Transforming growth factor-β and stem cell markers are highly expressed around necrotic areas in glioblastoma

Abstract

Invasion into surrounding normal brain and resistance to genotoxic therapies are the main devastating aspects of glioblastoma (GBM). These biological features may be associated with the stem cell phenotype, which can be induced through a dedifferentiation process known as epithelial-mesenchymal transition (EMT). We show here that tumor cells around pseudopalisading necrotic areas in human GBM tissues highly express the most important EMT inducer, transforming growth factor (TGF-β), concurrently with the EMT-related transcriptional factor, TWIST. In addition, the stem cell markers CD133 and alkaline phosphatase (ALPL) were also highly expressed around necrotic foci in GBM tissues. The high expression of TGF-β around necrotic regions was significantly correlated with shorter progression-free survival and overall survival in patients with GBM. High expression of stem cell markers, ALPL, CD133, and CD44 was also correlated with poor outcomes. These results collectively support the hypothesis that tissue hypoxia induces the stem cell phenotype through TGF-β-related EMT and contributes to the poor outcome of GBM patients.

Optimized monoclonal antibody treatment against ELTD1 for GBM in a G55 xenograft mouse model

“…[48][49][50] Alkaline phosphatase (ALPL) is a stem cell marker, that is highly expressed around necrotic areas within the tumour, and high expression of ALPL and CD133 (another stem cell marker) has been associated with poor prognosis for patients. 51 The mAb therapy against ELTD1 was successful in down-regulating ALPL. Glioma stem cells (GSC) are the main cause of GBM recurrence after therapy and are characterized by CD133.…”

“…Furthermore, our RNA-sequencing data demonstrated that 3 of the genes (SCN5A, L1CAM, BMP2) affected with the anti-ELTD1 treatment that were directly associated with gliomas influenced and interacted with Notch signalling. Alkaline phosphatase (ALPL) is a stem cell marker, that is highly expressed around necrotic areas within the tumour, and high expression of ALPL and CD133 (another stem cell marker) has been associated with poor prognosis for patients 51. However, the RNA-sequence analysis did not show specific gene changes with Notch.Aside from the possible relationship with Notch, the RNA-seq data gave further insight as to what pathways the anti-ELTD1 treatment is targeting.…”

The progression of epithelial-mesenchymal transformation in gliomas

“…TGF-β is well conserved in evolution, and it regulates multiple cell phenotypes such as adhesion, growth, apoptosis, differentiation and fibrosis [33]. In human cells, the TGF-β signaling pathway contains three ligand isoforms TGF-β1/2/3) and two TGF-β transmembrane receptors (TGFBR I/II).…”

“…Some studies have confirmed that E-cadherin also could be suppressed by TGF-β through ZEB, Snail and HMGA2. Another interesting finding is the discrepant expression of TGF-β existing between the necrotic and non-necrotic areas of many tumors [33].…”

“…The culminating expression of Urokinase receptor(uPAR) under hypoxia induces EMT, and intermittent hypoxia transcriptional inactivation of uPAR enhances the apoptotic response in medulloblastoma cells. A recent study reported that the mesenchymal EMT-TFs C/EBP-βand C/EBP-δwere highly expressed in GBM, especially in necrotic zones suffering from hypoxic conditions [33]. Hypoxia associates with most processes of EMT and more mechanisms are being discovered, so targeting HIF can be a new method to restrain EMT.…”