Glioblastoma (GBM) is the most common and fatal type of primary brain tumor. Gliosarcoma (GSM) is a rarer and more aggressive variant of GBM that has recently been considered a potentially different disease. Current clinical treatment for both GBM and GSM includes maximal surgical resection followed by post-operative radiotherapy and concomitant and adjuvant chemotherapy. Despite recent advances in treating other solid tumors, treatment for GBM and GSM still remains palliative, with a very poor prognosis and a median survival rate of 12–15 months. Treatment failure is a result of a number of causes, including resistance to radiotherapy and chemotherapy. Recent research has applied the cancer stem cells theory of carcinogenesis to these tumors, suggesting the existence of a small subpopulation of glioma stem-like cells (GSCs) within these tumors. GSCs are thought to contribute to tumor progression, treatment resistance, and tumor recapitulation post-treatment and have become the focus of novel therapy strategies. Their isolation and investigation suggest that GSCs share critical signaling pathways with normal embryonic and somatic stem cells, but with distinct alterations. Research must focus on identifying these variations as they may present novel therapeutic targets. Targeting pluripotency transcription factors, SOX2, OCT4, and Nanog homeobox, demonstrates promising therapeutic potential that if applied in isolation or together with current treatments may improve overall survival, reduce tumor relapse, and achieve a cure for these patients.
Pluripotent stem cells (PSCs) attracted considerable interest with the successful isolation of embryonic stem cells (ESCs) from the inner cell mass of murine, primate and human embryos. Whilst it was initially thought that the only PSCs were ESCs, in more recent years cells with similar properties have been isolated from organs of the adult, including the breast and brain. Adult PSCs in these organs have been suggested to be remnants of embryonic development that facilitate normal tissue homeostasis during repair and regeneration. They share certain characteristics with ESCs, such as an inherent capacity to self-renew and differentiate into cells of the three germ layers, properties that are regulated by master pluripotency transcription factors (TFs) OCT4 (octamer-binding transcription factor 4), SOX2 (sex determining region Y-box 2), and homeobox protein NANOG. Aberrant expression of these TFs can be oncogenic resulting in heterogeneous tumours fueled by cancer stem cells (CSC), which are resistant to conventional treatments and are associated with tumour recurrence post-treatment. Further to enriching our understanding of the role of pluripotency TFs in normal tissue function, research now aims to develop optimized isolation and propagation methods for normal adult PSCs and CSCs for the purposes of regenerative medicine, developmental biology, and disease modeling aimed at targeted personalised cancer therapies.
Glioblastoma (GBM) and its more aggressive variant gliosarcoma (GSM) are the most lethal primary brain tumours, containing glioma stem cells (GSCs) which are resistant to current treatments. We compared the cellular hierarchy and molecular heterogeneity of GBM and GSM to identify genetic drivers of tumour growth and potential therapeutic targets. Fresh frozen human GBM and GSM specimens and 6 cell lines were interrogated using qRT‐PCR for expression of genes controlling self‐renewal and multilineage differentiation. SOX2 was overexpressed, whereas its core partners OCT4 and NANOG showed 90‐180 fold lower expression. Downstream targets ESRRB, PROX1, NESTIN and PAX6 had variable expression. GSC‐associated marker CD133 was highly expressed in both frozen GBM and GSM, but less so in the cell lines. Neural genes MAP2 and GAP43 and glial genes GFAP and S100B showed variable expression. Epithelial signatures (cytokeratin 18) were detected in GSM and to a lesser extent in GBM. Expression of E‐cadherin was significantly higher in GBM than in GSM (P<0.05), suggesting greater cell motility in GSM. Endodermal signatures (GATA4) were more highly expressed in GBM. Overall, GSM showed greater variation in gene expression than GBM. The presence of neural, epithelial and endodermal signatures suggests multipotential of GSCs. The stronger presence of different lineages in GSM reflects its greater heterogeneity, providing further evidence that GSM is a different disease to GBM and highlighting the need for patient‐tailored treatments.
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