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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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Maintenance of glial progenitor-like phenotype, but enhanced CD133 expression in high-grade gliomas.In addition to multiple glial progenitor cell markers, a high proportion of glioma cells co-expressing CD133 was detected in most of the high-grade glioma specimens. Dot-plot profiles of glial progenitor cell surface markers and CD133 expression on high-grade glioma cells from representative patients (#14 (A) and #22 (B)) are shown. Freshly isolated glioma cells were simultaneously stained with the indicated antibodies. The hematopoietic cells were distinguished with anti-CD45 staining. The numbers in each quadrate represent the percentages of the cells stained positively or negatively by the respective antibodies.
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pone-0001936-g003: Maintenance of glial progenitor-like phenotype, but enhanced CD133 expression in high-grade gliomas.In addition to multiple glial progenitor cell markers, a high proportion of glioma cells co-expressing CD133 was detected in most of the high-grade glioma specimens. Dot-plot profiles of glial progenitor cell surface markers and CD133 expression on high-grade glioma cells from representative patients (#14 (A) and #22 (B)) are shown. Freshly isolated glioma cells were simultaneously stained with the indicated antibodies. The hematopoietic cells were distinguished with anti-CD45 staining. The numbers in each quadrate represent the percentages of the cells stained positively or negatively by the respective antibodies.

Mentions: As in low-grade glioma cells, high-grade glioma cells analyzed in this study maintained the expression profiles for PDGFRα, A2B5, O4 and CD44 ( Table 1 and Figure 3). In all these high-grade glioma cases, GFAP expression was detected with inter- as well as intra-glioma variation (Table 2 and Figure 2). The expression of CD24 was observed in 7 of 16 high-grade gliomas analyzed. In striking contrast to the low-grade glioma cells, distinct cell populations with high intensity of CD133 expression (ranging from 22 to 90% of the CD45− cell fraction) was detected in 12 of the 17 high-grade glioma specimens. In addition, EGFR over-expression was detected in 11 of the 17 high-grade glioma specimens analyzed. Of note, no detectable difference in cell surface marker expression profile was observed between the secondary (patients ID 15 and 16) and de novo GBM specimens analyzed (Table 1).


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)

Maintenance of glial progenitor-like phenotype, but enhanced CD133 expression in high-grade gliomas.In addition to multiple glial progenitor cell markers, a high proportion of glioma cells co-expressing CD133 was detected in most of the high-grade glioma specimens. Dot-plot profiles of glial progenitor cell surface markers and CD133 expression on high-grade glioma cells from representative patients (#14 (A) and #22 (B)) are shown. Freshly isolated glioma cells were simultaneously stained with the indicated antibodies. The hematopoietic cells were distinguished with anti-CD45 staining. The numbers in each quadrate represent the percentages of the cells stained positively or negatively by the respective antibodies.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001936-g003: Maintenance of glial progenitor-like phenotype, but enhanced CD133 expression in high-grade gliomas.In addition to multiple glial progenitor cell markers, a high proportion of glioma cells co-expressing CD133 was detected in most of the high-grade glioma specimens. Dot-plot profiles of glial progenitor cell surface markers and CD133 expression on high-grade glioma cells from representative patients (#14 (A) and #22 (B)) are shown. Freshly isolated glioma cells were simultaneously stained with the indicated antibodies. The hematopoietic cells were distinguished with anti-CD45 staining. The numbers in each quadrate represent the percentages of the cells stained positively or negatively by the respective antibodies.
Mentions: As in low-grade glioma cells, high-grade glioma cells analyzed in this study maintained the expression profiles for PDGFRα, A2B5, O4 and CD44 ( Table 1 and Figure 3). In all these high-grade glioma cases, GFAP expression was detected with inter- as well as intra-glioma variation (Table 2 and Figure 2). The expression of CD24 was observed in 7 of 16 high-grade gliomas analyzed. In striking contrast to the low-grade glioma cells, distinct cell populations with high intensity of CD133 expression (ranging from 22 to 90% of the CD45− cell fraction) was detected in 12 of the 17 high-grade glioma specimens. In addition, EGFR over-expression was detected in 11 of the 17 high-grade glioma specimens analyzed. Of note, no detectable difference in cell surface marker expression profile was observed between the secondary (patients ID 15 and 16) and de novo GBM specimens analyzed (Table 1).

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