Transcriptional Profiles of CD133+ and CD133− Glioblastoma-Derived Cancer Stem Cell Lines Suggest Different Cells of Origin

Abstract

Glioblastoma multiforme (GBM) is paradigmatic for the investigation of cancer stem cells (CSC) in solid tumors. Growing evidence suggests that different types of CSC lead to the formation of GBM. This has prompted the present comparison of gene expression profiles between 17 GBM CSC lines and their different putative founder cells. Using a newly derived 24-gene signature, we can now distinguish two subgroups of GBM: Type I CSC lines display "proneural" signature genes and resemble fetal neural stem cell (fNSC) lines, whereas type II CSC lines show "mesenchymal" transcriptional profiles similar to adult NSC (aNSC) lines. Phenotypically, type I CSC lines are CD133 positive and grow as neurospheres. Type II CSC lines, in contrast, display (semi-)adherent growth and lack CD133 expression. Molecular differences between type I and type II CSC lines include the expression of extracellular matrix molecules and the transcriptional activity of the WNT and the transforming growth factor-β/bone morphogenetic protein signaling pathways. Importantly, these characteristics were not affected by induced adherence on laminin. Comparing CSC lines with their putative cells of origin, we observed greatly increased proliferation and impaired differentiation capacity in both types of CSC lines but no cancer-associated activation of otherwise silent signaling pathways. Thus, our data suggest that the heterogeneous tumor entity GBM may derive from cells that have preserved or acquired properties of either fNSC or aNSC but lost the corresponding differentiation potential. Moreover, we propose a gene signature that enables the subclassification of GBM according to their putative cells of origin. Cancer Res; 70(5); 2030-40. ©2010 AACR.

Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms

“…In parallel, some studies suggested that there are also different subtypes of GSCs and identified two different subtypes of GSC: proneural type and mesenchymal type [82][83][84]. In the studies of Mao et al [82] and Bhat et al [83], Olig2 is recognised as a marker of proneural GSC.…”

Understanding cancer stem cell heterogeneity and plasticity

“…Similarly, the SP may or may not enrich BTSCs [63,73]. Furthermore, although it has been reported (or assumed) that there exists a lineage relationship between CD133 + and CD133 -brain tumor cells, the two populations of cells may have different cells-of-origin [70]. More studies are required to resolve these contradictory findings.…”

“…CSCs have been reported in brain tumors, especially in glioblastoma multiforme (GBM) [61][62][63][64][65][66][67][68][69][70][71][72][73][74]. The stemlike GBM cells have been enriched using cell surface molecules, such as CD133 [61,72], SSEA-1 (stagespecific embryonic antigen-1) [64], EGFR [67,68], and CD44 [69], or functional assays, including the SP analysis [7,63,73] and neurosphere assays [49,74].…”

“…In breast cancer, although the CD44 + CD24 -cell population is enriched with progenitor cells and the CD24 + population is luminally differentiated, in some tumors a lineage relationship does not exist between CD24 -and CD24 + epithelial cells as the two populations harbor different genetic alterations [116,117]. Similarly, CD133 + and CD133 -glioma cells may have different cells-of-origin [70]. There is evidence that the primary tumor genotypes dictate the overall phenotypes of tumor progenitors [44,66,110].…”

Activated Canonical Wnt Signaling in GBM is Associated with Increased Expression of Stem Cell Surface Markers

“…Because stem cells and tumor cells self-renew, they likely share similar signals to mediate this event. The role of Wnt signaling in GBM is a developing topic with a limited number of studies implicating this pathway in gliomagenesis [11][12][13][14].…”