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Tissue microarray analysis for epithelial membrane protein-2 as a novel biomarker for gliomas

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Abstract

Epithelial membrane protein-2 (EMP2) expression is noted in many human cancers. We evaluated EMP2 as a biomarker in gliomas. A large tissue microarray of lower grade glioma (WHO grades II–III, n = 19 patients) and glioblastoma (GBM) (WHO grade IV, n = 50 patients) was stained for EMP2. EMP2 expression was dichotomized to low or high expression scores and correlated with clinical data. The mean EMP2 expression was 1.68 in lower grade gliomas versus 2.20 in GBMs (P = 0.01). The percentage of samples with high EMP2 expression was greater in GBMs than lower grade gliomas (90.0 vs. 52.6%, P = 0.001). No significant difference was found between median survival among patients with GBM tumors exhibiting high EMP2 expression and survival of those with low EMP2 expression (8.38 vs. 10.98 months, P = 0.39). However, EMP2 expression ≥2 correlated with decreased survival (r = −0.39, P = 0.001). The EMP2 expression level also correlated with Ki-67 positivity (r = 0.34, P = 0.008). The mortality hazard ratio for GBM patients with EMP2 score of 3 or higher was 1.92 (CI 0.69–5.30). Our findings suggest that elevated EMP2 expression is associated with GBM. With other biomarkers, EMP2 may have use as a molecular target for the diagnosis and treatment of gliomas.

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References

  1. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477. doi:10.1016/j.cell.2013.09.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372(26):2481–2498. doi:10.1056/NEJMoa1402121

    Article  Google Scholar 

  3. Cohen AL, Holmen SL, Colman H (2013) IDH1 and IDH2 mutations in gliomas. Curr Neurol Neurosci Rep 13(5):345. doi:10.1007/s11910-013-0345-4

    Article  PubMed  PubMed Central  Google Scholar 

  4. Coons SW, Johnson PC, Scheithauer BW, Yates AJ, Pearl DK (1997) Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas. Cancer 79(7):1381–1393

    Article  CAS  PubMed  Google Scholar 

  5. Cox DR (1972) Regression models and life tables (with discussion). J R Stat Soc B 34:187–220

    Google Scholar 

  6. Desgrosellier JS, Cheresh DA (2010) Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 10(1):9–22. doi:10.1038/nrc2748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H et al (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372(26):2499–2508. doi:10.1056/NEJMoa1407279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Freije WA, Castro-Vargas FE, Fang Z, Horvath S, Cloughesy T, Liau LM et al (2004) Gene expression profiling of gliomas strongly predicts survival. Cancer Res 64(18):6503–6510. doi:10.1158/0008-5472.CAN-04-0452

    Article  CAS  PubMed  Google Scholar 

  9. Fu M, Maresh EL, Helguera GF, Kiyohara M, Qin Y, Ashki N et al (2014) Rationale and preclinical efficacy of a novel anti-EMP2 antibody for the treatment of invasive breast cancer. Mol Cancer Ther 13(4):902–915. doi:10.1158/1535-7163.MCT-13-0199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fu M, Maresh EL, Soslow RA, Alavi M, Mah V, Zhou Q et al (2010) Epithelial membrane protein-2 is a novel therapeutic target in ovarian cancer. Clin Cancer Res 16(15):3954–3963. doi:10.1158/1078-0432.CCR-10-0368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fu M, Rao R, Sudhakar D, Hogue CP, Rutta Z, Morales S et al (2011) Epithelial membrane protein-2 promotes endometrial tumor formation through activation of FAK and Src. PLoS One 6(5):e19945. doi:10.1371/journal.pone.0019945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gladson CL, Cheresh DA (1991) Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. J Clin Investig 88(6):1924–1932. doi:10.1172/JCI115516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gladson CL, Prayson RA, Liu WM (2010) The pathobiology of glioma tumors. Annu Rev Pathol 5:33–50. doi:10.1146/annurev-pathol-121808-102109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gordon LK, Kiyohara M, Fu M, Braun J, Dhawan P, Chan A et al (2013) EMP2 regulates angiogenesis in endometrial cancer cells through induction of VEGF. Oncogene 32(46):5369–5376. doi:10.1038/onc.2012.622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Greenall SA, Johns TG (2016) EGFRvIII: the promiscuous mutation. Cell Death Discov 2:16049. doi:10.1038/cddiscovery.2016.49

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gry M, Rimini R, Stromberg S, Asplund A, Ponten F, Uhlen M et al (2009) Correlations between RNA and protein expression profiles in 23 human cell lines. BMC Genom 10:365. doi:10.1186/1471-2164-10-365

    Article  Google Scholar 

  17. Habeeb O, Goodglick L, Soslow RA, Rao RG, Gordon LK, Schirripa O et al (2010) Epithelial membrane protein-2 expression is an early predictor of endometrial cancer development. Cancer 116(20):4718–4726. doi:10.1002/cncr.25259

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352(10):997–1003. doi:10.1056/NEJMoa043331

    Article  CAS  PubMed  Google Scholar 

  19. Hoos A, Stojadinovic A, Mastorides S, Urist MJ, Polsky D, Di Como CJ et al (2001) High Ki-67 proliferative index predicts disease specific survival in patients with high-risk soft tissue sarcomas. Cancer 92(4):869–874

    Article  CAS  PubMed  Google Scholar 

  20. Jahani-Asl A, Yin H, Soleimani VD, Haque T, Luchman HA, Chang NC et al (2016) Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat Neurosci 19(6):798–806. doi:10.1038/nn.4295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jansen M, Yip S, Louis DN (2010) Molecular pathology in adult gliomas: diagnostic, prognostic, and predictive markers. Lancet Neurol 9(7):717–726. doi:10.1016/S1474-4422(10)70105-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kanamori M, Kawaguchi T, Berger MS, Pieper RO (2006) Intracranial microenvironment reveals independent opposing functions of host alphaVbeta3 expression on glioma growth and angiogenesis. J Biol Chem 281(48):37256–37264. doi:10.1074/jbc.M605344200

    Article  CAS  PubMed  Google Scholar 

  23. Karsy M, Neil JA, Guan J, Mahan MA, Colman H, Jensen RL (2015) A practical review of prognostic correlations of molecular biomarkers in glioblastoma. Neurosurg Focus 38(3):E4. doi:10.3171/2015.1.FOCUS14755

    Article  PubMed  Google Scholar 

  24. Louis DN, Holland EC, Cairncross JG (2001) Glioma classification: a molecular reappraisal. Am J Pathol 159(3):779–786. doi:10.1016/S0002-9440(10)61750-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. McNamara MG, Sahebjam S, Mason WP (2013) Emerging biomarkers in glioblastoma. Cancers (Basel) 5(3):1103–1119. doi:10.3390/cancers5031103

    Article  CAS  Google Scholar 

  26. Mischel PS, Nelson SF, Cloughesy TF (2003) Molecular analysis of glioblastoma: pathway profiling and its implications for patient therapy. Cancer Biol Ther 2(3):242–247

    Article  CAS  PubMed  Google Scholar 

  27. Montano N, Cenci T, Martini M, D’Alessandris QG, Pelacchi F, Ricci-Vitiani L et al (2011) Expression of EGFRvIII in glioblastoma: prognostic significance revisited. Neoplasia 13(12):1113–1121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Montine TJ, Vandersteenhoven JJ, Aguzzi A, Boyko OB, Dodge RK, Kerns BJ et al (1994) Prognostic significance of Ki-67 proliferation index in supratentorial fibrillary astrocytic neoplasms. Neurosurgery 34(4):674–678 (discussion 678–679)

    Article  CAS  PubMed  Google Scholar 

  29. Nicolaidis S (2015) Biomarkers of glioblastoma multiforme. Metabolism 64(3 Suppl 1):S22–S27. doi:10.1016/j.metabol.2014.10.031

    Article  CAS  PubMed  Google Scholar 

  30. Philip R, Carrington L, Chan M (2011) US FDA perspective on challenges in co-developing in vitro companion diagnostics and targeted cancer therapeutics. Bioanalysis 3(4):383–389. doi:10.4155/bio.11.1

    Article  CAS  PubMed  Google Scholar 

  31. Polley MY, Lamborn KR, Chang SM, Butowski N, Clarke JL, Prados M (2011) Conditional probability of survival in patients with newly diagnosed glioblastoma. J Clin Oncol 29(31):4175–4180. doi:10.1200/JCO.2010.32.4343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Prayson RA, Agamanolis DP, Cohen ML, Estes ML, Kleinschmidt-DeMasters BK, Abdul-Karim F et al (2000) Interobserver reproducibility among neuropathologists and surgical pathologists in fibrillary astrocytoma grading. J Neurol Sci 175(1):33–39

    Article  CAS  PubMed  Google Scholar 

  33. Qin Y, Fu M, Takahashi M, Iwanami A, Kuga D, Rao RG et al (2014) Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma. J Biol Chem 289(20):13974–13985. doi:10.1074/jbc.M113.543728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP (1994) Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145(5):1175–1190

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Rickman DS, Bobek MP, Misek DE, Kuick R, Blaivas M, Kurnit DM et al (2001) Distinctive molecular profiles of high-grade and low-grade gliomas based on oligonucleotide microarray analysis. Cancer Res 61(18):6885–6891

    CAS  PubMed  Google Scholar 

  36. Riemenschneider MJ, Jeuken JW, Wesseling P, Reifenberger G (2010) Molecular diagnostics of gliomas: state of the art. Acta Neuropathol 120(5):567–584. doi:10.1007/s00401-010-0736-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182(3):311–322. doi:10.1002/(SICI)1097-4652(200003)182:3<311:AID-JCP1>3.0.CO;2-9

    Article  CAS  PubMed  Google Scholar 

  38. Teodorczyk M, Martin-Villalba A (2010) Sensing invasion: cell surface receptors driving spreading of glioblastoma. J Cell Physiol 222(1):1–10. doi:10.1002/jcp.21901

    Article  CAS  PubMed  Google Scholar 

  39. Wadehra M, Forbes A, Pushkarna N, Goodglick L, Gordon LK, Williams CJ et al (2005) Epithelial membrane protein-2 regulates surface expression of alphavbeta3 integrin in the endometrium. Dev Biol 287(2):336–345. doi:10.1016/j.ydbio.2005.09.003

    Article  CAS  PubMed  Google Scholar 

  40. Wadehra M, Goodglick L, Braun J (2004) The tetraspan protein EMP2 modulates the surface expression of caveolins and glycosylphosphatidylinositol-linked proteins. Mol Biol Cell 15(5):2073–2083. doi:10.1091/mbc.E03-07-0488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wadehra M, Natarajan S, Seligson DB, Williams CJ, Hummer AJ, Hedvat C et al (2006) Expression of epithelial membrane protein-2 is associated with endometrial adenocarcinoma of unfavorable outcome. Cancer 107(1):90–98. doi:10.1002/cncr.21957

    Article  CAS  PubMed  Google Scholar 

  42. Wadehra M, Sulur GG, Braun J, Gordon LK, Goodglick L (2003) Epithelial membrane protein-2 is expressed in discrete anatomical regions of the eye. Exp Mol Pathol 74(2):106–112

    Article  CAS  PubMed  Google Scholar 

  43. Wick W, Weller M, Weiler M, Batchelor T, Yung AW, Platten M (2011) Pathway inhibition: emerging molecular targets for treating glioblastoma. Neuro Oncol 13(6):566–579. doi:10.1093/neuonc/nor039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W et al (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360(8):765–773. doi:10.1056/NEJMoa0808710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhao J, Ma W, Zhao H (2014) Loss of heterozygosity 1p/19q and survival in glioma: a meta-analysis. Neuro Oncol 16(1):103–112. doi:10.1093/neuonc/not145

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, University of California, Los Angeles, 300 Stein Plaza, Los Angeles, CA, 90095, USA

    Lawrance K. Chung, Panayiotis E. Pelargos, Joanna V. Demos, Carlito Lagman, John P. Sheppard, Thien Nguyen, Robert M. Prins, Linda M. Liau & Isaac Yang

  2. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, 924 Westwood Blvd, Seventh Floor, Los Angeles, CA, 90095, USA

    Ann M. Chan, Yu-Ling Chang, Seyed A. Hojat, William H. Yong & Madhuri Wadehra

  3. Department of Neurology, University of California, Los Angeles, 710 Westwood Plaza, Los Angeles, CA, 90095, USA

    Leia Nghiemphu, Albert Lai & Timothy F. Cloughesy

  4. Department of Ophthalmology, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA, 90095, USA

    Lynn K. Gordon

  5. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, 8-684 Factor Building, Los Angeles, CA, 90095, USA

    Linda M. Liau, Madhuri Wadehra & Isaac Yang

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  1. Lawrance K. Chung
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Correspondence to Isaac Yang.

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Funding

L.K.C. was partially supported by the AMA Foundation Seed Grant and the AΩA Carolyn L. Kuckein Student Research Fellowship. P.P. was partially supported by the ABTA Medical Student Summer Fellowship. C.L. was partially supported by the Gurtin Skull Base Research Fellowship. J.P.S. and T.N. were supported by the David Geffen Medical Scholarship. M.W. was partially supported by the NCI R01 Grant (CA163971). I.Y. was partially supported by the UCLA Visionary Ball Fund Grant, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research UCLA Scholars in Translational Medicine Program Award, the Jason Dessel Memorial Seed Grant, the UCLA Honberger Endowment Brain Tumor Research Seed Grant, and the Stop Cancer! Research Career Development Award.

Conflict of interest

MW. and L.K.G. are inventors on the University of California patents related to EMP2 as a target for antibody therapy. They are also the founders of Paganini Biopharma. The remaining authors have no personal or institutional financial interest in drugs, materials, or devices described in this study.

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Chung, L.K., Pelargos, P.E., Chan, A.M. et al. Tissue microarray analysis for epithelial membrane protein-2 as a novel biomarker for gliomas. Brain Tumor Pathol 35, 1–9 (2018). https://doi.org/10.1007/s10014-017-0300-1

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