Skip to main content
Top
Published in: Child's Nervous System 11/2012

01-11-2012 | Original Paper

Differential proliferative index of cancer stem-like cells in primary and recurrent medulloblastoma in human

Authors: Xuqun Tang, Yu Yao, Jingjing Zhu, Kunlin Jin, Yin Wang, Ying Mao, Liangfu Zhou

Published in: Child's Nervous System | Issue 11/2012

Login to get access

Abstract

Purpose

Medulloblastoma is the most common malignant primitive neuroectodermal tumor found in children. It has a tendency to recur at a primary or distant site. The mechanism underlying the regulation of the recurrence of medulloblastoma remains largely unknown. Recently, several reports have described that cancer stem-like cells (CSCs) can be identified and isolated in medulloblastoma. The authors therefore attempted to demonstrate the correlation between the biological features of medulloblastoma’s CSCs and its recurrence.

Methods

The data used were obtained in five consecutive patients with medulloblastomas who subsequently experienced tumor recurrence from 2004 to 2007. The authors performed the immunohistochemical assays to analyze the expression of CSC markers, proliferation features, and proliferative status of CSCs in primary and recurrent medulloblastoma.

Results

Of the five patients, two had recurrence at the primary site and three had a distant recurrence. CSC markers such as CD133(Prominin-1), DCX, PSA-NCAM, TUC-4, and nestin were expressed regardless of primary or recurrent medulloblastoma. All the five tumor specimens had a high proliferation index (PI). The PI was even higher in the group of patients after recurrence at a distant site (p < 0.05), while the PI remained almost the same after primary recurrence. The Ki67/nestin-, Ki67/DCX-, and Ki67/TUC-4-positive cells were significantly increased in recurrent medulloblastoma at both the primary and distant sites, whereas CSCs in primary medulloblastoma showed much lower proliferative features (p < 0.05).

Conclusions

Our data suggest that tumorigenesis of medulloblastomas and their recurrence might be related to CSCs. More proliferating CSCs in medulloblastomas denote worse prognosis.
Literature
1.
go back to reference Ellison DW, Clifford SC, Gajjar A, Gilbertson RJ (2003) What’s new in neuro-oncology? Recent advances in medulloblastoma. Eur J Paediatr Neurol 7:53–66PubMedCrossRef Ellison DW, Clifford SC, Gajjar A, Gilbertson RJ (2003) What’s new in neuro-oncology? Recent advances in medulloblastoma. Eur J Paediatr Neurol 7:53–66PubMedCrossRef
2.
go back to reference Giangaspero H, Kleihues P, Pietsch T (2000) Medulloblastoma. In: Kleihues P, Cavenee WK (eds) Pathology and genetics of tumours of the nervous system. IARC Press, Lyon, pp 129–137 Giangaspero H, Kleihues P, Pietsch T (2000) Medulloblastoma. In: Kleihues P, Cavenee WK (eds) Pathology and genetics of tumours of the nervous system. IARC Press, Lyon, pp 129–137
3.
go back to reference Ries LAG, Smith MA, Gurney JG (eds) (1999) Cancer incidence and survival among children and adolescents: United States SEER program 1975–1995, National Cancer Institute, SEER Program. NIH Pub. No. 99–4649. Bethesda, MD Ries LAG, Smith MA, Gurney JG (eds) (1999) Cancer incidence and survival among children and adolescents: United States SEER program 1975–1995, National Cancer Institute, SEER Program. NIH Pub. No. 99–4649. Bethesda, MD
4.
go back to reference Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, Muraszko K, Rorke LB, Wara WM, Cohen BH, Boyett JM (1999) Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group study. J Clin Oncol 17:2127–2136PubMed Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, Muraszko K, Rorke LB, Wara WM, Cohen BH, Boyett JM (1999) Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a Children’s Cancer Group study. J Clin Oncol 17:2127–2136PubMed
5.
go back to reference Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM (2001) Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol 19:3470–3476PubMed Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM (2001) Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children’s Cancer Group study. J Clin Oncol 19:3470–3476PubMed
6.
go back to reference Giordana MT, Schiffer P, Schiffer D (1998) Prognostic factors in medulloblastoma. Childs Nerv Syst 14:256–262PubMedCrossRef Giordana MT, Schiffer P, Schiffer D (1998) Prognostic factors in medulloblastoma. Childs Nerv Syst 14:256–262PubMedCrossRef
7.
go back to reference Korshunov A, Savostikova M, Ozerov S (2002) Immunohistochemical markers for prognosis of average-risk pediatric medulloblastomas. The effect of apoptotic index, TrkC, and c-myc expression. J Neurooncol 58:271–279PubMedCrossRef Korshunov A, Savostikova M, Ozerov S (2002) Immunohistochemical markers for prognosis of average-risk pediatric medulloblastomas. The effect of apoptotic index, TrkC, and c-myc expression. J Neurooncol 58:271–279PubMedCrossRef
8.
go back to reference Shim KW, Joo SY, Kim SH, Choi JU, Kim DS (2008) Prediction of prognosis in children with medulloblastoma by using immunohistochemical analysis and tissue microarray. J Neurosurg Pediatr 1:196–205PubMedCrossRef Shim KW, Joo SY, Kim SH, Choi JU, Kim DS (2008) Prediction of prognosis in children with medulloblastoma by using immunohistochemical analysis and tissue microarray. J Neurosurg Pediatr 1:196–205PubMedCrossRef
9.
go back to reference Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMed Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMed
10.
go back to reference Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRef Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRef
11.
go back to reference Annabi B, Rojas-Sutterlin S, Laflamme C, Lachambre MP, Rolland Y, Sartelet H, Béliveau R (2008) Tumor environment dictates medulloblastoma cancer stem cell expression and invasive phenotype. Mol Cancer Res 6:907–916PubMedCrossRef Annabi B, Rojas-Sutterlin S, Laflamme C, Lachambre MP, Rolland Y, Sartelet H, Béliveau R (2008) Tumor environment dictates medulloblastoma cancer stem cell expression and invasive phenotype. Mol Cancer Res 6:907–916PubMedCrossRef
12.
go back to reference Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66:7843–7848PubMedCrossRef Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, Shi Q, McLendon RE, Bigner DD, Rich JN (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66:7843–7848PubMedCrossRef
13.
go back to reference Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:66–77CrossRef Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR, Lu L, Irvin D, Black KL, Yu JS (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:66–77CrossRef
14.
go back to reference Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRef Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedCrossRef
15.
go back to reference Blazek ER, Foutch JL, Maki G (2007) Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133− cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67:1–5PubMedCrossRef Blazek ER, Foutch JL, Maki G (2007) Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133− cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67:1–5PubMedCrossRef
16.
go back to reference Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC (2008) PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 22:436–448PubMedCrossRef Hambardzumyan D, Becher OJ, Rosenblum MK, Pandolfi PP, Manova-Todorova K, Holland EC (2008) PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 22:436–448PubMedCrossRef
17.
go back to reference Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende CC (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14:123–129PubMedCrossRef Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N, Lichter P, Unterberg A, Radlwimmer B, Herold-Mende CC (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14:123–129PubMedCrossRef
18.
go back to reference Kong DS, Kim MH, Park WY, Suh YL, Lee JI, Park K, Kim JH, Nam DH (2008) The progression of gliomas is associated with cancer stem cell phenotype. Oncol Rep 19:639–643PubMed Kong DS, Kim MH, Park WY, Suh YL, Lee JI, Park K, Kim JH, Nam DH (2008) The progression of gliomas is associated with cancer stem cell phenotype. Oncol Rep 19:639–643PubMed
19.
go back to reference Beier D, Wischhusen J, Dietmaier W, Hau P, Proescholdt M, Brawanski A, Bogdahn U, Beier CP (2008) CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol (Zurich, Switzerland) 18:370–377CrossRef Beier D, Wischhusen J, Dietmaier W, Hau P, Proescholdt M, Brawanski A, Bogdahn U, Beier CP (2008) CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors. Brain Pathol (Zurich, Switzerland) 18:370–377CrossRef
20.
go back to reference Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay T, Hamou MF, de Tribolet N, Regli L, Wick W, Kouwenhoven MC, Hainfellner JA, Heppner FL, Dietrich PY, Zimmer Y, Cairncross JG, Janzer RC, Domany E, Delorenzi M, Stupp R, Hegi ME (2008) Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 26:3015–3024PubMedCrossRef Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay T, Hamou MF, de Tribolet N, Regli L, Wick W, Kouwenhoven MC, Hainfellner JA, Heppner FL, Dietrich PY, Zimmer Y, Cairncross JG, Janzer RC, Domany E, Delorenzi M, Stupp R, Hegi ME (2008) Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 26:3015–3024PubMedCrossRef
21.
go back to reference Pallini R, Ricci-Vitiani L, Banna GL, Signore M, Lombardi D, Todaro M, Stassi G, Martini M, Maira G, Larocca LM, De Maria R (2008) Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin Cancer Res 14:8205–8212PubMedCrossRef Pallini R, Ricci-Vitiani L, Banna GL, Signore M, Lombardi D, Todaro M, Stassi G, Martini M, Maira G, Larocca LM, De Maria R (2008) Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme. Clin Cancer Res 14:8205–8212PubMedCrossRef
22.
go back to reference Mao Y, Zhou L, Zhu W, Wang X, Yang G, Xie L, Mao X, Jin K (2007) Proliferative status of tumor stem cells may be correlated with malignancy grade of human astrocytomas. Front Biosci 12:2252–2259PubMedCrossRef Mao Y, Zhou L, Zhu W, Wang X, Yang G, Xie L, Mao X, Jin K (2007) Proliferative status of tumor stem cells may be correlated with malignancy grade of human astrocytomas. Front Biosci 12:2252–2259PubMedCrossRef
23.
go back to reference Yao Y, Tang X, Li S, Mao Y, Zhou L (2009) Brain tumor stem cells: view from cell proliferation. Surg Neurol 71:274–279PubMedCrossRef Yao Y, Tang X, Li S, Mao Y, Zhou L (2009) Brain tumor stem cells: view from cell proliferation. Surg Neurol 71:274–279PubMedCrossRef
24.
go back to reference Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) WHO classification of tumor of the central nervous system, 4th edn. IARC Press, Lyon Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) WHO classification of tumor of the central nervous system, 4th edn. IARC Press, Lyon
25.
go back to reference Yao Y, Wang X, Jin K, Zhu J, Wang Y, Xiong S, Mao Y, Zhou L (2008) B7-H4 is preferentially expressed in non-dividing brain tumor cells and in a subset of brain tumor stem-like cells. J Neurooncol 89:121–129PubMedCrossRef Yao Y, Wang X, Jin K, Zhu J, Wang Y, Xiong S, Mao Y, Zhou L (2008) B7-H4 is preferentially expressed in non-dividing brain tumor cells and in a subset of brain tumor stem-like cells. J Neurooncol 89:121–129PubMedCrossRef
26.
go back to reference Bowers DC, Gargan L, Weprin BE, Mulne AF, Elterman RD, Munoz L, Giller CA, Winick NJ (2007) Impact of site of tumor recurrence upon survival for children with recurrent or progressive medulloblastoma. J Neurosurg 107:5–10PubMed Bowers DC, Gargan L, Weprin BE, Mulne AF, Elterman RD, Munoz L, Giller CA, Winick NJ (2007) Impact of site of tumor recurrence upon survival for children with recurrent or progressive medulloblastoma. J Neurosurg 107:5–10PubMed
27.
go back to reference Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 100:15178–15183PubMedCrossRef Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M, Kornblum HI (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 100:15178–15183PubMedCrossRef
Metadata
Title
Differential proliferative index of cancer stem-like cells in primary and recurrent medulloblastoma in human
Authors
Xuqun Tang
Yu Yao
Jingjing Zhu
Kunlin Jin
Yin Wang
Ying Mao
Liangfu Zhou
Publication date
01-11-2012
Publisher
Springer-Verlag
Published in
Child's Nervous System / Issue 11/2012
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI
https://doi.org/10.1007/s00381-012-1856-z

Other articles of this Issue 11/2012

Child's Nervous System 11/2012 Go to the issue