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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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Glioma cells are compromised in downstream differentiation at the O4 stage.Glioma cells were stained with APC conjugated anti-CD45 and anti-CD31 mAbs in combination with staining for A2B5, or O4 or O1. Data shown are the ratio of the percentages between O4+/CD45−CD31− and A2B5+/CD45−CD31− phenotype or between O1+/CD45−CD31− and A2B5+/CD45−CD31− phenotype in each patient. The ependymoma patient was not included in this analysis.
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pone-0001936-g005: Glioma cells are compromised in downstream differentiation at the O4 stage.Glioma cells were stained with APC conjugated anti-CD45 and anti-CD31 mAbs in combination with staining for A2B5, or O4 or O1. Data shown are the ratio of the percentages between O4+/CD45−CD31− and A2B5+/CD45−CD31− phenotype or between O1+/CD45−CD31− and A2B5+/CD45−CD31− phenotype in each patient. The ependymoma patient was not included in this analysis.

Mentions: In agreement with previous studies demonstrating glioma expression of oligodendrocyte progenitor cell transcription factor Olig1/2 and surface antigen NG2 [1]–[3], the concomitant expression of A2B5 (a marker for multiple types of progenitor cells in glial lineage [20]–[27], [41]), PDGFRα (a marker for early oligodendrocyte progenitor cells at O-2A stage [22], [25], [26], [42]–[44]) and O4 (a marker for late oligodendrocyte progenitor cells [29]) suggests that glioma cells, irrespective of their morphological characteristics, are committed to the oligodendrocyte lineage. To further characterize the differentiation stages along the oligodendrocyte lineage downstream of the A2B5 expressing glial progenitor cell level, we analyzed the expression of O1, a marker for pre-myelinating oligodendrocytes [29]. In contrast to the high level A2B5 and O4 expression, the frequency of O1+ cells were significantly diminished in all low-grade and the majority of GBM specimens analyzed (Table 1 and Figure 5). The expression of GFAP and these oligodendrocyte progenitor surface markers suggests that along the oligodendrocyte lineage differentiation hierarchy, A2B5+/PDGFRα+ glioma cells were compromised in differentiation downstream of A2B5/O4, but upstream of the O1 stage.


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)

Glioma cells are compromised in downstream differentiation at the O4 stage.Glioma cells were stained with APC conjugated anti-CD45 and anti-CD31 mAbs in combination with staining for A2B5, or O4 or O1. Data shown are the ratio of the percentages between O4+/CD45−CD31− and A2B5+/CD45−CD31− phenotype or between O1+/CD45−CD31− and A2B5+/CD45−CD31− phenotype in each patient. The ependymoma patient was not included in this analysis.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0001936-g005: Glioma cells are compromised in downstream differentiation at the O4 stage.Glioma cells were stained with APC conjugated anti-CD45 and anti-CD31 mAbs in combination with staining for A2B5, or O4 or O1. Data shown are the ratio of the percentages between O4+/CD45−CD31− and A2B5+/CD45−CD31− phenotype or between O1+/CD45−CD31− and A2B5+/CD45−CD31− phenotype in each patient. The ependymoma patient was not included in this analysis.
Mentions: In agreement with previous studies demonstrating glioma expression of oligodendrocyte progenitor cell transcription factor Olig1/2 and surface antigen NG2 [1]–[3], the concomitant expression of A2B5 (a marker for multiple types of progenitor cells in glial lineage [20]–[27], [41]), PDGFRα (a marker for early oligodendrocyte progenitor cells at O-2A stage [22], [25], [26], [42]–[44]) and O4 (a marker for late oligodendrocyte progenitor cells [29]) suggests that glioma cells, irrespective of their morphological characteristics, are committed to the oligodendrocyte lineage. To further characterize the differentiation stages along the oligodendrocyte lineage downstream of the A2B5 expressing glial progenitor cell level, we analyzed the expression of O1, a marker for pre-myelinating oligodendrocytes [29]. In contrast to the high level A2B5 and O4 expression, the frequency of O1+ cells were significantly diminished in all low-grade and the majority of GBM specimens analyzed (Table 1 and Figure 5). The expression of GFAP and these oligodendrocyte progenitor surface markers suggests that along the oligodendrocyte lineage differentiation hierarchy, A2B5+/PDGFRα+ glioma cells were compromised in differentiation downstream of A2B5/O4, but upstream of the O1 stage.

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