The Renin–Angiotensin System in the Tumor Microenvironment of Glioblastoma

O'Rawe, Michael; Kilmister, Ethan J.; Mantamadiotis, Theo; Kaye, Andrew H.; Tan, Swee T.; Wickremesekera, Agadha

doi:10.3390/cancers13164004

Cited by 15 publications

(16 citation statements)

References 178 publications

(217 reference statements)

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“…By interacting with the immune system, the RAS influences the TME which regulates resident ESC-like cells ( 5 , 35 ), including CSCs ( 5 ). Aberrant RAS signaling is associated with organ dysfunction, and its role in these different groups of diseases is supported by both in vitro and in vivo studies ( 1 , 3 , 8 ) which highlight its fundamental homeostatic role in cell growth, migration and death, and inflammation ( 5 , 68 ).…”

Section: The Renin-angiotensin Systemmentioning

confidence: 99%

“…Components of the RAS have been demonstrated in many cancer types ( 3 – 5 , 33 – 35 ), VAs ( 1 ), and fibroproliferative conditions ( 8 , 36 ), and are localized to cell populations that express stemness-associated markers ( 1 , 3 , 8 , 37 ). This article provides an overview of the current knowledge of ESC-like cells and the RAS in these conditions and highlights a new line of research and novel therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

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Insights Into Vascular Anomalies, Cancer, and Fibroproliferative Conditions: The Role of Stem Cells and the Renin-Angiotensin System

Kilmister

Tan

2022

Front. Surg.

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Cells exhibiting embryonic stem cell (ESC) characteristics have been demonstrated in vascular anomalies (VAs), cancer, and fibroproliferative conditions, which are commonly managed by plastic surgeons and remain largely unsolved. The efficacy of the mTOR inhibitor sirolimus, and targeted therapies that block the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways in many types of cancer and VAs, further supports the critical role of ESC-like cells in the pathogenesis of these conditions. ESC-like cells in VAs, cancer, and fibroproliferative conditions express components of the renin-angiotensin system (RAS) – a homeostatic endocrine signaling cascade that regulates cells with ESC characteristics. ESC-like cells are influenced by the Ras/BRAF/MEK/ERK1/2 and PI3KCA/AKT/mTOR pathways, which directly regulate cellular proliferation and stemness, and interact with the RAS at multiple points. Gain-of-function mutations affecting these pathways have been identified in many types of cancer and VAs, that have been treated with targeted therapies with some success. In cancer, the RAS promotes tumor progression, treatment resistance, recurrence, and metastasis. The RAS modulates cellular invasion, migration, proliferation, and angiogenesis. It also indirectly regulates ESC-like cells via its direct influence on the tissue microenvironment and by its interaction with the immune system. In vitro studies show that RAS inhibition suppresses the hallmarks of cancer in different experimental models. Numerous epidemiological studies show a reduced incidence of cancer and improved survival outcomes in patients taking RAS inhibitors, although some studies have shown no such effect. The discovery of ESC-like cells that express RAS components in infantile hemangioma (IH) underscores the paradigm shift in the understanding of its programmed biologic behavior and accelerated involution induced by β-blockers and angiotensin-converting enzyme inhibitors. The findings of SOX18 inhibition by R-propranolol suggests the possibility of targeting ESC-like cells in IH without β-adrenergic blockade, and its associated side effects. This article provides an overview of the current knowledge of ESC-like cells and the RAS in VAs, cancer, and fibroproliferative conditions. It also highlights new lines of research and potential novel therapeutic approaches for these unsolved problems in plastic surgery, by targeting the ESC-like cells through manipulation of the RAS, its bypass loops and converging signaling pathways using existing low-cost, commonly available, and safe oral medications.

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Section: The Renin-angiotensin Systemmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Insights Into Vascular Anomalies, Cancer, and Fibroproliferative Conditions: The Role of Stem Cells and the Renin-Angiotensin System

Kilmister

Tan

2022

Front. Surg.

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“…Cathepsins B, D and G which constitute bypass loops of the RAS, are expressed in glioblastoma [26,27] with cathepsins B and D being expressed by GSCs [28]. The RAS also plays a role in the CSCs [29] and tumor microenvironment [30] in glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

Treatment of glioblastoma with re-purposed renin-angiotensin system modulators: Results of a phase I clinical trial

O'Rawe

Wickremesekera

Pandey

et al. 2022

Journal of Clinical Neuroscience

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Glioblastoma is the most common and most aggressive primary brain cancer in adults. Standard treatment of glioblastoma consisting of maximal safe resection, adjuvant radiotherapy and chemotherapy with temozolomide, results in an overall median survival of 14.6 months. The aggressive nature of glioblastoma has been attributed to the presence of glioblastoma stem cells which express components of the renin-angiotensin system (RAS). This phase I clinical trial investigated the tolerability and efficacy of a treatment targeting the RAS and its converging pathways in patients with glioblastoma. Patients who had relapsed following standard treatment of glioblastoma who met the trial criteria were commenced on dose-escalated oral RAS modulators (propranolol, aliskiren, cilazapril, celecoxib, curcumin with piperine, aspirin, and metformin). Of the 17 patients who were enrolled, ten completed full dose-escalation of the treatment. The overall median survival was 19.9 (95% CI:14.1-25.7) months. Serial FET-PET/CTs showed a reduction in both tumor volume and uptake in one patient, an increase in tumor uptake in nine patients with decreased (n = 1), unchanged (n = 1) and increased (n = 7) tumor volume, in the ten patients who had completed full dose-escalation of the treatment. Two patients experienced mild side effects and all patients had preservation of quality of life and performance status during the treatment. There is a trend towards increased survival by 5.3 months although it was not statistically significant. These encouraging results warrant further clinical trials on this potential novel, well-tolerated and costeffective therapeutic option for patients with glioblastoma.

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“…Even though there have been limited advances in the progression of GBM therapeutics to significantly increase patient survival compared to other cancers, this has not dampened the motivation of researchers and clinicians to investigate novel treatment strategies for combating this disease. The Special Issue, ‘Novel Treatment Strategies for Glioblastoma’ [ 3 ], contains twelve articles (five original research articles and seven reviews) that explore a range of novel and strategic approaches for improving the treatment of GBM [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. This editorial aims to briefly summarize the content of these articles.…”

mentioning

confidence: 99%

“…The seven review articles focus on topics of great interest. O’Rawe et al [ 9 ] highlight the dynamic relationship between the renin–angiotensin system (RAS), the GBM cancer stem cell niche and the tumor microenvironment (TME), and how it contributes to driving tumorigenesis and treatment resistance. They provide a concise overview on the effect of the RAS and its convergent signaling pathways on the TME, directly influencing various factors of cancer progression, including proliferation, invasion and survival.…”

mentioning

confidence: 99%