Glioblastoma (GBM) is a heterogeneous tumor of the brain with a poor prognosis due to recurrence and drug resistance following therapy. Genome-wide profiling has revealed the existence of distinct GBM molecular subtypes that respond differently to aggressive therapies. Despite this, molecular subtype does not predict recurrence or drug resistance and overall survival is similar across subtypes. One of the key features contributing to tumor recurrence and resistance to therapy is proposed to be an underlying subpopulation of resistant glioma stem cells (GSC). CD133 expression has been used as a marker of GSCs, however recent evidence suggests the relationship between CD133 expression, GSCs and molecular subtype is more complex than initially proposed. The expression of CD133, Olig2 and CD44 was investigated using patient derived glioma stem-like cells (PDGCs) in vitro and in vivo. Different PDGCs exhibited a characteristic equilibrium of distinct CD133+ and CD44+ subpopulations and the influence of environmental factors on the intra-tumor equilibrium of CD133+ and CD44+ cells in PDGCs was also investigated, with hypoxia inducing a CD44+ to CD133+ shift and chemo-radiotherapy inducing a CD133+ to CD44+ shift. These data suggest that surveillance and modulation of intra-tumor heterogeneity using molecular markers at initial surgery and surgery for recurrent GBM may be important for more effective management of GBM.

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.

No abstract

No abstract