Expression of heat shock proteins in medulloblastoma

Laboratory investigation

Restricted access


Medulloblastoma (MB) is the most common malignant brain tumor in children. Heat shock proteins (HSPs) comprise a superfamily of proteins that serve as molecular chaperones and are overexpressed in a wide range of human cancers. The purpose of the present study was to investigate the expression of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt by multiplex bead array assay of MBs. The results of HSP and Akt expression were correlated with MB subtype; immunohistochemical expression of Ki-67 index, bcl-2, and p53; and patients' prognosis.


The authors retrospectively evaluated 25 children with MB who underwent surgery. Immunohistochemical analysis of Ki-67, p53, and bcl-2 expression was performed in all cases. By using multiplex bead array assay, a simultaneous detection of HSP27 (pSer82), HSP27 (pSer15), HSP40, HSP60, HSP70, HSP90-α, Akt, and phospho-Akt was performed.


Medulloblastoma with extensive nodularity had significantly lower HSP27 (pSer15) expression (p = 0.039) but significantly higher HSP60 expression (p = 0.021) than classic MB. Large-cell MB had significantly higher HSP70 expression (p = 0.028) than classic MB. No significant difference was found between HSP27 (pSer82), HSP40, HSP90-α, Akt, or phospho-Akt expression and MB subtype. Large-cell MBs had significantly higher Ki-67 index compared with classic MBs (p = 0.033). When analyzing all MBs, there was a significant negative correlation between HSP27 (pSer15) and Ki-67 index (r = −0.475, p = 0.016); a significant positive correlation between HSP70 expression and Ki-67 index (r = 0.407, p = 0.043); and a significant positive correlation between HSP70 expression and bcl-2 index (r = 0.491, p = 0.023). Patients with large-cell MB had a worse survival than those with classic MB, but the difference did not reach statistical significance (p = 0.076).


A substantial expression of several HSPs in MB was observed. Given that HSPs represent an attractive strategy for anticancer therapy, further studies, involving larger series of patients, are obviously necessary to clarify the relationship of HSPs with tumor aggressiveness and prognosis.

Abbreviations used in this paper:HSP = heat shock protein; MB = medulloblastoma; SHH = sonic hedgehog; WNT = wingless.

Article Information

Address correspondence to: George Alexiou, M.D., Aetideon 52, Holargos, Attikis 11561, Greece. email:

Please include this information when citing this paper: published online August 30, 2013; DOI: 10.3171/2013.7.PEDS1376.

© AANS, except where prohibited by US copyright law.



  • View in gallery

    A: Heterogeneous immunohistochemical expression of Ki-67 (40%). B: High expression (60%) of p53 in MB. C: High (70%) immunohistochemical expression of bcl-2 protein. Original magnification ×200.



Alexiou GAMoschovi MStefanaki KSfakianos GProdromou N: Epidemiology of pediatric brain tumors in Greece (1991–2008). Experience from the Agia Sofia Children's Hospital. Cent Eur Neurosurg 72:142011


Ayrault OGodeny MDDillon CZindy FFitzgerald PRoussel MF: Inhibition of Hsp90 via 17-DMAG induces apoptosis in a p53-dependent manner to prevent medulloblastoma. Proc Natl Acad Sci U S A 106:17037170422009


Balaburski GMLeu JIBeeharry NHayik SAndrake MDZhang G: A modified HSP70 inhibitor shows broad activity as an anticancer agent. Mol Cancer Res 11:2192292013


Ciocca DRCalderwood SK: Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones 10:861032005


Ciocca DRRozados VRCuello-Carrión FDGervasoni SIMatar PScharovsky OG: Hsp25 and Hsp70 in rodent tumors treated with doxorubicin and lovastatin. Cell Stress Chaperones 8:26362003


Cruickshanks NShervington LPatel RMunje CThakkar DShervington A: Can hsp90alpha-targeted siRNA combined with TMZ be a future therapy for glioma?. Cancer Invest 28:6086142010


Ellison DWDalton JKocak MNicholson SLFraga CNeale G: Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121:3813962011


Elshal MFMcCoy JP: Multiplex bead array assays: performance evaluation and comparison of sensitivity to ELISA. Methods 38:3173232006


Garrido C: Size matters: of the small HSP27 and its large oligomers. Cell Death Differ 9:4834852002


Giangaspero FWellek SMasuoka JGessi MKleihues POhgaki H: Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol 112:5122006


Graner MWBigner DD: Chaperone proteins and brain tumors: potential targets and possible therapeutics. Neuro Oncol 7:2602782005


Hartmann WDigon-Söntgerath BKoch AWaha AEndl EDani I: Phosphatidylinositol 3′-kinase/AKT signaling is activated in medulloblastoma cell proliferation and is associated with reduced expression of PTEN. Clin Cancer Res 12:301930272006


Hauser PHanzély ZJakab ZOláh LSzabó EJeney A: Expression and prognostic examination of heat shock proteins (HSP 27, HSP 70, and HSP 90) in medulloblastoma. J Pediatr Hematol Oncol 28:4614662006


Jhaveri KMiller KRosen LSchneider BChap LHannah A: A phase I dose-escalation trial of trastuzumab and alvespimycin hydrochloride (KOS-1022; 17 DMAG) in the treatment of advanced solid tumors. Clin Cancer Res 18:509050982012


Kato SKato MHirano ATakikawa MOhama E: The immunohistochemical expression of stress-response protein (srp) 60 in human brain tumours: relationship of srp 60 to the other five srps, proliferating cell nuclear antigen and p53 protein. Histol Histopathol 16:8098202001


Khalil AAKabapy NFDeraz SFSmith C: Heat shock proteins in oncology: diagnostic biomarkers or therapeutic targets?. Biochim Biophys Acta 1816:891042011


Khong TSpencer A: Targeting HSP 90 induces apoptosis and inhibits critical survival and proliferation pathways in multiple myeloma. Mol Cancer Ther 10:190919172011


Leng AMLiu TYang JCui JFLi XHZhu YN: The apoptotic effect and associated signalling of HSP90 inhibitor 17-DMAG in hepatocellular carcinoma cells. Cell Biol Int 36:8938992012


Massimino MAntonelli MGandola LMiceli RPollo BBiassoni V: Histological variants of medulloblastoma are the most powerful clinical prognostic indicators. Pediatr Blood Cancer 60:2102162013


McManamy CSLamont JMTaylor RECole MPearson ADClifford SC: Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62:6276322003


McManamy CSPears JWeston CLHanzely ZIronside JWTaylor RE: Nodule formation and desmoplasia in medulloblastomas-defining the nodular/desmoplastic variant and its biological behavior. Brain Pathol 17:1511642007


Moschovi MAlexiou GAPatereli ASiozos GSfakianos GProdromou N: Immunohistochemical expression of cell-cycle regulators in pediatric embryonal brain tumors. J Neurooncol 109:5295342012


Moschovi MAlexiou GAPatereli AStefanaki KDoussis-Anagnostopoulou IStofas A: Prognostic significance of cyclin A and B1 in pediatric embryonal tumors. J Neurooncol 103:6997042011


Moschovi MKoultouki EStefanaki KSfakianos GTourkantoni NProdromou N: Prognostic significance of angiogenesis in relation to Ki-67, p-53, p-27, and bcl-2 expression in embryonal tumors. Pediatr Neurosurg 47:2412472011


Murshid AGong JStevenson MACalderwood SK: Heat shock proteins and cancer vaccines: developments in the past decade and chaperoning in the decade to come. Expert Rev Vaccines 10:155315682011


Northcott PAKorshunov AWitt HHielscher TEberhart CGMack S: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29:140814142011


Ohba SHirose YYoshida KYazaki TKawase T: Inhibition of 90-kD heat shock protein potentiates the cytotoxicity of chemotherapeutic agents in human glioma cells. Laboratory investigation. J Neurosurg 112:33422010


Panner AMurray JCBerger MSPieper RO: Heat shock protein 90alpha recruits FLIPS to the death-inducing signaling complex and contributes to TRAIL resistance in human glioma. Cancer Res 67:948294892007


Ray AHo MMa JParkes RKMainprize TGUeda S: A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 10:761376202004


Robinson GParker MKranenburg TALu CChen XDing L: Novel mutations target distinct subgroups of medulloblastoma. Nature 488:43482012


Stefanaki KAlexiou GAProdromou N: Embryonal brain tumours in children. Encephalos 49:182012


Taylor MDNorthcott PAKorshunov ARemke MCho YJClifford SC: Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:4654722012


Vargas-Roig LMFanelli MALópez LAGago FETello OAznar JC: Heat shock proteins and cell proliferation in human breast cancer biopsy samples. Cancer Detect Prev 21:4414511997


von Hoff KHartmann Wvon Bueren AOGerber NUGrotzer MAPietsch T: Large cell/anaplastic medulloblastoma: outcome according to myc status, histopathological, and clinical risk factors. Pediatr Blood Cancer 54:3693762010


Yiu CCChanplakorn NChan MSLoo WTChow LWToi M: Down-regulation of heat-shock protein 70 (HSP-70) correlated with responsiveness to neoadjuvant aromatase inhibitor therapy in breast cancer patients. Anticancer Res 30:346534722010




All Time Past Year Past 30 Days
Abstract Views 59 59 13
Full Text Views 67 67 4
PDF Downloads 154 154 6
EPUB Downloads 0 0 0


Google Scholar