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Glial progenitor-like phenotype in low-grade glioma and enhanced CD133-expression and neuronal lineage differentiation potential in high-grade glioma.

Rebetz J, Tian D, Persson A, Widegren B, Salford LG, Englund E, Gisselsson D, Fan X - PLoS ONE (2008)

Bottom Line: In parallel, the expression of glial fibrillary acidic protein (GFAP), synaptophysin and neuron-specific enolase (NSE) was immunohistochemically analyzed in fixed tissue specimens.The rare CD133 expressing cells in low-grade glioma specimens typically co-expressed vessel endothelial marker CD31.The CD133 expression correlates inversely with length of patient survival.

View Article: PubMed Central - PubMed

Affiliation: The Rausing Laboratory, Division of Neurosurgery, Lund University Hospital, Lund, Sweden.

ABSTRACT

Background: While neurosphere- as well as xenograft tumor-initiating cells have been identified in gliomas, the resemblance between glioma cells and neural stem/progenitor cells as well as the prognostic value of stem/progenitor cell marker expression in glioma are poorly clarified.

Methodology/principal findings: Viable glioma cells were characterized for surface marker expression along the glial genesis hierarchy. Six low-grade and 17 high-grade glioma specimens were flow-cytometrically analyzed for markers characteristics of stem cells (CD133); glial progenitors (PDGFRalpha, A2B5, O4, and CD44); and late oligodendrocyte progenitors (O1). In parallel, the expression of glial fibrillary acidic protein (GFAP), synaptophysin and neuron-specific enolase (NSE) was immunohistochemically analyzed in fixed tissue specimens. Irrespective of the grade and morphological diagnosis of gliomas, glioma cells concomitantly expressed PDGFRalpha, A2B5, O4, CD44 and GFAP. In contrast, O1 was weakly expressed in all low-grade and the majority of high-grade glioma specimens analyzed. Co-expression of neuronal markers was observed in all high-grade, but not low-grade, glioma specimens analyzed. The rare CD133 expressing cells in low-grade glioma specimens typically co-expressed vessel endothelial marker CD31. In contrast, distinct CD133 expression profiles in up to 90% of CD45-negative glioma cells were observed in 12 of the 17 high-grade glioma specimens and the majority of these CD133 expressing cells were CD31 negative. The CD133 expression correlates inversely with length of patient survival. Surprisingly, cytogenetic analysis showed that gliomas contained normal and abnormal cell karyotypes with hitherto indistinguishable phenotype.

Conclusions/significance: This study constitutes an important step towards clarification of lineage commitment and differentiation blockage of glioma cells. Our data suggest that glioma cells may resemble expansion of glial lineage progenitor cells with compromised differentiation capacity downstream of A2B5 and O4 expression. The concurrent expression of neuronal markers demonstrates that high-grade glioma cells are endowed with multi-lineage differentiation potential in vivo. Importantly, enhanced CD133 expression marks a poor prognosis in gliomas.

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CD133 expression correlates inversely with grade II to IV glioma patient survival time.The survival time calculated from the day of operation was plotted against the percentage of CD133+ cells in the CD45− cell fraction from the specimens of each patient. UD: undetectable CD133 expression. Bold black bars indicate the median survival time for patients in groups with CD133+ cells either lower or higher than 30% of total CD45− cells.
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pone-0001936-g006: CD133 expression correlates inversely with grade II to IV glioma patient survival time.The survival time calculated from the day of operation was plotted against the percentage of CD133+ cells in the CD45− cell fraction from the specimens of each patient. UD: undetectable CD133 expression. Bold black bars indicate the median survival time for patients in groups with CD133+ cells either lower or higher than 30% of total CD45− cells.

Mentions: Finally, we investigated whether the glial progenitor or stem cell markers expressed on glioma cells could serve as prognostic markers for patient survival. Glioblastoma patients receiving immune therapy and patients with pilocytic astrocytoma or ependymoma, were excluded from the prognosis analysis. We divided all analyzed grade II to IV glioma patients into a CD133+ low group (CD133+ cells less than 30%) and a CD133+ high group (CD133+ cells higher than 30%). The median survival time in the CD133+ high group was 5.0±9.2 months (n = 9) compared to more than 22.0±17.3 months (n = 10) in the CD133+ low group (P = 0.026, t test; Figure 6). Thus, CD133 expression inversely correlates with glioma patient survival time.


Glial progenitor-like phenotype in low-grade glioma and enhanced CD133-expression and neuronal lineage differentiation potential in high-grade glioma.

Rebetz J, Tian D, Persson A, Widegren B, Salford LG, Englund E, Gisselsson D, Fan X - PLoS ONE (2008)

CD133 expression correlates inversely with grade II to IV glioma patient survival time.The survival time calculated from the day of operation was plotted against the percentage of CD133+ cells in the CD45− cell fraction from the specimens of each patient. UD: undetectable CD133 expression. Bold black bars indicate the median survival time for patients in groups with CD133+ cells either lower or higher than 30% of total CD45− cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2277459&req=5

pone-0001936-g006: CD133 expression correlates inversely with grade II to IV glioma patient survival time.The survival time calculated from the day of operation was plotted against the percentage of CD133+ cells in the CD45− cell fraction from the specimens of each patient. UD: undetectable CD133 expression. Bold black bars indicate the median survival time for patients in groups with CD133+ cells either lower or higher than 30% of total CD45− cells.
Mentions: Finally, we investigated whether the glial progenitor or stem cell markers expressed on glioma cells could serve as prognostic markers for patient survival. Glioblastoma patients receiving immune therapy and patients with pilocytic astrocytoma or ependymoma, were excluded from the prognosis analysis. We divided all analyzed grade II to IV glioma patients into a CD133+ low group (CD133+ cells less than 30%) and a CD133+ high group (CD133+ cells higher than 30%). The median survival time in the CD133+ high group was 5.0±9.2 months (n = 9) compared to more than 22.0±17.3 months (n = 10) in the CD133+ low group (P = 0.026, t test; Figure 6). Thus, CD133 expression inversely correlates with glioma patient survival time.

Bottom Line: In parallel, the expression of glial fibrillary acidic protein (GFAP), synaptophysin and neuron-specific enolase (NSE) was immunohistochemically analyzed in fixed tissue specimens.The rare CD133 expressing cells in low-grade glioma specimens typically co-expressed vessel endothelial marker CD31.The CD133 expression correlates inversely with length of patient survival.

View Article: PubMed Central - PubMed

Affiliation: The Rausing Laboratory, Division of Neurosurgery, Lund University Hospital, Lund, Sweden.

ABSTRACT

Background: While neurosphere- as well as xenograft tumor-initiating cells have been identified in gliomas, the resemblance between glioma cells and neural stem/progenitor cells as well as the prognostic value of stem/progenitor cell marker expression in glioma are poorly clarified.

Methodology/principal findings: Viable glioma cells were characterized for surface marker expression along the glial genesis hierarchy. Six low-grade and 17 high-grade glioma specimens were flow-cytometrically analyzed for markers characteristics of stem cells (CD133); glial progenitors (PDGFRalpha, A2B5, O4, and CD44); and late oligodendrocyte progenitors (O1). In parallel, the expression of glial fibrillary acidic protein (GFAP), synaptophysin and neuron-specific enolase (NSE) was immunohistochemically analyzed in fixed tissue specimens. Irrespective of the grade and morphological diagnosis of gliomas, glioma cells concomitantly expressed PDGFRalpha, A2B5, O4, CD44 and GFAP. In contrast, O1 was weakly expressed in all low-grade and the majority of high-grade glioma specimens analyzed. Co-expression of neuronal markers was observed in all high-grade, but not low-grade, glioma specimens analyzed. The rare CD133 expressing cells in low-grade glioma specimens typically co-expressed vessel endothelial marker CD31. In contrast, distinct CD133 expression profiles in up to 90% of CD45-negative glioma cells were observed in 12 of the 17 high-grade glioma specimens and the majority of these CD133 expressing cells were CD31 negative. The CD133 expression correlates inversely with length of patient survival. Surprisingly, cytogenetic analysis showed that gliomas contained normal and abnormal cell karyotypes with hitherto indistinguishable phenotype.

Conclusions/significance: This study constitutes an important step towards clarification of lineage commitment and differentiation blockage of glioma cells. Our data suggest that glioma cells may resemble expansion of glial lineage progenitor cells with compromised differentiation capacity downstream of A2B5 and O4 expression. The concurrent expression of neuronal markers demonstrates that high-grade glioma cells are endowed with multi-lineage differentiation potential in vivo. Importantly, enhanced CD133 expression marks a poor prognosis in gliomas.

Show MeSH
Related in: MedlinePlus