Skip to main content

Advertisement

SpringerLink
Log in

CD133 identifies perivascular niches in grade II–IV astrocytomas

  • Laboratory Investigation - human/animal tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The aim of the present study was to investigate the localization and distribution of the putative brain tumour stem cell marker CD133 in formalin fixed paraffin embedded astrocytomas. A retrospective analysis of 114 grade II, III and IV astrocytomas was undertaken. The immunohistochemical expression of CD133 in paraffin sections was analysed using morphometry. In all grades, CD133 was expressed on tumour and endothelial cells. Tumour cells were found in perivascular niches, as dispersed single cells and in pseudopalisade formations around necrosis. There was no correlation between the mean volume fraction of CD133+ niches and all CD133+ tumour cells and tumour grade. However, the volume fraction of CD133+ blood vessels increased significantly from 0.4% in diffuse astrocytomas to 2.2% in glioblastomas. Neither of them was related to patient survival. Double immunofluorescence stainings showed that the CD133+ niches both contained CD133+ cells with and without co-expression of the intermediate filament protein marker nestin, and only few CD133+/MIB-1+ proliferating cells were found. In conclusion, a CD133+ perivascular stem cell-like entity exists in astrocytomas. CD133+ tumour vessels may play an important role in a brain tumour stem cell context, while CD133 alone does not appear to be a specific tumour stem cell marker related to patient survival.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737. doi:10.1038/nm0797-730

    Article  PubMed  CAS  Google Scholar 

  2. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648. doi:10.1038/367645a0

    Article  PubMed  CAS  Google Scholar 

  3. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988. doi:10.1073/pnas.0530291100

    Article  PubMed  CAS  Google Scholar 

  4. Zhang T, Otevrel T, Gao Z, Gao Z, Ehrlich SM, Fields JZ et al (2001) Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer. Cancer Res 61:8664–8667

    PubMed  CAS  Google Scholar 

  5. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037. doi:10.1158/0008-5472.CAN-06-2030

    Article  PubMed  CAS  Google Scholar 

  6. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828

    PubMed  CAS  Google Scholar 

  7. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al (2004) Identification of human brain tumour initiating cells. Nature 432:396–401. doi:10.1038/nature03128

    Article  PubMed  CAS  Google Scholar 

  8. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N et al (2004) Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304:1338–1340. doi:10.1126/science.1095505

    Article  PubMed  CAS  Google Scholar 

  9. Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494. doi :10.1002/1096-9861(20001002)425:4<479::AID-CNE2>3.0.CO;2-3

    Article  PubMed  CAS  Google Scholar 

  10. Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S et al (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427:740–744. doi:10.1038/nature02301

    Article  PubMed  CAS  Google Scholar 

  11. Fuchs E, Tumbar T, Guasch G (2004) Socializing with the neighbors: stem cells and their niche. Cell 116:769–778. doi:10.1016/S0092-8674(04)00255-7

    Article  PubMed  CAS  Google Scholar 

  12. Gilbertson RJ, Rich JN (2007) Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 7:733–736. doi:10.1038/nrc2246

    Article  PubMed  CAS  Google Scholar 

  13. Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66:4553–4557. doi:10.1158/0008-5472.CAN-05-3986

    Article  PubMed  CAS  Google Scholar 

  14. Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N et al (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14:123–129. doi:10.1158/1078-0432.CCR-07-0932

    Article  PubMed  CAS  Google Scholar 

  15. Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11:69–82. doi:10.1016/j.ccr.2006.11.020

    Article  PubMed  CAS  Google Scholar 

  16. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560–3564. doi:10.1158/0008-5472.CAN-06-4238

    Article  PubMed  CAS  Google Scholar 

  17. Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB et al (2006) Stem cell-like glioma cells promote tumor angiogenesis through Vascular Endothelial Growth Factor. Cancer Res 66:7843–7848. doi:10.1158/0008-5472.CAN-06-1010

    Article  PubMed  CAS  Google Scholar 

  18. Hemmati HD, Nakano I, Lazareff JA, Masterman Smith M, Geschwind DH, Bronner Fraser M et al (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183. doi:10.1073/pnas.2036535100

    Article  PubMed  CAS  Google Scholar 

  19. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760. doi:10.1038/nature05236

    Article  PubMed  CAS  Google Scholar 

  20. Gal H, Makovitzki A, Amariglio N, Rechavi G, Ram Z, Givol D (2007) A rapid assay for drug sensitivity of glioblastoma stem cells. Biochem Biophys Res Commun 358:908–913. doi:10.1016/j.bbrc.2007.05.020

    Article  PubMed  CAS  Google Scholar 

  21. Ma YH, Mentlein R, Knerlich F, Kruse ML, Mehdorn HM, Held-Feindt J (2008) Expression of stem cell markers in human astrocytomas of different WHO grades. J Neurooncol 86:31–45. doi:10.1007/s11060-007-9439-7

    Article  PubMed  Google Scholar 

  22. Shi SR, Liu C, Pootrakul L, Tang L, Young A, Chen R et al (2008) Evaluation of the value of frozen tissue section used as “gold standard” for immunohistochemistry. Am J Clin Pathol 129:358–366. doi:10.1309/7CXUYXT23E5AL8KQ

    Article  PubMed  CAS  Google Scholar 

  23. Fernebro E, Bendahl PO, Dictor M, Persson A, Ferno M, Nilbert M (2004) Immunohistochemical patterns in rectal cancer: application of tissue microarray with prognostic correlations. Int J Cancer 111:921–928. doi:10.1002/ijc.20229

    Article  PubMed  CAS  Google Scholar 

  24. Fernebro E, Dictor M, Bendahl PO, Ferno M, Nilbert M (2002) Evaluation of the tissue microarray technique for immunohistochemical analysis in rectal cancer. Arch Pathol Lab Med 126:702–705

    PubMed  Google Scholar 

  25. Rosen DG, Huang X, Deavers MT, Malpica A, Silva EG, Liu J (2004) Validation of tissue microarray technology in ovarian carcinoma. Mod Pathol 17:790–797. doi:10.1038/modpathol.3800120

    Article  PubMed  CAS  Google Scholar 

  26. Graham DI, Lantos PL (2002) Tumours of the nervous system. In: Graham DI, Lantos PL (eds) Greenfield’s neuropathology, vol 2, 7th edn. Arnold, Great Britain, pp 768–1052

    Google Scholar 

  27. Kleihues P, Cavenee WK (eds) (2000) Pathology and genetics of tumours of the nervous system. IARC Press, Lyon

    Google Scholar 

  28. Neckelmann K, Kristensen BW, Schroder HD (2004) Improved histopathological evaluation of gliomas using tissue fragments obtained by ultrasonic aspiration. Clin Neuropathol 23:47–52

    PubMed  CAS  Google Scholar 

  29. Silverman JF, Jones FD, Unverferth M, Berns L (1989) Cytopathology of neoplasms of the central nervous system in specimens obtained by the Cavitron Ultrasonic Surgical Aspirator. Acta Cytol 33:576–582

    PubMed  CAS  Google Scholar 

  30. Malhotra V, Malik R, Gondal R, Beohar PC, Parkash B (1986) Evaluation of histological appearance of tissues removed by cavitron ultrasonic surgical aspirator (CUSA). Acta Neurochir (Wien) 81:132–134. doi:10.1007/BF01401235

    Article  CAS  Google Scholar 

  31. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) (2007) WHO classification of tumours of the central nervous system. International Agency for Research on Cancer, Lyon

    Google Scholar 

  32. Kania G, Corbeil D, Fuchs J, Tarasov KV, Blyszczuk P, Huttner WB et al (2005) Somatic stem cell marker prominin-1/CD133 is expressed in embryonic stem cell-derived progenitors. Stem Cells 23:791–804. doi:10.1634/stemcells.2004-0232

    Article  PubMed  CAS  Google Scholar 

  33. Florek M, Haase M, Marzesco AM, Freund D, Ehninger G, Huttner WB et al (2005) Prominin-1/CD133, a neural and hematopoietic stem cell marker, is expressed in adult human differentiated cells and certain types of kidney cancer. Cell Tissue Res 319:15–26. doi:10.1007/s00441-004-1018-z

    Article  PubMed  CAS  Google Scholar 

  34. Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263

    PubMed  CAS  Google Scholar 

  35. Gundersen HJ, Bendtsen TF, Korbo L, Marcussen N, Moller A, Nielsen K et al (1988) Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96:379–394

    PubMed  CAS  Google Scholar 

  36. Gundersen HJ (1992) Stereology: the fast lane between neuroanatomy and brain function—or still only a tightrope? Acta Neurol Scand Suppl 137:8–13

    Article  PubMed  CAS  Google Scholar 

  37. Gundersen HJ (1986) Stereology of arbitrary particles. A review of unbiased number and size estimators and the presentation of some new ones, in memory of William R. Thompson. J Microsc 143:3–45

    PubMed  CAS  Google Scholar 

  38. Pfenninger CV, Roschupkina T, Hertwig F, Kottwitz D, Englund E, Bengzon J et al (2007) CD133 is not present on neurogenic astrocytes in the adult subventricular zone, but on embryonic neural stem cells, ependymal cells, and glioblastoma cells. Cancer Res 67:5727–5736. doi:10.1158/0008-5472.CAN-07-0183

    Article  PubMed  CAS  Google Scholar 

  39. Almqvist PM, Mah R, Lendahl U, Jacobsson B, Hendson G (2002) Immunohistochemical detection of nestin in pediatric brain tumors. J Histochem Cytochem 50:147–158

    PubMed  CAS  Google Scholar 

  40. Jaros E, Perry RH, Adam L, Kelly PJ, Crawford PJ, Kalbag RM et al (1992) Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumours. Br J Cancer 66:373–385

    PubMed  CAS  Google Scholar 

  41. Kanemura Y, Mori K, Sakakibara S, Fujikawa H, Hayashi H, Nakano A et al (2001) Musashi1, an evolutionarily conserved neural RNA-binding protein, is a versatile marker of human glioma cells in determining their cellular origin, malignancy, and proliferative activity. Differentiation 68:141–152. doi:10.1046/j.1432-0436.2001.680208.x

    Article  PubMed  CAS  Google Scholar 

  42. Homma T, Fukushima T, Vaccarella S, Yonekawa Y, Di Patre PL, Franceschi S et al (2006) Correlation among pathology, genotype, and patient outcomes in glioblastoma. J Neuropathol Exp Neurol 65:846–854. doi:10.1097/01.jnen.0000235118.75182.94

    Article  PubMed  CAS  Google Scholar 

  43. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951. doi:10.1158/0008-5472.CAN-05-2018

    Article  PubMed  CAS  Google Scholar 

  44. von Wasielewski R, Mengel M, Gignac S, Wilkens L, Werner M, Georgii A (1997) Tyramine amplification technique in routine immunohistochemistry. J Histochem Cytochem 45:1455–1459

    Google Scholar 

  45. Rebetz J, Tian D, Persson A, Widegren B, Salford LG, Englund E, Gisselsson D, Fan X (2008) Glial progenitor-like phenotype in low-grade glioma and enhanced CD133-expression and neuronal lineage differentiation potential in high-grade glioma. PLoS ONE. doi:10.1371/journal.pone.0001936

  46. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115. doi:10.1038/nature05384

    Article  PubMed  CAS  Google Scholar 

  47. Hilbe W, Dirnhofer S, Oberwasserlechner F, Schmid T, Gunsilius E, Hilbe G et al (2004) CD133 positive endothelial progenitor cells contribute to the tumour vasculature in non-small cell lung cancer. J Clin Pathol 57:965–969. doi:10.1136/jcp. 2004.016444

    Article  PubMed  CAS  Google Scholar 

  48. Sakariassen PO, Prestegarden L, Wang J, Skaftnesmo KO, Mahesparan R, Molthoff C, Sminia P, Sundlisaeter E, Misra A, Tysnes BB, Chekenya M, Peters H, Lende G, Kalland KH, Oyan AM, Petersen K, Jonassen I, van der Kogel A, Feuerstein BG, Terzis AJ, Bjerkvig R, Enger PO (2006) Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci USA 103:16466–16471. doi:10.1073/pnas.0607668103

    Article  PubMed  CAS  Google Scholar 

  49. Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ et al (2007) CD133+ and CD133− glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67:4010–4015. doi:10.1158/0008-5472.CAN-06-4180

    Article  PubMed  CAS  Google Scholar 

  50. Ogden AT, Waziri AE, Lochhead RA, Fusco D, Lopez K, Ellis JA et al (2008) Identification of A2B5+CD133− tumor-initiating cells in adult human gliomas. Neurosurgery 62:505–514. doi:10.1227/01.neu.0000316019.28421.95

    Article  PubMed  Google Scholar 

  51. O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110. doi:10.1038/nature05372

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Ole Nielsen for critical comments and suggestions regarding the immunohistochemical and immunofluorescence protocols. The excellent laboratory work of Tanja Dreehsen and Helle Wohlleben is gratefully acknowledged. This work was supported by the Danish Cancer Society, Danish Medical Research Council, Danish Cancer Research Foundation, Johs. Clemmesen’s Research Foundation, Hørslev Foundation, Memorial Foundation for Alice Brenå, Merchant M. Kristian Kjær and wife Margrethe Kjær born la Cour-Holmen’s Foundation, Karen A. Tolstrup’s Foundation, Dagmar Marshall’s Foundation, Harboe’s Foundation, Kathrine and Vigo Skovgaard’s Foundation, Eva and Henry Frænkel’s Memorial Foundation, and Merchant M. Brogaard and wife’s Memorial Foundation.

Author information

Authors and Affiliations

  1. Department of Pathology, Odense University Hospital, Odense, Denmark

    Karina Christensen, Henrik D. Schrøder & Bjarne W. Kristensen

Authors
  1. Karina Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henrik D. Schrøder
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bjarne W. Kristensen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karina Christensen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Christensen, K., Schrøder, H.D. & Kristensen, B.W. CD133 identifies perivascular niches in grade II–IV astrocytomas. J Neurooncol 90, 157–170 (2008). https://doi.org/10.1007/s11060-008-9648-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-008-9648-8

Keywords

Search

Navigation