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Open Access 01-04-2017 | Original Article

Region Specific Differences of Claudin-5 Expression in Pediatric Intracranial Ependymomas: Potential Prognostic Role in Supratentorial Cases

Authors: József Virág, Christine Haberler, Gábor Baksa, Violetta Piurkó, Zita Hegedüs, Lilla Reiniger, Katalin Bálint, Monika Chocholous, András Kiss, Gábor Lotz, Tibor Glasz, Zsuzsa Schaff, Miklós Garami, Balázs Hegedűs

Published in: Pathology & Oncology Research | Issue 2/2017

Abstract

Ependymomas are common pediatric brain tumors that originate from the ependyma and characterized by poor prognosis due to frequent recurrence. However, the current WHO grading system fails to accurately predict outcome. In a retrospective study, we analyzed 54 intracranial pediatric ependymomas and found a significantly higher overall survival in supratentorial cases when compared to infratentorial tumors. Next we performed region-specific immunohistochemical analysis of the ependyma in neonatal and adult ependyma from the central canal of spinal cord to the choroid plexus of lateral ventricles for components of cell-cell junctions including cadherins, claudins and occludin. We found robust claudin-5 expression in the choroid plexus epithelia but not in other compartments of the ependyma. Ultrastructural studies demonstrated distinct regional differences in cell-cell junction organization. Surprisingly, we found that 9 out of 20 supratentorial but not infratentorial ependymomas expressed high levels of the brain endothelial tight junction component claudin-5 in tumor cells. Importantly, we observed an increased overall survival in claudin-5 expressing supratentorial ependymoma. Our data indicates that claudin-5 expressing ependymomas may follow a distinct course of disease. The assessment of claudin-5 expression in ependymoma has the potential to become a useful prognostic marker in this pediatric malignancy.

Bergeron C, Philip T (2004) Childhood cancer. Epidemiologic, diagnostic, and therapeutic aspects. La Revue du praticien 54(13):1489–1495PubMed

Maksoud YA, Hahn YS, Engelhard HH (2002) Intracranial ependymoma. Neurosurg Focus 13(3):e4CrossRefPubMed

Gelabert Gonzalez M, Garcia Allut A, Fernandez Villa JM, Gonzalez Garcia J, Martinez Rumbo R (2001) Intracranial ependymomas. Rev Neurol 33(10):980–986PubMed

Yang CP, Hung IJ, Jaing TH, Shih LY, Chang WH (2005) Cancer in infants: a review of 82 cases. Pediatr Hematol Oncol 22(6):463–481CrossRefPubMed

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109. doi:10.1007/s00401-007-0243-4 CrossRefPubMedPubMedCentral

Kilday JP, Rahman R, Dyer S, Ridley L, Lowe J, Coyle B, Grundy R (2009) Pediatric ependymoma: biological perspectives. Mol Cancer Res 7(6):765–786. doi:10.1158/1541-7786.MCR-08-0584 CrossRefPubMed

Godfraind C (2009) Classification and controversies in pathology of ependymomas. Childs Nerv Syst 25(10):1185–1193. doi:10.1007/s00381-008-0804-4 CrossRefPubMed

Preusser M, Heinzl H, Gelpi E, Hoftberger R, Fischer I, Pipp I, Milenkovic I, Wohrer A, Popovici F, Wolfsberger S, Hainfellner JA (2008) Ki67 index in intracranial ependymoma: a promising histopathological candidate biomarker. Histopathology 53(1):39–47. doi:10.1111/j.1365-2559.2008.03065.x CrossRefPubMed

Milde T, Hielscher T, Witt H, Kool M, Mack SC, Deubzer HE, Oehme I, Lodrini M, Benner A, Taylor MD, von Deimling A, Kulozik AE, Pfister SM, Witt O, Korshunov A (2012) Nestin expression identifies ependymoma patients with poor outcome. Brain Pathol. doi:10.1111/j.1750-3639.2012.00600.x

10.

Ridley L, Rahman R, Brundler MA, Ellison D, Lowe J, Robson K, Prebble E, Luckett I, Gilbertson RJ, Parkes S, Rand V, Coyle B, Grundy RG (2008) Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma. Neuro-Oncology 10(5):675–689. doi:10.1215/15228517-2008-036 CrossRefPubMedPubMedCentral

11.

Figarella-Branger D, Civatte M, Bouvier-Labit C, Gouvernet J, Gambarelli D, Gentet JC, Lena G, Choux M, Pellissier JF (2000) Prognostic factors in intracranial ependymomas in children. J Neurosurg 93(4):605–613. doi:10.3171/jns.2000.93.4.0605 CrossRefPubMed

12.

Jaing TH, Wang HS, Tsay PK, Tseng CK, Jung SM, Lin KL, Lui TN (2004) Multivariate analysis of clinical prognostic factors in children with intracranial ependymomas. J Neuro-Oncol 68(3):255–261CrossRef

13.

Kuncova K, Janda A, Kasal P, Zamecnik J (2009) Immunohistochemical prognostic markers in intracranial ependymomas: systematic review and meta-analysis. Pathol Oncol Res 15(4):605–614. doi:10.1007/s12253-009-9160-2 CrossRefPubMed

14.

Carter M, Nicholson J, Ross F, Crolla J, Allibone R, Balaji V, Perry R, Walker D, Gilbertson R, Ellison DW (2002) Genetic abnormalities detected in ependymomas by comparative genomic hybridisation. Br J Cancer 86(6):929–939. doi:10.1038/sj.bjc.6600180 CrossRefPubMedPubMedCentral

15.

Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M, Milde T, Bender S, Wittmann A, Schottler A, Kulozik AE, Witt O, von Deimling A, Lichter P, Pfister S (2010) Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28(19):3182–3190. doi:10.1200/JCO.2009.27.3359 CrossRefPubMed

16.

Mendrzyk F, Korshunov A, Benner A, Toedt G, Pfister S, Radlwimmer B, Lichter P (2006) Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma. Clin Cancer Res 12 (7 Pt 1):2070–2079. doi:10.1158/1078-0432.CCR-05-2363

17.

Monoranu CM, Huang B, Zangen IL, Rutkowski S, Vince GH, Gerber NU, Puppe B, Roggendorf W (2008) Correlation between 6q25.3 deletion status and survival in pediatric intracranial ependymomas. Cancer Genet Cytogenet 182(1):18–26. doi:10.1016/j.cancergencyto.2007.12.008 CrossRefPubMed

18.

Puget S, Grill J, Valent A, Bieche I, Dantas-Barbosa C, Kauffmann A, Dessen P, Lacroix L, Geoerger B, Job B, Dirven C, Varlet P, Peyre M, Dirks PB, Sainte-Rose C, Vassal G (2009) Candidate genes on chromosome 9q33–34 involved in the progression of childhood ependymomas. J Clin Oncol 27(11):1884–1892. doi:10.1200/JCO.2007.15.4195 CrossRefPubMed

19.

Witt H, Mack SC, Ryzhova M, Bender S, Sill M, Isserlin R, Benner A, Hielscher T, Milde T, Remke M, Jones DT, Northcott PA, Garzia L, Bertrand KC, Wittmann A, Yao Y, Roberts SS, Massimi L, Van Meter T, Weiss WA, Gupta N, Grajkowska W, Lach B, Cho YJ, von Deimling A, Kulozik AE, Witt O, Bader GD, Hawkins CE, Tabori U, Guha A, Rutka JT, Lichter P, Korshunov A, Taylor MD, Pfister SM (2011) Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20(2):143–157. doi:10.1016/j.ccr.2011.07.007 CrossRefPubMedPubMedCentral

20.

Raghunathan A, Wani K, Armstrong TS, Vera-Bolanos E, Fouladi M, Gilbertson R, Gajjar A, Goldman S, Lehman NL, Metellus P, Mikkelsen T, Necesito-Reyes MJ, Omuro A, Packer RJ, Partap S, Pollack IF, Prados MD, Robins HI, Soffietti R, Wu J, Miller CR, Gilbert MR, Aldape KD, Collaborative Ependymoma Research N (2013) Histological predictors of outcome in ependymoma are dependent on anatomic site within the central nervous system. Brain Pathol 23(5):584–594. doi:10.1111/bpa.12050 CrossRefPubMed

21.

Phi JH, Wang KC, Park SH, Kim IH, Kim IO, Park KD, Ahn HS, Lee JY, Son YJ, Kim SK (2012) Pediatric infratentorial ependymoma: prognostic significance of anaplastic histology. J Neuro-Oncol 106(3):619–626. doi:10.1007/s11060-011-0699-x CrossRef

22.

Maret D, Gruzglin E, Sadr MS, Siu V, Shan W, Koch AW, Seidah NG, Del Maestro RF, Colman DR (2010) Surface expression of precursor N-cadherin promotes tumor cell invasion. Neoplasia 12(12):1066–1080CrossRefPubMedPubMedCentral

23.

Lewis-Tuffin LJ, Rodriguez F, Giannini C, Scheithauer B, Necela BM, Sarkaria JN, Anastasiadis PZ (2010) Misregulated E-cadherin expression associated with an aggressive brain tumor phenotype. PLoS One 5(10):e13665. doi:10.1371/journal.pone.0013665 CrossRefPubMedPubMedCentral

24.

Krause G, Winkler L, Mueller SL, Haseloff RF, Piontek J, Blasig IE (2008) Structure and function of claudins. Biochim Biophys Acta 1778(3):631–645. doi:10.1016/j.bbamem.2007.10.018 CrossRefPubMed

25.

Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH, Kalbacher H, Wolburg H (2000) Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol 100(3):323–331CrossRefPubMed

26.

Takei H, Bhattacharjee MB, Rivera A, Dancer Y, Powell SZ (2007) New immunohistochemical markers in the evaluation of central nervous system tumors: a review of 7 selected adult and pediatric brain tumors. Arch Pathol Lab Med 131(2):234–241PubMed

27.

Wolburg H, Wolburg-Buchholz K, Kraus J, Rascher-Eggstein G, Liebner S, Hamm S, Duffner F, Grote EH, Risau W, Engelhardt B (2003) Localization of claudin-3 in tight junctions of the blood-brain barrier is selectively lost during experimental autoimmune encephalomyelitis and human glioblastoma multiforme. Acta Neuropathol 105(6):586–592PubMed

28.

Szmydynger-Chodobska J, Pascale CL, Pfeffer AN, Coulter C, Chodobski A (2007) Expression of junctional proteins in choroid plexus epithelial cell lines: a comparative study. Cerebrospinal Fluid Res 4:11

29.

Schulzke JD, Fromm M (2009) Tight junctions: molecular structure meets function. Annals of the New York Academy of Sciences 1165:1–6

30.

Fanning AS, Mitic LL, Anderson JM (1999) Transmembrane proteins in the tight junction barrier. J Am Soc Nephrol 10(6):1337–1345PubMed

31.

Forster C (2008) Tight junctions and the modulation of barrier function in disease. Histochem Cell Biol 130(1):55–70CrossRefPubMedPubMedCentral

32.

Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo BE (2003) Tight junction proteins. Prog Biophys Mol Biol 81(1):1–44CrossRefPubMed

33.

Nordfors K, Haapasalo J, Sallinen PK, Haapasalo H, Soini Y (2013) Expression of claudins relates to tumour aggressivity, location and recurrence in ependymomas. Histol Histopathol 28(9):1137–1146PubMed

34.

Masseguin C, Mani-Ponset L, Herbute S, Tixier-Vidal A, Gabrion J (2001) Persistence of tight junctions and changes in apical structures and protein expression in choroid plexus epithelium of rats after short-term head-down tilt. J Neurocytol 30(5):365–377CrossRefPubMed

35.

Mathew TC (2008) Regional analysis of the ependyma of the third ventricle of rat by light and electron microscopy. Anat Histol Embryol 37(1):9–18PubMed

36.

Wolburg H, Wolburg-Buchholz K, Liebner S, Engelhardt B (2001) Claudin-1, claudin-2 and claudin-11 are present in tight junctions of choroid plexus epithelium of the mouse. Neurosci Lett 307(2):77–80CrossRefPubMed

37.

Dahiya S, Lee d Y, Gutmann DH (2011) Comparative characterization of the human and mouse third ventricle germinal zones. J Neuropathol Exp Neurol 70(7):622–633. doi:10.1097/NEN.0b013e31822200aa CrossRefPubMedPubMedCentral

38.

Vigh B, Manzano e Silva MJ, Frank CL, Vincze C, Czirok SJ, Szabo A, Lukats A, Szel A (2004) The system of cerebrospinal fluid-contacting neurons. Its supposed role in the nonsynaptic signal transmission of the brain. Histol Histopathol 19(2):607–628PubMed

39.

Vigh B, Vigh-Teichmann I (1998) Actual problems of the cerebrospinal fluid-contacting neurons. Microsc Res Tech 41(1):57–83CrossRefPubMed

40.

Patonai A, Erdelyi-Belle B, Korompay A, Somoracz A, Straub BK, Schirmacher P, Kovalszky I, Lotz G, Kiss A, Schaff Z (2011) Claudins and tricellulin in fibrolamellar hepatocellular carcinoma. Virchows Arch 458(6):679–688. doi:10.1007/s00428-011-1077-y CrossRefPubMed

41.

Schnitzer J, Franke WW, Schachner M (1981) Immunocytochemical demonstration of vimentin in astrocytes and ependymal cells of developing and adult mouse nervous system. J Cell Biol 90(2):435–447CrossRefPubMedPubMedCentral

42.

Palm T, Figarella-Branger D, Chapon F, Lacroix C, Gray F, Scaravilli F, Ellison DW, Salmon I, Vikkula M, Godfraind C (2009) Expression profiling of ependymomas unravels localization and tumor grade-specific tumorigenesis. Cancer 115(17):3955–3968CrossRefPubMed

43.

Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, Magdaleno S, Dalton J, Calabrese C, Board J, Macdonald T, Rutka J, Guha A, Gajjar A, Curran T, Gilbertson RJ (2005) Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 8(4):323–335. doi:10.1016/j.ccr.2005.09.001 CrossRefPubMed

44.

Rogers HA, Kilday JP, Mayne C, Ward J, Adamowicz-Brice M, Schwalbe EC, Clifford SC, Coyle B, Grundy RG (2012) Supratentorial and spinal pediatric ependymomas display a hypermethylated phenotype which includes the loss of tumor suppressor genes involved in the control of cell growth and death. Acta Neuropathol 123(5):711–725. doi:10.1007/s00401-011-0904-1 CrossRefPubMed

45.

Pérez-Ramírez M, Hernández-Jiménez AJ, Guerrero-Guerrero A, Benadón-Darszon E, Pérezpeña-Díazconti M, Siordia-Reyes AG, García-Méndez A, de León FC-P, Salamanca-Gómez FA, García-Hernández N (2016) Genomics and epigenetics: A study of ependymomas in pediatric patients. Clin Neurol Neurosurg 144:53–58. doi:10.1016/j.clineuro.2016.02.041

46.

Rajeshwari M, Sharma MC, Kakkar A, Nambirajan A, Suri V, Sarkar C, Singh M, Saran RK, Gupta RK (2016) Evaluation of chromosome 1q gain in intracranial ependymomas. J Neuro-Oncol 127(2):271–278. doi:10.1007/s11060-015-2047-z CrossRef

47.

Lippoldt A, Liebner S, Andbjer B, Kalbacher H, Wolburg H, Haller H, Fuxe K (2000) Organization of choroid plexus epithelial and endothelial cell tight junctions and regulation of claudin-1, −2 and −5 expression by protein kinase C. Neuroreport 11(7):1427–1431CrossRefPubMed

48.

Lee d Y, Gianino SM, Gutmann DH (2012) Innate neural stem cell heterogeneity determines the patterning of glioma formation in children. Cancer Cell 22(1):131–138. doi:10.1016/j.ccr.2012.05.036 CrossRefPubMedPubMedCentral

49.

Sharma MK, Mansur DB, Reifenberger G, Perry A, Leonard JR, Aldape KD, Albin MG, Emnett RJ, Loeser S, Watson MA, Nagarajan R, Gutmann DH (2007) Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res 67(3):890–900. doi:10.1158/0008-5472.CAN-06-0973 CrossRefPubMed

50.

Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, Kranenburg TA, Hogg T, Poppleton H, Martin J, Finkelstein D, Pounds S, Weiss A, Patay Z, Scoggins M, Ogg R, Pei Y, Yang ZJ, Brun S, Lee Y, Zindy F, Lindsey JC, Taketo MM, Boop FA, Sanford RA, Gajjar A, Clifford SC, Roussel MF, McKinnon PJ, Gutmann DH, Ellison DW, Wechsler-Reya R, Gilbertson RJ (2010) Subtypes of medulloblastoma have distinct developmental origins. Nature 468(7327):1095–1099. doi:10.1038/nature09587 CrossRefPubMedPubMedCentral

51.

Ellison DW, Kocak M, Figarella-Branger D, Felice G, Catherine G, Pietsch T, Frappaz D, Massimino M, Grill J, Boyett JM, Grundy RG (2011) Histopathological grading of pediatric ependymoma: reproducibility and clinical relevance in European trial cohorts. J Negat Results Biomed 10(7). doi:10.1186/1477-5751-10-7

Title: Region Specific Differences of Claudin-5 Expression in Pediatric Intracranial Ependymomas: Potential Prognostic Role in Supratentorial Cases
Authors: József Virág
Christine Haberler
Gábor Baksa
Violetta Piurkó
Zita Hegedüs
Lilla Reiniger
Katalin Bálint
Monika Chocholous
András Kiss
Gábor Lotz
Tibor Glasz
Zsuzsa Schaff
Miklós Garami
Balázs Hegedűs
Publication date: 01-04-2017
Publisher: Springer Netherlands
Published in: Pathology & Oncology Research / Issue 2/2017
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-016-0084-3

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