Abstract
BackgroundWhile 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 FindingsViable 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 (PDGFRα, 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 PDGFRα, 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/SignificanceThis 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.
Highlights
Gliomas, the most common primary tumors in the adult central nervous system, are currently classified according to their morphological features, into low- and high-grade glioma
We have analyzed the expression of platelet-derived growth factor receptor-a (PDGFRa), A2B5, O4 and CD44 as surface markers for glial precursor cells [17,20,21,22,23,24,27,28,29,30], and CD133 for stem cells [7,17] on freshly prepared glioma cells using flow cytometry
The concomitant expression of these progenitor cell markers was observed in most low-grade glioma specimens analyzed (Table 1). These data, combined with the homogenous glial fibrillary acidic protein (GFAP) staining and the absence of neuron-specific enolase (NSE)/synaptophysin staining (Table 2 and Figure 2), suggest that low-grade glioma cells are reminiscent of glial-progenitor cells
Summary
The most common primary tumors in the adult central nervous system, are currently classified according to their morphological features, into low- and high-grade glioma. Cells of low-grade (I and II) gliomas are well differentiated with clear histological similarity to astrocyte or oligodendrocyte lineage. High-grade (III and IV) gliomas are more anaplastic, with features resembling immature astrocytes, oligodendrocytes or a mixture of both types. The GBM in older patients are mostly diagnosed as de novo without any clinically detectable history. It is unclear whether the early stages of de novo GBM development resemble low-grade gliomas. Previous studies suggested glioma expression of oligodendrocyte progenitor cell antigen NG2 and PDGFRa, and transcription factor Olig1/2 [1,2,3], the lineage commitment and the stage of differentiation blockage of glioma cells are not clarified [4]. 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
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