Tuomi T, Vanhala E, Mattson K, Linnainmaa K: Asbestos-related malignant mesothelioma: growth, cytology, tumorigenicity and consistent chromosome findings in cell lines from five patients. Carcinogenesis. 1990, 11 (4): 673-681. 10.1093/carcin/11.4.673.CrossRefPubMed
35.
Otvos R, Skribek H, Kis LL, Gloghini A, Markasz L, Flaberg E, Eksborg S, Konya J, Gergely L, Carbone A, Szekely L: Drug sensitivity patterns of HHV8 carrying body cavity lymphoma cell lines. BMC Cancer. 2011, 11: 441-10.1186/1471-2407-11-441.CrossRefPubMedPubMedCentral
36.
Skribek H, Otvos R, Flaberg E, Nagy N, Markasz L, Eksborg S, Masszi T, Kozma A, Adam E, Miseta A, Szekely L: Chronic lymphoid leukemia cells are highly sensitive to the combination of prednisolone and daunorubicin, but much less to doxorubicin or epirubicin. Exp Hematol. 2010, 38 (12): 1219-1230. 10.1016/j.exphem.2010.09.001.CrossRefPubMed
37.
Flaberg E, Sabelstrom P, Strandh C, Szekely L: Extended Field Laser Confocal Microscopy (EFLCM): combining automated Gigapixel image capture with in silico virtual microscopy. BMC Med Imaging. 2008, 8: 13-10.1186/1471-2342-8-13.CrossRefPubMedPubMedCentral
38.
Fennell DA, Gaudino G, O'Byrne KJ, Mutti L, van Meerbeeck J: Advances in the systemic therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol. 2008, 5 (3): 136-147. 10.1038/ncponc1039.CrossRefPubMed
39.
Ellis P, Davies AM, Evans WK, Haynes AE, Lloyd NS: The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline. J Thorac Oncol. 2006, 1 (6): 591-601. 10.1097/01243894-200607000-00017.CrossRefPubMed
40.
41.
Nilsonne G, Olm E, Szulkin A, Mundt F, Stein A, Kocic B, Rundlof AK, Fernandes AP, Bjornstedt M, Dobra K: Phenotype-dependent apoptosis signalling in mesothelioma cells after selenite exposure. J Exp Clin Cancer Res. 2009, 28: 92-10.1186/1756-9966-28-92.CrossRefPubMedPubMedCentral
42.
Vilmar AC, Santoni-Rugiu E, Sorensen JB: Predictive impact of RRM1 protein expression on vinorelbine efficacy in NSCLC patients randomly assigned in a chemotherapy phase III trial. Ann Oncol. 2013, 24 (2): 309-314. 10.1093/annonc/mds335.CrossRefPubMed
43.
Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, Ceribelli A, Bearz A, Morenghi E, Cavina R, Santoro A: Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006, 24 (9): 1443-1448. 10.1200/JCO.2005.04.3190.CrossRefPubMed
44.
Katirtzoglou N, Gkiozos I, Makrilia N, Tsaroucha E, Rapti A, Stratakos G, Fountzilas G, Syrigos KN: Carboplatin plus pemetrexed as first-line treatment of patients with malignant pleural mesothelioma: a phase II study. Clin Lung Cancer. 2010, 11 (1): 30-35. 10.3816/CLC.2010.n.005.CrossRefPubMed
45.
Hillerdal G, Sorensen JB, Sundstrom S, Riska H, Vikstrom A, Hjerpe A: Treatment of malignant pleural mesothelioma with carboplatin, liposomized doxorubicin, and gemcitabine: a phase II study. J Thorac Oncol. 2008, 3 (11): 1325-1331. 10.1097/JTO.0b013e31818b174d.CrossRefPubMed
Metadata
Title
Characterization and drug sensitivity profiling of primary malignant mesothelioma cells from pleural effusions
Authors
Adam Szulkin
Rita Ötvös
Carl-Olof Hillerdal
Aytekin Celep
Eviane Yousef-Fadhel
Henriette Skribek
Anders Hjerpe
László Székely
Katalin Dobra
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-709

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