Coexpression analysis of CD133 and CD44 identifies Proneural and Mesenchymal subtypes of glioblastoma multiforme

Abstract

Accumulating evidence suggests that the stem cell markers CD133 and CD44 indicate molecular subtype in Glioblastoma Multiforme (GBM). Gene coexpression analysis of The Cancer Genome Atlas GBM dataset was undertaken to compare markers of the Glioblastoma Stem-Progenitor Cell (GSPC) phenotype. Pearson correlation identified genes coexpressed with stem cell markers, which were then used to build a gene signature that classifies patients based on a CD133 coexpression module signature (CD133-M) or CD44-M subtype. CD133-M tumors were enriched for the Proneural (PN) GBM subtype compared to Mesenchymal (MES) subtype for CD44-M tumors. Gene set enrichment identified DNA replication/cell cycle genes in the CD133-M and invasion/migration in CD44-M, while functional experiments showed enhanced cellular growth in CD133 expressing cells and enhanced invasion in cells expressing CD44. As with the 4 major molecular subtypes of GBM, there was no long-term survival difference between CD44-M and CD133-M patients, although CD44-M patients responded better to temozolomide while CD133-M patients benefited from radiotherapy. The use of a targeted coexpression approach to predict functional properties of surface marker expressing cells is novel, and in the context of GBM, supports accumulating evidence that CD133 and CD44 protein marker expression correlates with molecular subtype.

Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells

“…It has been demonstrated previously that the invasive behavior exhibited by glioma cells hinges on the coordinated activation of multiple cell signaling pathways (3,5,50). For the most aggressive TPC cells, that is, those of the mesenchymal hGBM cluster, this translates into a specific signature in which cell motility, migration, and aggressiveness pathways are enriched (39,40,49). Our analysis identified this molecular module in highly invasive Wnt5a…”

“…S1E). Strikingly, the expression levels of the genes associated with the Wnt-Ca 2þ signaling pathway were higher in tissues from mesenchymal hGBMs, which are endowed with higher aggressiveness and invasiveness (38)(39)(40) as compared with healthy brain tissues (Fig. 1C).…”

Evolving Strategies for Therapeutically Targeting Cancer Stem Cells

“…This previously unidentified relationship between MDA-9 and CSCs, on multiple molecular levels, emphasizes the significance of this gene as a potential new exciting therapeutic target. CD133 a proneural GBM CSC and poor prognosis marker, as wells as CD44, a characteristic marker for mesenchymal GBM CSCs (Brown et al, 2015;Mao et al, 2013;Wang et al, 2009) were both significantly downregulated post mda-9 knock-down (unpublished observation). These results indicate the efficacy of MDA-9 in regulation of CSCs at multiple levels ( Fig.…”

Prognostic relevance of NG2/CSPG4, CD44 and Ki-67 in patients with glioblastoma

“…19 CD44 belongs to glioblastoma cancer stem cell (CSC) markers and might promote cancer cell stemness by interacting with ECM components, growth factors and cytokines. 20,21 CD44 protein marker expression correlates with molecular subtype of GBM 22 and positively associated with radioresistance of glioblastoma. 23 Data on the prognostic significance of CD44 in glioblastoma are controversial -it was suggested that enhanced CD44 expression is associated with poor survival rates in glioblastoma although this finding was not statistically significant; 24 lower levels of CD44 expression surprisingly correlated with lower survival for GBM patients.…”