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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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Vessel or glioma origin of CD133 expressing cells.In contrast to high-grade glioma specimens, CD133 expressing cells detected in low-grade glioma specimens are predominantly derived from blood vessel endothelial cells. Dot-plot profiles of CD133 expression versus CD45 and/or CD31 expression of cells from glioma specimens of indicated patients are shown. 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-g004: Vessel or glioma origin of CD133 expressing cells.In contrast to high-grade glioma specimens, CD133 expressing cells detected in low-grade glioma specimens are predominantly derived from blood vessel endothelial cells. Dot-plot profiles of CD133 expression versus CD45 and/or CD31 expression of cells from glioma specimens of indicated patients are shown. The numbers in each quadrate represent the percentages of the cells stained positively or negatively by the respective antibodies.

Mentions: As gliomas, particularly the high-grade gliomas, are highly vascularized, newly formed blood vessel endothelial cells may also express CD133 [39]. To ascertain the glioma origin of the CD133+ cell fraction in our low-grade and high-grade glioma specimens, we subsequently performed CD133 expression analysis in combination with CD45 and CD31 staining. By doing so, it is possible to distinguish glioma cells from both hematopoietic cells (via CD45 expression) and tumor blood vessel endothelial cells (via CD31 expression) [40]. As shown in Figure 4, a small population of CD45−, but CD133+ cells can be detected in low-grade glioma specimens. Relatively higher frequencies of such cells were found in GBM specimens. However, such CD45−CD133+ cells were predominantly CD31+ in low-grade glioma specimens (ranging from 0.3 to 7% of the total living cells, n = 4). This indicates that CD133+ cells, if present in low-grade gliomas, are predominantly derived from newly formed blood vessel endothelial cells, and not from the glioma cells. In GBM specimens, the majority of CD133+ cells were of glioma origin, although CD31+CD133+ cells (ranging from 0.5 to 10% of the total living cells, n = 9) were also found.


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)

Vessel or glioma origin of CD133 expressing cells.In contrast to high-grade glioma specimens, CD133 expressing cells detected in low-grade glioma specimens are predominantly derived from blood vessel endothelial cells. Dot-plot profiles of CD133 expression versus CD45 and/or CD31 expression of cells from glioma specimens of indicated patients are shown. 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-g004: Vessel or glioma origin of CD133 expressing cells.In contrast to high-grade glioma specimens, CD133 expressing cells detected in low-grade glioma specimens are predominantly derived from blood vessel endothelial cells. Dot-plot profiles of CD133 expression versus CD45 and/or CD31 expression of cells from glioma specimens of indicated patients are shown. The numbers in each quadrate represent the percentages of the cells stained positively or negatively by the respective antibodies.
Mentions: As gliomas, particularly the high-grade gliomas, are highly vascularized, newly formed blood vessel endothelial cells may also express CD133 [39]. To ascertain the glioma origin of the CD133+ cell fraction in our low-grade and high-grade glioma specimens, we subsequently performed CD133 expression analysis in combination with CD45 and CD31 staining. By doing so, it is possible to distinguish glioma cells from both hematopoietic cells (via CD45 expression) and tumor blood vessel endothelial cells (via CD31 expression) [40]. As shown in Figure 4, a small population of CD45−, but CD133+ cells can be detected in low-grade glioma specimens. Relatively higher frequencies of such cells were found in GBM specimens. However, such CD45−CD133+ cells were predominantly CD31+ in low-grade glioma specimens (ranging from 0.3 to 7% of the total living cells, n = 4). This indicates that CD133+ cells, if present in low-grade gliomas, are predominantly derived from newly formed blood vessel endothelial cells, and not from the glioma cells. In GBM specimens, the majority of CD133+ cells were of glioma origin, although CD31+CD133+ cells (ranging from 0.5 to 10% of the total living cells, n = 9) were also found.

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