Abstract
ATP-binding cassette transporters (ABC transporters) regulate traffic of multiple compounds, including chemotherapeutic agents, through biological membranes. They are expressed by multiple cell types and have been implicated in the drug resistance of some cancer cells. Despite significant research in ABC transporters in the context of many diseases, little is known about their expression and clinical value in glioblastoma (GBM). We analyzed expression of 49 ABC transporters in both commercial and patient-derived GBM cell lines as well as from 51 human GBM tumor biopsies. Using The Cancer Genome Atlas (TCGA) cohort as a training dataset and our cohort as a validation dataset, we also investigated the prognostic value of these ABC transporters in newly diagnosed GBM patients, treated with the standard of care. In contrast to commercial GBM cell lines, GBM-patient derived cell lines (PDCL), grown as neurospheres in a serum-free medium, express ABC transporters similarly to parental tumors. Serum appeared to slightly increase resistance to temozolomide correlating with a tendency for an increased expression of ABCB1. Some differences were observed mainly due to expression of ABC transporters by microenvironmental cells. Together, our data suggest that the efficacy of chemotherapeutic agents may be misestimated in vitro if they are the targets of efflux pumps whose expression can be modulated by serum. Interestingly, several ABC transporters have prognostic value in the TCGA dataset. In our cohort of 51 GBM patients treated with radiation therapy with concurrent and adjuvant temozolomide, ABCA13 overexpression is associated with a decreased progression free survival in univariate (p < 0.01) and multivariate analyses including MGMT promoter methylation (p = 0.05) suggesting reduced sensitivity to temozolomide in ABCA13 overexpressing GBM. Expression of ABC transporters is: (i) detected in GBM and microenvironmental cells and (ii) better reproduced in GBM-PDCL. ABCA13 expression is an independent prognostic factor in newly diagnosed GBM patients. Further prospective studies are warranted to investigate whether ABCA13 expression can be used to further personalize treatments for GBM.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Change history
16 March 2018
The names of authors Marc Sanson and Jean-Yves Delattre were incorrectly presented in the initial online publication. The original article has been corrected.
References
Ostrom QT, Bauchet L, Davis FG et al (2014) The epidemiology of glioma in adults: a “state of the science” review. Neuro-Oncol 16:896–913. https://doi.org/10.1093/neuonc/nou087
Dréan A, Goldwirt L, Verreault M et al (2016) Blood-brain barrier, cytotoxic chemotherapies and glioblastoma. Expert Rev Neurother. https://doi.org/10.1080/14737175.2016.1202761
Vasiliou V, Vasiliou K, Nebert DW (2009) Human ATP-binding cassette (ABC) transporter family. Hum Genom 3:281–290
Hartz AMS, Bauer B (2011) ABC transporters in the CNS - an inventory. Curr Pharm Biotechnol 12:656–673
Sparreboom A, Danesi R, Ando Y et al (2003) Pharmacogenomics of ABC transporters and its role in cancer chemotherapy. Drug Resist Updat 6:71–84
Khamisipour G, Jadidi-Niaragh F, Jahromi AS et al (2016) Mechanisms of tumor cell resistance to the current targeted-therapy agents. Tumour Biol J Int Soc Oncodev Biol Med 37:10021–10039. https://doi.org/10.1007/s13277-016-5059-1
Brennan CW, Verhaak RGW, McKenna A et al (2013) The somatic genomic landscape of glioblastoma. Cell 155:462–477. https://doi.org/10.1016/j.cell.2013.09.034
Lundberg E, Fagerberg L, Klevebring D et al (2010) Defining the transcriptome and proteome in three functionally different human cell lines. Mol Syst Biol 6:450. https://doi.org/10.1038/msb.2010.106
Uhlén M, Hallström BM, Lindskog C et al (2016) Transcriptomics resources of human tissues and organs. Mol Syst Biol 12:862
Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330
Rosenberg S, Verreault M, Schmitt C et al (2016) Multi-omics analysis of primary glioblastoma cell lines shows recapitulation of pivotal molecular features of parental tumors. Neuro-Oncol. https://doi.org/10.1093/neuonc/now160
Kamoun A, Idbaih A, Dehais C et al (2016) Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas. Nat Commun 7:11263. https://doi.org/10.1038/ncomms11263
Zhang Y, Chen K, Sloan SA et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci Off J Soc Neurosci 34:11929–11947. https://doi.org/10.1523/JNEUROSCI.1860-14.2014
Goldwirt L, Beccaria K, Carpentier A et al (2014) Irinotecan and temozolomide brain distribution: a focus on ABCB1. Cancer Chemother Pharmacol 74:185–193. https://doi.org/10.1007/s00280-014-2490-0
Tomioka M, Toda Y, Kurisu J et al (2012) The effects of neurological disorder-related codon variations of ABCA13 on the function of the ABC protein. Biosci Biotechnol Biochem 76:2289–2293. https://doi.org/10.1271/bbb.120563
Knight HM, Pickard BS, Maclean A et al (2009) A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression. Am J Hum Genet 85:833–846. https://doi.org/10.1016/j.ajhg.2009.11.003
Dwyer S, Williams H, Jones I et al (2011) Investigation of rare non-synonymous variants at ABCA13 in schizophrenia and bipolar disorder. Mol Psychiatry 16:790–791. https://doi.org/10.1038/mp.2011.2
Pickard BS, Van Den Bossche MJA, Malloy MP et al (2012) Multiplex amplicon quantification screening the ABCA13 gene for copy number variation in schizophrenia and bipolar disorder. Psychiatr Genet 22:269–270. https://doi.org/10.1097/YPG.0b013e32835185b3
Degenhardt F, Priebe L, Strohmaier J et al (2013) No evidence for an involvement of copy number variation in ABCA13 in schizophrenia, bipolar disorder, or major depressive disorder. Psychiatr Genet 23:45–46. https://doi.org/10.1097/YPG.0b013e328358645b
Ma J, Lan X, Gao N et al (2013) A genetic association study between common variants in the ABCA13 gene and schizophrenia in a Han Chinese population. Psychiatry Res 209:748–749. https://doi.org/10.1016/j.psychres.2013.07.013
Chen J, Khan RAW, Wang M et al (2016) Association between the variability of the ABCA13 gene and the risk of major depressive disorder and schizophrenia in the Han Chinese population. World J Biol Psychiatry Off J World Fed Soc Biol Psychiatry. https://doi.org/10.1080/15622975.2016.1245442
Shah AA, Haynes C, Craig DM et al (2015) Genetic variants associated with vein graft stenosis after coronary artery bypass grafting. Heart Surg Forum 18:E1–E5
Yun E-J, Zhou J, Lin C-J et al (2017) The network of DAB2IP-miR-138 in regulating drug resistance of renal cell carcinoma associated with stem-like phenotypes. Oncotarget. https://doi.org/10.18632/oncotarget.17756
Araújo TM, Seabra AD, Lima EM et al (2016) Recurrent amplification of RTEL1 and ABCA13 and its synergistic effect associated with clinicopathological data of gastric adenocarcinoma. Mol Cytogenet 9:52. https://doi.org/10.1186/s13039-016-0260-x
Nymoen DA, Holth A, Hetland Falkenthal TE et al (2015) CIAPIN1 and ABCA13 are markers of poor survival in metastatic ovarian serous carcinoma. Mol Cancer 14:44. https://doi.org/10.1186/s12943-015-0317-1
Hlaváč V, Brynychová V, Václavíková R et al (2013) The expression profile of ATP-binding cassette transporter genes in breast carcinoma. Pharmacogenomics 14:515–529. https://doi.org/10.2217/pgs.13.26
Hlavata I, Mohelnikova-Duchonova B, Vaclavikova R et al (2012) The role of ABC transporters in progression and clinical outcome of colorectal cancer. Mutagenesis 27:187–196. https://doi.org/10.1093/mutage/ger075
Acknowledgements
Institut Universitaire de Cancérologie. Fondation ARC pour la recherche sur le cancer. Association pour la Recherche sur les Tumeurs Cérébrales. Dr Michael Canney. OncoNeuroTek tissue bank, Paris.
Funding
This study was funded by the Fondation ARC pour la recherche sur le cancer and the Association pour la Recherche sur les Tumeurs Cérébrales.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors declare they have no conflict of interest with the present study.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from participants included in the study.
Additional information
The original version of this article has been revised: the names of two authors have been corrected.
Electronic supplementary material
Below is the link to the electronic supplementary material.
11060_2018_2819_MOESM1_ESM.pptx
Supplementary material 1. Supplementary Fig. 1: mRNA expression levels of ABCB1, ABCG1 and ABCG2 (from top to bottom) in the 9 GBM-PDCL versus their paired parental tumors measured used RNAseq and Affymetrix microarray expression profiling and validated using qPCR (from left to right). RNAseq levels are closer to qPCR level compared to Affymetrix microarray expression profiling. Error bars are in SD. Supplementary Fig. 2: mRNA expression levels of the 49 ABC transporters using RNA sequencing for the TCGA set of patients compared to the 9 tumors corresponding to our PDCL presented in Fig. 1. (PPTX 618 KB)
Rights and permissions
About this article
Cite this article
Dréan, A., Rosenberg, S., Lejeune, FX. et al. ATP binding cassette (ABC) transporters: expression and clinical value in glioblastoma. J Neurooncol 138, 479–486 (2018). https://doi.org/10.1007/s11060-018-2819-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-018-2819-3