Expression of the stem cell marker CD133 in recurrent glioblastoma and its value for prognosis

Abstract

BACKGROUND: Experimental data suggest that glioblastoma cells expressing the stem cell marker CD133 play a major role in radiochemoresistance and tumor aggressiveness. To date, however, there is no clinical evidence that the fraction of CD133-positive cells in glioblastoma that recurs after radiochemotherapy may be relevant for prognosis. METHODS: The authors used immunohistochemistry to assess CD133 expression in 37 paired glioblastoma samples, including 1 primary tumor sample and 1 recurrent tumor sample, after patients received adjuvant radiochemotherapy. To assess the actual composition of the CD133-positive glioblastoma cell population, fluorescence-associated cell sorting (FACS) analysis was used to sort CD133-positive/CD45-negative cells that were assayed for tumor-specific chromosomal aberrations using interphase fluorescence in situ hybridization. To rule out endothelial precursor cells, CD133-positive fractions also were assayed with anti-CD34 by FACS. RESULTS: In recurrent glioblastomas, the percentage of CD133-positive cells was increased by 4.6-fold compared with the percentage in primary glioblastomas, although, in some tumors, it increased up to 10-fold and 20-fold. Unexpectedly, the increase in CD133 expression was associated significantly with longer survival after tumor recurrence. An analysis of tumor-specific chromosomal aberrations and in vivo studies revealed that the CD133-positive cell compartment of recurrent glioblastoma was composed of both cancer stem cells and nontumor neural stem cells. The latter cells represented from 20% to 60% of the CD133-positive cell population, and their relative percentage favorably affected the survival of patients with recurrent glioblastoma. Endothelial CD133-positive/CD34-positive precursors did not contribute to the CD133-positive cell population. CONCLUSIONS: The authors hypothesized that, similar to the phenomenon described in glioblastoma models, neural stem/progenitor cells that are recruited by the tumor from surrounding brain may exert an antitumorigenic effect. Cancer 2011;117:162-74.

Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells

“…As CD133 was originally described as the NSC (Uchida et al, 2000) and BTIC (Singh et al, 2004) marker, its ability to exclusively isolate tumor-initiating cells has been debated in the literature, especially in adult glioblastoma. In this heterogeneous tumor, CD133À cells in long-term culture were found to be capable of tumor initiation in mice (Chen et al, 2010), although many recent publications maintain that not only is the CD133 þ fraction enriched in BTIC capacity Yan et al, 2011), but the features of 'stemness' marked by CD133 are associated with increasing malignancy and poor patient outcome (Bao et al, 2006;Thon et al, 2008;McCord et al, 2009;Pallini et al, 2010). In medulloblastoma, evidence more uniformly supports the application of CD133 as a BTIC marker, as CD133 þ multipotent NSCs were described in the postnatal cerebellum (Lee et al, 2005), and further studies showed that CD133 enriched for brain tumor-initiating capacity and radioresistance in primary and Daoy medulloblastoma-derived tumors (Fan et al, 2006;Blazek et al, 2007;Annabi et al, 2008Annabi et al, , 2010Pistollato et al, 2010;Yu et al, 2010).…”

Isolation, cultivation and characterization of CD133+ stem cells from human glioblastoma

“…These authors determined that these CD133 + cells were glioblastoma stem cells, and also identified a more aggressive subtype of the disease (21) , insofar as these cells are highly resistant to radiation and chemotherapy procedures (16) . Other studies have also suggested that the expression of the marker CD133 + could be a molecular indicator of glioblastoma spreading (16,22) , which justifies its prognostic value (23) and the recent demand for drugs that act against this subset of cells (CD133 + ) in order to inhibit or retard the proliferation of highly invasive gliomas (24) .…”

Brain tumor stem cells: phenotypic characterization and directed therapeutic approaches

“…Thus the data obtained by Pallini R. et al (2011) who investigated CD133 expression in 44 glioblastomas (GBMs) and found that presence of 2 % of CD133 + cells and CD133/ Ki67 co-expression were correlated with unfavorable survivorship outcomes in patients with brain tumors [15]. Zeppernick F. et al [2008] revealed that the presence of CD133 clusters and large number of CD133 + cells correlated with short survival term [16].…”