The Renin-Angiotensin System in the Tumor Microenvironment of Glioblastoma

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.

Keywords: cancer stem cell niche; cancer stem cells; glioblastoma; organoids; pluripotent stem cells; renin–angiotensin system; tumor microenvironment.

Figure 1

A schema demonstrating the role of the renin–angiotensin system (RAS) and its convergent signaling pathways in the glioblastoma tumor microenvironment (TME) and cancer stem cells (CSCs). A cancer stem cell (with the cytoplasm depicted in light blue and the nucleus in purple) residing within the glioblastoma TME. Angiotensin II (ATII), the physiologically active end-product of the paracrine RAS, activates ATII receptor 1 (AT₁R) leading to increased tumor cell proliferation, oxidative stress, hypoxia and angiogenesis, and inflammation—the hallmarks of cancer. This contributes to an inflammatory TME by increasing the number of inflammatory cells, partly by increasing the number of NADPH complexes, leading to tumor cell proliferation, DNA damage from oxidative stress, and release of growth factors. AT₁R also activates phosphatidylinositol signaling, which increases cytosolic Ca²⁺ to promote mitogenesis. Hypoxia increases paracrine RAS activity by upregulating angiotensin-converting enzyme (ACE) and the expression of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α, which increase tumor progression and treatment resistance. HIF-1α, HIF-2α, and hypoxia increase the expression of vascular endothelial growth factor (VEGF) which increases angiogenesis. AT₁R, via MAPK-STAT3 signaling, contributes to a cytokine release that leads to CSC renewal. C-X-C chemokine receptor type 4 (CXCR4) promotes tumor cell migration and invasion. AT₁R signaling and the prorenin receptor, which act in a feedback loop with Wnt/β-catenin, increase Wnt signaling which promotes CSC stemness by upregulating stemness-associated markers. Myeloid-derived suppressor cells (MDSCs) promote CSC characteristics by increasing microRNA-101 expression that induces expression of stemness-related genes in CSCs. The Ang(1–7)/MasR axis opposes the ACE/ATII/AT₁R axis. Cathepsins B, D, and G act as bypass loops for the RAS. Under the influence of the TME, polarization of tumor-associated macrophages (TAMs)—immune cells that are located within the TME—changes from the M1 to M2 phenotype. M2 TAMs induce the proliferation of CSCs via interleukin 6 (IL-6)-induced activation of STAT3, leading to cytokine release and positive feedback contributing to CSC renewal. Glioblastoma CSCs secrete Wnt-induced signaling protein 1 (WISP1), which facilitates a pro-tumor TME by promoting the survival of CSCs and M2 TAMs, and also promotes CSC maintenance. Abbreviations: ATI, angiotensin I; AT₂R, ATII receptor 2; Ang(1–7), angiotensin 1–7; ATIII, angiotensin III; MAPK, mitogen-activated protein kinase. Figure modified and reproduced with permission from the J Histochem Cytochem [19].

Figure 2

A schema showing the effect of the renin–angiotensin system (RAS) and its convergent signaling pathways on the tumor microenvironment to influence cellular proliferation, invasiveness, and cell survival in cancer development. The RAS interacts with downstream pathways, such as the Ras/RAF/MEK/ERK (light blue) pathway and the PI3K/AKT/mTOR (dark blue) pathway, and the upstream Wnt/β-catenin pathway (intermediate blue) that influence cellular proliferation, migration, inhibition of apoptosis, migration, and invasion (see text). PRR, pro-renin receptor; LRP6, low-density lipoprotein receptor-related protein; Fzd, frizzled receptor; Cath G, cathepsin G; Cath B, cathepsin B; Cath D, cathepsin D; ACE1, angiotensin-converting enzyme 1; ACE2, angiotensin-converting enzyme 2; ADP, adenosine diphosphate; AGT, angiotensinogen; ATP, adenosine triphosphate; Ang(1–7), angiotensin (1–7); Ang(1–9), angiotensin (1–9); AP-A, aminopeptidase-A; NEP, neutral endopeptidase; AP-N, aminopeptidase-N; ATI, angiotensin I; ATII, angiotensin II; ATIII, angiotensin III; ATIV, angiotensin IV; AT₁R, angiotensin II receptor 1; AT₂R, angiotensin II receptor 2; AT₄R, angiotensin II receptor 4; MrgD, Mas-related-G protein coupled receptor; MasR, Mas receptor; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa B; TGF-β₁, transforming growth factor-β₁; V-ATPase, vacuolar H⁺-adenosine triphosphate.