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Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Overexpression of endothelin B receptor in glioblastoma: a prognostic marker and therapeutic target?

Authors: Suhas Vasaikar, Giorgos Tsipras, Natalia Landázuri, Helena Costa, Vanessa Wilhelmi, Patrick Scicluna, Huanhuan L. Cui, Abdul-Aleem Mohammad, Belghis Davoudi, Mingmei Shang, Sharan Ananthaseshan, Klas Strååt, Giuseppe Stragliotto, Afsar Rahbar, Kum Thong Wong, Jesper Tegner, Koon-Chu Yaiw, Cecilia Söderberg-Naucler

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Glioblastoma (GBM) is the most common malignant brain tumor with median survival of 12-15 months. Owing to uncertainty in clinical outcome, additional prognostic marker(s) apart from existing markers are needed. Since overexpression of endothelin B receptor (ETBR) has been demonstrated in gliomas, we aimed to test whether ETBR is a useful prognostic marker in GBM and examine if the clinically available endothelin receptor antagonists (ERA) could be useful in the disease treatment.

Methods

Data from The Cancer Genome Atlas and the Gene Expression Omnibus database were analyzed to assess ETBR expression. For survival analysis, glioblastoma samples from 25 Swedish patients were immunostained for ETBR, and the findings were correlated with clinical history. The druggability of ETBR was assessed by protein-protein interaction network analysis. ERAs were analyzed for toxicity in in vitro assays with GBM and breast cancer cells.

Results

By bioinformatics analysis, ETBR was found to be upregulated in glioblastoma patients, and its expression levels were correlated with reduced survival. ETBR interacts with key proteins involved in cancer pathogenesis, suggesting it as a druggable target. In vitro viability assays showed that ERAs may hold promise to treat glioblastoma and breast cancer.

Conclusions

ETBR is overexpressed in glioblastoma and other cancers and may be a prognostic marker in glioblastoma. ERAs may be useful for treating cancer patients.
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Literature
1.
go back to reference Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005;64(6):479–89.CrossRefPubMed Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol. 2005;64(6):479–89.CrossRefPubMed
3.
go back to reference Gruber ML, Buster WP. Temozolomide in combination with irinotecan for treatment of recurrent malignant glioma. Am J Clin Oncol. 2004;27(1):33–8.CrossRefPubMed Gruber ML, Buster WP. Temozolomide in combination with irinotecan for treatment of recurrent malignant glioma. Am J Clin Oncol. 2004;27(1):33–8.CrossRefPubMed
4.
go back to reference Mazzuca MQ, Khalil RA. Vascular endothelin receptor type B: structure, function and dysregulation in vascular disease. Biochem Pharmacol. 2012;84(2):147–62.CrossRefPubMedPubMedCentral Mazzuca MQ, Khalil RA. Vascular endothelin receptor type B: structure, function and dysregulation in vascular disease. Biochem Pharmacol. 2012;84(2):147–62.CrossRefPubMedPubMedCentral
5.
go back to reference Eltze E, Bertolin M, Korsching E, Wulfing P, Maggino T, Lelle R. Expression and prognostic relevance of endothelin-B receptor in vulvar cancer. Oncol Rep. 2007;18(2):305–11.PubMed Eltze E, Bertolin M, Korsching E, Wulfing P, Maggino T, Lelle R. Expression and prognostic relevance of endothelin-B receptor in vulvar cancer. Oncol Rep. 2007;18(2):305–11.PubMed
6.
go back to reference Wuttig D, Zastrow S, Fussel S, Toma MI, Meinhardt M, Kalman K, Junker K, Sanjmyatav J, Boll K, Hackermuller J, et al. CD31, EDNRB and TSPAN7 are promising prognostic markers in clear-cell renal cell carcinoma revealed by genome-wide expression analyses of primary tumors and metastases. Int J Cancer. 2012;131(5):E693–704.CrossRefPubMed Wuttig D, Zastrow S, Fussel S, Toma MI, Meinhardt M, Kalman K, Junker K, Sanjmyatav J, Boll K, Hackermuller J, et al. CD31, EDNRB and TSPAN7 are promising prognostic markers in clear-cell renal cell carcinoma revealed by genome-wide expression analyses of primary tumors and metastases. Int J Cancer. 2012;131(5):E693–704.CrossRefPubMed
7.
go back to reference Tanaka T, Sho M, Takayama T, Wakatsuki K, Matsumoto S, Migita K, Ito M, Hamada K, Nakajima Y. Endothelin B receptor expression correlates with tumour angiogenesis and prognosis in oesophageal squamous cell carcinoma. Br J Cancer. 2014;110(4):1027–33.CrossRefPubMed Tanaka T, Sho M, Takayama T, Wakatsuki K, Matsumoto S, Migita K, Ito M, Hamada K, Nakajima Y. Endothelin B receptor expression correlates with tumour angiogenesis and prognosis in oesophageal squamous cell carcinoma. Br J Cancer. 2014;110(4):1027–33.CrossRefPubMed
8.
go back to reference Bagnato A, Loizidou M, Pflug BR, Curwen J, Growcott J. Role of the endothelin axis and its antagonists in the treatment of cancer. Brit J Pharmacol. 2011;163(2):220–33.CrossRef Bagnato A, Loizidou M, Pflug BR, Curwen J, Growcott J. Role of the endothelin axis and its antagonists in the treatment of cancer. Brit J Pharmacol. 2011;163(2):220–33.CrossRef
9.
go back to reference Wan X, Zhang LB, Jiang B. Role of endothelin B receptor in oligodendroglioma proliferation and survival: in vitro and in vivo evidence. Mol Med Rep. 2014;9(1):229–34.CrossRefPubMed Wan X, Zhang LB, Jiang B. Role of endothelin B receptor in oligodendroglioma proliferation and survival: in vitro and in vivo evidence. Mol Med Rep. 2014;9(1):229–34.CrossRefPubMed
10.
go back to reference Asundi J, Reed C, Arca J, McCutcheon K, Ferrando R, Clark S, Luis E, Tien J, Firestein R, Polakis P. An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma. Clin Cancer Res. 2011;17(5):965–75.CrossRefPubMed Asundi J, Reed C, Arca J, McCutcheon K, Ferrando R, Clark S, Luis E, Tien J, Firestein R, Polakis P. An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma. Clin Cancer Res. 2011;17(5):965–75.CrossRefPubMed
11.
go back to reference Kim SJ, Lee HJ, Kim MS, Choi HJ, He J, Wu Q, Aldape K, Weinberg JS, Yung WK, Conrad CA, et al. Macitentan, a dual Endothelin receptor antagonist, in combination with Temozolomide leads to Glioblastoma regression and long-term survival in mice. Clin Cancer Res. 2015;21(20):4630–41.CrossRefPubMedPubMedCentral Kim SJ, Lee HJ, Kim MS, Choi HJ, He J, Wu Q, Aldape K, Weinberg JS, Yung WK, Conrad CA, et al. Macitentan, a dual Endothelin receptor antagonist, in combination with Temozolomide leads to Glioblastoma regression and long-term survival in mice. Clin Cancer Res. 2015;21(20):4630–41.CrossRefPubMedPubMedCentral
12.
go back to reference Shen C, Yang L, Yuan X. Endothelin B receptor expression in human astrocytoma: association with clinicopathological variables and survival outcomes. Int J Neurosci. 2011;121(11):626–31.CrossRefPubMed Shen C, Yang L, Yuan X. Endothelin B receptor expression in human astrocytoma: association with clinicopathological variables and survival outcomes. Int J Neurosci. 2011;121(11):626–31.CrossRefPubMed
13.
go back to reference Ratneswaren T, Jack RM, Tataru D, Davies EA. The survival of patients with high grade glioma from different ethnic groups in south East England. J Neuro-Oncol. 2014;120(3):531–6.CrossRef Ratneswaren T, Jack RM, Tataru D, Davies EA. The survival of patients with high grade glioma from different ethnic groups in south East England. J Neuro-Oncol. 2014;120(3):531–6.CrossRef
14.
go back to reference Chen P, Aldape K, Wiencke JK, Kelsey KT, Miike R, Davis RL, Liu J, Kesler-Diaz A, Takahashi M, Wrensch M. Ethnicity delineates different genetic pathways in malignant glioma. Cancer Res. 2001;61(10):3949–54.PubMed Chen P, Aldape K, Wiencke JK, Kelsey KT, Miike R, Davis RL, Liu J, Kesler-Diaz A, Takahashi M, Wrensch M. Ethnicity delineates different genetic pathways in malignant glioma. Cancer Res. 2001;61(10):3949–54.PubMed
15.
go back to reference Rahbar A, Orrego A, Peredo I, Dzabic M, Wolmer-Solberg N, Straat K, Stragliotto G, Soderberg-Naucler C. Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival. J Clin Virol. 2013;57(1):36–42.CrossRefPubMed Rahbar A, Orrego A, Peredo I, Dzabic M, Wolmer-Solberg N, Straat K, Stragliotto G, Soderberg-Naucler C. Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival. J Clin Virol. 2013;57(1):36–42.CrossRefPubMed
16.
go back to reference Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.CrossRefPubMedPubMedCentral Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.CrossRefPubMedPubMedCentral
17.
go back to reference Vasaikar SV, Padhi AK, Jayaram B, Gomes J. NeuroDNet - an open source platform for constructing and analyzing neurodegenerative disease networks. BMC Neurosci. 2013;14:3.CrossRefPubMedPubMedCentral Vasaikar SV, Padhi AK, Jayaram B, Gomes J. NeuroDNet - an open source platform for constructing and analyzing neurodegenerative disease networks. BMC Neurosci. 2013;14:3.CrossRefPubMedPubMedCentral
18.
go back to reference Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2011;27(3):431–2.CrossRefPubMed Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2011;27(3):431–2.CrossRefPubMed
19.
go back to reference Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. P Natl Acad Sci USA. 2005;102(43):15545–50.CrossRef Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. P Natl Acad Sci USA. 2005;102(43):15545–50.CrossRef
20.
go back to reference Egidy G, Eberl LP, Valdenaire O, Irmler M, Majdi R, Diserens AC, Fontana A, Janzer RC, Pinet F, Juillerat-Jeanneret L. The endothelin system in human glioblastoma. Lab Investig. 2000;80(11):1681–9.CrossRefPubMed Egidy G, Eberl LP, Valdenaire O, Irmler M, Majdi R, Diserens AC, Fontana A, Janzer RC, Pinet F, Juillerat-Jeanneret L. The endothelin system in human glioblastoma. Lab Investig. 2000;80(11):1681–9.CrossRefPubMed
21.
go back to reference Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.CrossRefPubMedPubMedCentral Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17(1):98–110.CrossRefPubMedPubMedCentral
22.
go back to reference Rubio-Perez C, Tamborero D, Schroeder MP, Antolin AA, Deu-Pons J, Perez-Llamas C, Mestres J, Gonzalez-Perez A, Lopez-Bigas N. In silico prescription of anticancer drugs to cohorts of 28 tumor types reveals targeting opportunities. Cancer Cell. 2015;27(3):382–96.CrossRefPubMed Rubio-Perez C, Tamborero D, Schroeder MP, Antolin AA, Deu-Pons J, Perez-Llamas C, Mestres J, Gonzalez-Perez A, Lopez-Bigas N. In silico prescription of anticancer drugs to cohorts of 28 tumor types reveals targeting opportunities. Cancer Cell. 2015;27(3):382–96.CrossRefPubMed
23.
go back to reference Bagnato A, Spinella F, Rosano L. The endothelin axis in cancer: the promise and the challenges of molecularly targeted therapy. Can J Physiol Pharm. 2008;86(8):473–84.CrossRef Bagnato A, Spinella F, Rosano L. The endothelin axis in cancer: the promise and the challenges of molecularly targeted therapy. Can J Physiol Pharm. 2008;86(8):473–84.CrossRef
24.
go back to reference Eltze E, Wild PJ, Wulfing C, Zwarthoff EC, Burger M, Stoehr R, Korsching E, Hartmann A. Expression of the endothelin axis in noninvasive and superficially invasive bladder cancer: relation to clinicopathologic and molecular prognostic parameters. Eur Urol. 2009;56(5):837–45.CrossRefPubMed Eltze E, Wild PJ, Wulfing C, Zwarthoff EC, Burger M, Stoehr R, Korsching E, Hartmann A. Expression of the endothelin axis in noninvasive and superficially invasive bladder cancer: relation to clinicopathologic and molecular prognostic parameters. Eur Urol. 2009;56(5):837–45.CrossRefPubMed
25.
go back to reference Demunter A, De Wolf-Peeters C, Degreef H, Stas M, van den Oord JJ. Expression of the endothelin-B receptor in pigment cell lesions of the skin - evidence for its role as tumor progression marker in malignant melanoma. Virchows Arch. 2001;438(5):485–91.CrossRefPubMed Demunter A, De Wolf-Peeters C, Degreef H, Stas M, van den Oord JJ. Expression of the endothelin-B receptor in pigment cell lesions of the skin - evidence for its role as tumor progression marker in malignant melanoma. Virchows Arch. 2001;438(5):485–91.CrossRefPubMed
26.
go back to reference Blouquit-Laye S, Regnier A, Beauchet A, Zimmermann U, Devillier P, Chinet T. Expression of endothelin receptor subtypes in bronchial tumors. Oncol Rep. 2010;23(2):457–63.PubMed Blouquit-Laye S, Regnier A, Beauchet A, Zimmermann U, Devillier P, Chinet T. Expression of endothelin receptor subtypes in bronchial tumors. Oncol Rep. 2010;23(2):457–63.PubMed
27.
go back to reference de Tayrac M, Aubry M, Saikali S, Etcheverry A, Surbled C, Guenot F, Galibert MD, Hamlat A, Lesimple T, Quillien V, et al. A 4-gene signature associated with clinical outcome in high-grade gliomas. Clin Cancer Res. 2011;17(2):317–27.CrossRefPubMed de Tayrac M, Aubry M, Saikali S, Etcheverry A, Surbled C, Guenot F, Galibert MD, Hamlat A, Lesimple T, Quillien V, et al. A 4-gene signature associated with clinical outcome in high-grade gliomas. Clin Cancer Res. 2011;17(2):317–27.CrossRefPubMed
28.
go back to reference Vatter H, Seifert V. Ambrisentan, a non-peptide endothelin receptor antagonist. Cardiovasc Drug Rev. 2006;24(1):63–76.CrossRefPubMed Vatter H, Seifert V. Ambrisentan, a non-peptide endothelin receptor antagonist. Cardiovasc Drug Rev. 2006;24(1):63–76.CrossRefPubMed
29.
go back to reference Nakashima S, Sugita Y, Miyoshi H, Arakawa F, Muta H, Ishibashi Y, Niino D, Ohshima K, Terasaki M, Nakamura Y, et al. Endothelin B receptor expression in malignant gliomas: the perivascular immune escape mechanism of gliomas. J Neuro-Oncol. 2016;127(1):23–32.CrossRef Nakashima S, Sugita Y, Miyoshi H, Arakawa F, Muta H, Ishibashi Y, Niino D, Ohshima K, Terasaki M, Nakamura Y, et al. Endothelin B receptor expression in malignant gliomas: the perivascular immune escape mechanism of gliomas. J Neuro-Oncol. 2016;127(1):23–32.CrossRef
30.
go back to reference Inskip PD, Linet MS, Heineman EF. Etiology of brain tumors in adults. Epidemiol Rev. 1995;17(2):382–414.CrossRefPubMed Inskip PD, Linet MS, Heineman EF. Etiology of brain tumors in adults. Epidemiol Rev. 1995;17(2):382–414.CrossRefPubMed
31.
go back to reference Jha P, Suri V, Jain A, Sharma MC, Pathak P, Srivastava A, Suri A, Gupta D, Chosdol K, Chattopadhyay P, et al. O6-methylguanine DNA methyltransferase gene promoter methylation status in gliomas and its correlation with other molecular alterations: first Indian report with review of challenges for use in customized treatment. Neurosurgery. 2010;67(6):1681–91.CrossRefPubMed Jha P, Suri V, Jain A, Sharma MC, Pathak P, Srivastava A, Suri A, Gupta D, Chosdol K, Chattopadhyay P, et al. O6-methylguanine DNA methyltransferase gene promoter methylation status in gliomas and its correlation with other molecular alterations: first Indian report with review of challenges for use in customized treatment. Neurosurgery. 2010;67(6):1681–91.CrossRefPubMed
32.
go back to reference Rogers SD, Peters CM, Pomonis JD, Hagiwara H, Ghilardi JR, Mantyh PW. Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS. Glia. 2003;41(2):180–90.CrossRefPubMed Rogers SD, Peters CM, Pomonis JD, Hagiwara H, Ghilardi JR, Mantyh PW. Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS. Glia. 2003;41(2):180–90.CrossRefPubMed
33.
go back to reference Cavanagh JB. Corpora-amylacea and the family of polyglucosan diseases. Brain Res Brain Res Rev. 1999;29(2-3):265–95.CrossRefPubMed Cavanagh JB. Corpora-amylacea and the family of polyglucosan diseases. Brain Res Brain Res Rev. 1999;29(2-3):265–95.CrossRefPubMed
34.
go back to reference Libard S, Popova SN, Amini RM, Karja V, Pietilainen T, Hamalainen KM, Sundstrom C, Hesselager G, Bergqvist M, Ekman S et al: Human Cytomegalovirus Tegument Protein pp65 Is Detected in All Intra- and Extra-Axial Brain Tumours Independent of the Tumour Type or Grade. PLoS One. 2014; 9(9):e108861(1-14). Libard S, Popova SN, Amini RM, Karja V, Pietilainen T, Hamalainen KM, Sundstrom C, Hesselager G, Bergqvist M, Ekman S et al: Human Cytomegalovirus Tegument Protein pp65 Is Detected in All Intra- and Extra-Axial Brain Tumours Independent of the Tumour Type or Grade. PLoS One. 2014; 9(9):e108861(1-14).
35.
Metadata
Title
Overexpression of endothelin B receptor in glioblastoma: a prognostic marker and therapeutic target?
Authors
Suhas Vasaikar
Giorgos Tsipras
Natalia Landázuri
Helena Costa
Vanessa Wilhelmi
Patrick Scicluna
Huanhuan L. Cui
Abdul-Aleem Mohammad
Belghis Davoudi
Mingmei Shang
Sharan Ananthaseshan
Klas Strååt
Giuseppe Stragliotto
Afsar Rahbar
Kum Thong Wong
Jesper Tegner
Koon-Chu Yaiw
Cecilia Söderberg-Naucler
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4012-7

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