The Renin–Angiotensin System in the Tumor Microenvironment of Glioblastoma

SIMPLE SUMMARY: Glioblastoma (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. ABSTRACT: 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.