The Role of the Renin–Angiotensin System in the Cancer Stem Cell Niche

Kilmister, Ethan J.; Tan, Swee T.

doi:10.1369/00221554211026295

Cited by 18 publications

(18 citation statements)

References 118 publications

(161 reference statements)

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“…182 Not all macrophages are protumoral but for successful application of antitumor macrophages, a better understanding of interactions of GSCs and macrophages is urgently needed. 183 Recently, involvement of cell types and proteins in CSCs and in particular in GSCs has been reviewed, such as a novel cell type, the telocyte, 184 scaffold proteins, 185,186 the renin-angiotensin system, 187 and specific proteases and their endogenous inhibitors. 188 MSCs are another cell type that infiltrates glioblastoma tumors and are present in GSC niches, as they are in HSC niches in bone marrow (Fig.…”

Section: Energy Metabolism Of Gscsmentioning

confidence: 99%

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

Noorden

Breznik

Novak

et al. 2021

J Histochem Cytochem.

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Energy production by means of ATP synthesis in cancer cells has been investigated frequently as a potential therapeutic target in this century. Both (an)aerobic glycolysis and oxidative phosphorylation (OXPHOS) have been studied. Here, we review recent literature on energy production in glioblastoma stem cells (GSCs) and leukemic stem cells (LSCs) versus their normal counterparts, neural stem cells (NSCs) and hematopoietic stem cells (HSCs), respectively. These two cancer stem cell types were compared because their niches in glioblastoma tumors and in bone marrow are similar. In this study, it became apparent that (1) ATP is produced in NSCs and HSCs by anaerobic glycolysis, whereas fatty acid oxidation (FAO) is essential for their stem cell fate and (2) ATP is produced in GSCs and LSCs by OXPHOS despite the hypoxic conditions in their niches with FAO and amino acids providing its substrate. These metabolic processes appeared to be under tight control of cellular regulation mechanisms which are discussed in depth. However, our conclusion is that systemic therapeutic targeting of ATP production via glycolysis or OXPHOS is not an attractive option because of its unwanted side effects in cancer patients.

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Section: Energy Metabolism Of Gscsmentioning

confidence: 99%

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

Noorden

Breznik

Novak

et al. 2021

J Histochem Cytochem.

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“…Anatomically distinct regions of the TME, known as tumor niches, are thought to contain CSCs and play a fundamental role in the regulation of metabolism, immune surveillance, survival, invasion, and self-maintenance with the renin-angiotensin system (RAS) playing a critical role [15,18,19]. The GB TME may consist of several distinct tumor niches including the hypoxic tumor niche, the perivascular or angiogenic tumor niche, and the vascular-invasive tumor niche.…”

Section: Gb Tumor Microenvironmentmentioning

confidence: 99%

“…The RAS has been proposed to play an important role in the TME [19] in various cancer types, including lung cancer, through its effect on tumor cells, non-malignant cells, hypoxia, angiogenesis, and the inflammatory response [99]. The RAS is a complex physiological system and has a multitude of interactions with many different convergent signaling pathways that operate in carcinogenesis, some of which lie outside the scope of this article.…”

Section: The Renin-angiotensin System and Convergent Signaling Pathways In Glioblastomamentioning

confidence: 99%

“…A recent trial on repurposing multiple drugs in combination with temozolomide, including two drugs that affect the RAS (i.e., captopril and celecoxib) for patients with GB, observed maintenance of good quality of life [159]. Captopril, an ACE inhibitor, and celecoxib, which inhibits cyclocoxygenase-2, reduce RAS activity [19]. In addition, RASis, in combination with bevacizumab, improve survival in patients with GB [160], although there is no overall survival benefit of this VEGF inhibitor as a monotherapy for de novo or recurrent GB [161].…”

Section: The Renin-angiotensin System and Convergent Signaling Pathways In Glioblastomamentioning

confidence: 99%

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The Renin–Angiotensin System in the Tumor Microenvironment of Glioblastoma

O'Rawe

Kilmister

Mantamadiotis

et al. 2021

Cancers

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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.

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“…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%

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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The Role of the Renin–Angiotensin System in the Cancer Stem Cell Niche

Cited by 18 publications

References 118 publications

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

Cell Biology Meets Cell Metabolism: Energy Production Is Similar in Stem Cells and in Cancer Stem Cells in Brain and Bone Marrow

The Renin–Angiotensin System in the Tumor Microenvironment of Glioblastoma

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

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