Abstract
Simple SummaryGlioblastoma (GB) is the most aggressive brain cancer in humans. Patient survival outcomes have remained dismal despite intensive research over the past 50 years, with a median overall survival of only 14.6 months. We highlight the critical role of the renin–angiotensin system (RAS) on GB cancer stem cells and the tumor microenvironment which, in turn, influences cancer stem cells in driving tumorigenesis and treatment resistance. We present recent developments and underscore the need for further research into the GB tumor microenvironment. We discuss the novel therapeutic targeting of the RAS using existing commonly available medications and utilizing model systems to further this critical investigation.Glioblastoma (GB) is an aggressive primary brain tumor. Despite intensive research over the past 50 years, little advance has been made to improve the poor outcome, with an overall median survival of 14.6 months following standard treatment. Local recurrence is inevitable due to the quiescent cancer stem cells (CSCs) in GB that co-express stemness-associated markers and components of the renin–angiotensin system (RAS). The dynamic and heterogeneous tumor microenvironment (TME) plays a fundamental role in tumor development, progression, invasiveness, and therapy resistance. There is increasing evidence showing the critical role of the RAS in the TME influencing CSCs via its upstream and downstream pathways. Drugs that alter the hallmarks of cancer by modulating the RAS present a potential new therapeutic alternative or adjunct to conventional treatment of GB. Cerebral and GB organoids may offer a cost-effective method for evaluating the efficacy of RAS-modulating drugs on GB. We review the nexus between the GB TME, CSC niche, and the RAS, and propose re-purposed RAS-modulating drugs as a potential therapeutic alternative or adjunct to current standard therapy for GB.
Highlights
Glioblastoma (GB), the most common and most aggressive primary brain cancer in humans, is classified as a WHO grade IV astrocytoma, and is characterized by microvascular proliferation and central necrosis [1]
The classical subtype includes amplification or mutation of epidermal growth factor receptor (EGFR), the mesenchymal subtype includes deletions of the 17q11.2 region containing the gene NF1, and the proneural subtype is characterized by high levels of platelet-derived growth factor receptor α (PDGFRα) expression and point mutations in isocitrate dehydrogenase 1 (IDH1)
We reviewed the dynamic relationship between the tumor microenvironment (TME), the renin–angiotensin system (RAS), and cancer stem cells (CSCs) in GB
Summary
Glioblastoma (GB), the most common and most aggressive primary brain cancer in humans, is classified as a WHO grade IV astrocytoma, and is characterized by microvascular proliferation and central necrosis [1]. Various genetic or epigenetic changes may affect the prognosis of GB patients including IDH mutations and O6-methylguanine-DNA methyltransferase (MGMT) methylation status. IDH-wild-type GB is more common, tends to arise de novo, and is generally more aggressive with a worse prognosis than IDH-mutant GB. IDH-mutant GB is predominantly observed in secondary GB and is associated with a better prognosis [6]. MGMT methylation is associated with an improved overall survival in GB patients [9]. Despite this intensive treatment, tumor recurrence in GB patients is inevitable with an overall median survival time of 14.6 months with a range of 12–14 months which has not changed since the introduction of the Stupp protocol in 2005 [10,11].
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