Comparison of glioma stem cells to neural stem cells from the adult human brain identifies dysregulated Wnt- signaling and a fingerprint associated with clinical outcome

Abstract

Glioblastoma is the most common brain tumor. Median survival in unselected patients is <10 months. The tumor harbors stem-like cells that self-renew and propagate upon serial transplantation in mice, although the clinical relevance of these cells has not been well documented. We have performed the first genome-wide analysis that directly relates the gene expression profile of nine enriched populations of glioblastoma stem cells (GSCs) to five identically isolated and cultivated populations of stem cells from the normal adult human brain. Although the two cell types share common stem- and lineage-related markers, GSCs show a more heterogeneous gene expression. We identified a number of pathways that are dysregulated in GSCs. A subset of these pathways has previously been identified in leukemic stem cells, suggesting that cancer stem cells of different origin may have common features. Genes upregulated in GSCs were also highly expressed in embryonic and induced pluripotent stem cells. We found that canonical Wnt-signaling plays an important role in GSCs, but not in adult human neural stem cells. As well we identified a 30-gene signature highly overexpressed in GSCs. The expression of these signature genes correlates with clinical outcome and demonstrates the clinical relevance of GSCs.

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

“…1E-G; refs. [41][42][43]. In contrast, the classical TPCs type predominantly expressed canonical Wnt3a ( Supplementary Fig.…”

Hedgehog signaling sensitizes Glioma stem cells to endogenous nano-irradiation

“…CD133 was shown to promote the tumorigenic capacity of GCS by activation of the PI3K/Akt pathway via the interaction with the regulatory subunit of PI3K p85. The elevated expression of the activating co-receptor Smoothened (Smo) and the transcription factor Glioma-Associated Oncogene homolog 1 (Gli 1) on the one hand, and the strongly reduced expression of the repressor receptors Patched 1 (Ptch1) and hedgehog-interacting protein (Hip) on the other hand, confer the GSC the unique self-renewal and tumorgenicity potential [7, 11, 12]. The deregulation of the HH pathway represses the retinoblastoma tumor suppressor-gene (Rb) and induces expression of the proto-onco gene N-myc , a key transcription factor which is overexpressed in malignant glioma cells [13].…”

Kallikrein-related peptidase 6 orchestrates astrocyte form and function through proteinase activated receptor-dependent mechanisms

“…By contrast, KLK6 promotes resistance to irradiation and temozolomide in astrocytoma cell lines in a PAR1-dependent manner (Drucker et al 2013; Drucker et al 2015), with the role of β-catenin yet to be determined. In high-grade astrocytoma, nuclear β-catenin is associated with the invasive front of the tumor (Paul et al 2013) and high levels of WNT/β-catenin are associated with poor patient survival (Sandberg et al 2013). Taken with prior studies, the current findings point to Klk6-PAR as an important regulatory node for β-catenin signaling and additional efforts are needed to clarify the full impact on astrocyte biology in general and astrocytoma pathology in particular.…”