Letter to the Editor: CD133-positive stem cells

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To The Editor: Recently, we read with interest the article by Tamura et al.6 (Tamura K, Aoyagi M, Ando N, et al: Expansion of CD133-positive glioma cells in recurrent de novo glioblastomas after radiotherapy and chemotherapy. Laboratory investigation. J Neurosurg 119:1145–1155, November 2013). In this article, Tamura et al.6 reported that the mean percentage of CD133-positive glioma cells in sections from glioblastomas (GBMs) recurring after radiotherapy and chemotherapy was 12.2% ± 10.3%, which was significantly higher than that obtained at the primary surgery (1.08% ± 1.78%). In addition, the mean Ki 67 index of CD133-positive glioma cells in recurrent tumors (14.5% ± 6.67%, n = 20) was significantly higher than that in primary tumors (2.16% ± 2.60%, n = 14, p < 0.000001, unpaired t-test). On the basis of these results, the authors concluded that CD133-positive glioma cells could survive, change to a proliferative cancer stem cell phenotype, and lead to recurrence of GBM.

The glycosylated CD133 epitope has been identified as a reliable tumor marker for the purification of a subpopulation of GBM cells demonstrating cancer stem cell phenotypes.2 CD133-positive glioma cells display significant resistance to conventional radiation and chemotherapy. A previous study has shown that CD133-positive glioma cells persist in greater fractions after treatment with ionizing radiation through preferentially activating Chk1 and Chk2 checkpoint kinases, and this radioresistance is lost following Chk1 and Chk2 inhibition.1 In addition, CD133-positive glioma cells are associated with resistance to chemotherapy. This resistance is probably related to higher expression of BCRP1 and MGMT, as well as the antiapoptosis protein and inhibitors of apoptosis protein families in CD133-positive glioma cells. CD133 expression was significantly higher in recurrent GBM tissue obtained from 5 patients as compared to their respective newly diagnosed tumors.4 Most importantly, there was marked accumulation of CD133-positive glioma cells in sections obtained after Gamma Knife surgery (GKS) plus external beam radiation therapy (EBRT), whereas CD133-positive cells appeared very infrequently in primary sections prior to adjuvant treatment. In addition, high MIB-1 indices but reduced numbers of tumor blood vessels were observed in recurrent GBM after GKS and EBRT.7 These findings suggest that accumulation of CD133-positive glioma cells contributes to radiochemoresistance and is related to an adverse prognosis.

A recent study from Pallini et al.5 showed that in recurrent GBM, CD133-positive cells were significantly increased compared with the percentage in primary GBMs, but, unexpectedly, the increase in CD133 expression was significantly associated with longer survival after tumor recurrence. Interestingly, the CD133-positive cell compartment of recurrent GBM was composed of both cancer stem cells and nontumor neural stem cells (NSCs). Nontumor CD133-positive cells are thought to migrate from surrounding brain toward the tumor, which is linked significantly to a better outcome. This is consistent with the finding that in a mouse model, the GBM-induced attraction of endogenous neural precursor cells was associated with improved survival because of antiproliferative and proapoptotic actions of the neural precursors in GBM cells.3 These results suggest that tumor and nontumor CD133-positive cells may play completely different roles in recurrent GBM.

In summary, although many investigators agree that accumulation of CD133-positive cells in recurrent GBM after radiochemotherapy is correlated with a worse prognosis, subsequent scenarios seem to lead to opposite outcomes. The role of CD133-positive cells in recurrent GBM seems to be controversial. To ascertain the exact mechanisms of action of CD133-positive cells in recurrent GBM, both more animal studies and additional human studies with larger patient populations will be needed. Unraveling the role of tumor and nontumor CD133-positive cells in recurrent GBM may then allow for the identification of relevant targets for therapeutic intervention.

Disclosure

This project was supported by the National Science Foundation of China (No. 81072066). The authors report no conflict of interest.

References

  • 1

    Bao SWu QMcLendon REHao YShi QHjelmeland AB: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:7567602006

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  • 2

    Choy WNagasawa DTTrang AThill KSpasic MYang I: CD133 as a marker for regulation and potential for targeted therapies in glioblastoma multiforme. Neurosurg Clin N Am 23:3914052012

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    • Export Citation
  • 3

    Glass RSynowitz MKronenberg GWalzlein JHMarkovic DSWang LP: Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci 25:263726462005

    • Search Google Scholar
    • Export Citation
  • 4

    Liu GYuan XZeng ZTunici PNg HAbdulkadir IR: Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:672006

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    • Export Citation
  • 5

    Pallini RRicci-Vitiani LMontano NMollinari CBiffoni MCenci T: Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis. Cancer 117:1621742011

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    • Export Citation
  • 6

    Tamura KAoyagi MAndo NOgishima TWakimoto HYamamoto M: Expansion of CD133-positive glioma cells in recurrent de novo glioblastomas after radiotherapy and chemotherapy. Laboratory investigation. J Neurosurg 119:114511552013

    • Search Google Scholar
    • Export Citation
  • 7

    Tamura KAoyagi MWakimoto HAndo NNariai TYamamoto M: Accumulation of CD133-positive glioma cells after high-dose irradiation by Gamma Knife surgery plus external beam radiation. Clinical article. J Neurosurg 113:3103182010

    • Search Google Scholar
    • Export Citation

Response

We would like to thank Bian and colleagues for their interest in our work.

The infiltration of nontumor cells is frequently observed in GBM tissues. In a murine experimental GBM model, endogenous neural precursors could migrate toward the tumor and suppress tumor growth by antiproliferative and proapoptotic actions.1 In the recent report by Pallini et al.2 (mentioned by Bian et al.), recurrent GBMs showed an increase in CD133-positive cells composed of both cancer stem cells and nontumor cells. The authors used elegant but somewhat complex methods to show that recurrent GBM tissues contain nontumor CD133-positive cells. The nontumor CD133-positive cells may represent NSCs that could exert an antiglioma effect causing a better prognosis for tumors with a high frequency of CD133 expression on recurrence. In our series, increase in the frequency of CD133-positive cells was greater in specimens from recurrent GBMs obtained after high-dose radiation with EBRT and GKS than in those subjected to EBRT alone. The survival of the patients with GBMs treated with high-dose radiation therapy appeared to be longer (no significant difference) than that of patients treated with EBRT alone. We thought that the better prognosis was caused primarily by high-dose irradiation. However, the survival of patients with GBMs may be influenced by many factors, including tumor biological behavior, tumor location, methods of treatment, and patient selection bias. In the article by Pallini et al.,2 no direct evidence was provided for the antitumor effects of nontumor CD133-positive cells on recurrent GBM. The cellular origin of nontumor CD133-positive cells was not known. The role of nontumor CD133-postive cells in recurrent GBMs after radiochemotherapy awaits further validation.

References

  • 1

    Glass RSynowitz MKronenberg GWalzlein JHMarkovic DSWang LP: Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci 25:263726462005

    • Search Google Scholar
    • Export Citation
  • 2

    Pallini RRicci-Vitiani LMontano NMollinari CBiffoni MCenci T: Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis. Cancer 117:1621742011

    • Search Google Scholar
    • Export Citation

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Article Information

Please include this information when citing this paper: published online February 7, 2014; DOI: 10.3171/2013.10.JNS132261.

© AANS, except where prohibited by US copyright law.

Headings

References

  • 1

    Bao SWu QMcLendon REHao YShi QHjelmeland AB: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:7567602006

    • Search Google Scholar
    • Export Citation
  • 2

    Choy WNagasawa DTTrang AThill KSpasic MYang I: CD133 as a marker for regulation and potential for targeted therapies in glioblastoma multiforme. Neurosurg Clin N Am 23:3914052012

    • Search Google Scholar
    • Export Citation
  • 3

    Glass RSynowitz MKronenberg GWalzlein JHMarkovic DSWang LP: Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci 25:263726462005

    • Search Google Scholar
    • Export Citation
  • 4

    Liu GYuan XZeng ZTunici PNg HAbdulkadir IR: Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5:672006

    • Search Google Scholar
    • Export Citation
  • 5

    Pallini RRicci-Vitiani LMontano NMollinari CBiffoni MCenci T: Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis. Cancer 117:1621742011

    • Search Google Scholar
    • Export Citation
  • 6

    Tamura KAoyagi MAndo NOgishima TWakimoto HYamamoto M: Expansion of CD133-positive glioma cells in recurrent de novo glioblastomas after radiotherapy and chemotherapy. Laboratory investigation. J Neurosurg 119:114511552013

    • Search Google Scholar
    • Export Citation
  • 7

    Tamura KAoyagi MWakimoto HAndo NNariai TYamamoto M: Accumulation of CD133-positive glioma cells after high-dose irradiation by Gamma Knife surgery plus external beam radiation. Clinical article. J Neurosurg 113:3103182010

    • Search Google Scholar
    • Export Citation
  • 1

    Glass RSynowitz MKronenberg GWalzlein JHMarkovic DSWang LP: Glioblastoma-induced attraction of endogenous neural precursor cells is associated with improved survival. J Neurosci 25:263726462005

    • Search Google Scholar
    • Export Citation
  • 2

    Pallini RRicci-Vitiani LMontano NMollinari CBiffoni MCenci T: Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis. Cancer 117:1621742011

    • Search Google Scholar
    • Export Citation

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