Cancer Stem Cells in Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma Express Components of the Renin-Angiotensin System

We investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cell (CSC) subpopulations in metastatic head and neck cutaneous squamous cell carcinoma (mHNcSCC). Immunohistochemical staining demonstrated expression of prorenin receptor (PRR), angiotensin-converting enzyme (ACE), and angiotensin II receptor 2 (AT2R) in all cases and angiotensinogen in 14 cases; however, renin and ACE2 were not detected in any of the 20 mHNcSCC tissue samples. Western blotting showed protein expression of angiotensinogen in all six mHNcSCC tissue samples, but in none of the four mHNcSCC-derived primary cell lines, while PRR was detected in the four cell lines only. RT-qPCR confirmed transcripts of angiotensinogen, PRR, ACE, and angiotensin II receptor 1 (AT1R), but not renin or AT2R in all four mHNcSCC tissue samples and all four mHNcSCC-derived primary cell lines, while ACE2 was expressed in the tissue samples only. Double immunohistochemical staining on two of the mHNcSCC tissue samples showed expression of angiotensinogen by the SOX2+ CSCs within the tumor nests (TNs), and immunofluorescence showed expression of PRR and AT2R by the SOX2+ CSCs within the TNs and the peritumoral stroma (PTS). ACE was expressed on the endothelium of the tumor microvessels within the PTS. We demonstrated expression of angiotensinogen by CSCs within the TNs, PRR, and AT2R by the CSCs within the TNs and the PTS, in addition to ACE on the endothelium of tumor microvessels in mHNcSCC.

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Alterations in Gene Expression of Components of the Renin-Angiotensin System and Its Related Enzymes in Lung Cancer

Lung Cancer International ◽

10.1155/2017/6914976 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Benjamin Goldstein ◽

Malav Trivedi ◽

Robert C. Speth

Keyword(s):

Angiotensin Ii ◽

Renin Angiotensin System ◽

System Component ◽

Receptor Subtype ◽

Angiotensin Ii Receptor ◽

Statistical Tool ◽

Tissue Samples ◽

Angiotensin System ◽

Lung Cancers ◽

Renin Angiotensin

Objectives. The study assessed the existence and significance of associations between the expression of fifteen renin-angiotensin system component genes and lung adenocarcinoma. Materials and Methods. NCBI’s built-in statistical tool, GEO2R, was used to calculate Student’s t-tests for the associations found in a DNA expression study of adenocarcinoma and matched healthy lung tissue samples. The raw data was processed with GeneSpring™ and then used to generate figures with and without Sidak’s multiple comparison correction. Results. Ten genes were found to be significantly associated with adenocarcinoma. Seven of these associations remained statistically significant after correction for multiple comparisons. Notably, AGTR2, which encodes the AT2 angiotensin II receptor subtype, was significantly underexpressed in adenocarcinoma tissue (p<0.01). AGTR1, ACE, ENPEP, MME, and PRCP, which encode the AT1 angiotensin II receptor, angiotensin-converting enzyme, aminopeptidase N, neprilysin, and prolylcarboxypeptidase, respectively, were also underexpressed. AGT, which encodes angiotensinogen, the angiotensin peptide precursor, was overexpressed in adenocarcinoma tissue. Conclusion. The results suggest an association between the expression of the genes for renin-angiotensin system-related proteins and adenocarcinoma. While further research is necessary to conclusively demonstrate a link between the renin-angiotensin system and lung cancers, the results suggest that the renin-angiotensin system plays a role in the pathology of adenocarcinoma.

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Cancer Stem Cells in Head and Neck Metastatic Malignant Melanoma Express Components of the Renin-Angiotensin System

Life ◽

10.3390/life10110268 ◽

2020 ◽

Vol 10 (11) ◽

pp. 268

Author(s):

Sam Siljee ◽

Tessa Pilkington ◽

Helen D. Brasch ◽

Nicholas Bockett ◽

Josie Patel ◽

...

Keyword(s):

Stem Cells ◽

Malignant Melanoma ◽

Cancer Stem Cells ◽

Cell Lines ◽

Renin Angiotensin System ◽

Metastatic Malignant Melanoma ◽

Primary Cell ◽

Tissue Samples ◽

Angiotensin System ◽

Primary Cell Lines

Components of the renin-angiotensin system (RAS) are expressed by cancer stem cells (CSCs) in many cancer types. We here investigated expression of the RAS by the CSC subpopulations in human head and neck metastatic malignant melanoma (HNmMM) tissue samples and HNmMM-derived primary cell lines. Immunohistochemical staining demonstrated expression of pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), and angiotensin II receptor 2 (AT2R) in all; renin in one; and ACE2 in none of the 20 HNmMM tissue samples. PRR was localized to cells within the tumor nests (TNs), while AT2R was expressed by cells within the TNs and the peritumoral stroma (PTS). ACE was localized to the endothelium of the tumor microvessels within the PTS. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) detected transcripts for PRR, ACE, ACE2, and AT1R, in all the five HNmMM tissue samples and four HNmMM-derived primary cell lines; renin in one tissue sample and one cell line, and AT2R in none of the five HNmMM tissue samples and cell lines. Western blotting showed variable expression of ACE, PRR, and AT2R, but not ACE2, in six HNmMM tissue samples and two HNmMM-derived primary cell lines. Immunofluorescence staining of two HNmMM tissue samples demonstrated expression of PRR and AT2R by the SOX2+ CSCs within the TNs and the OCT4+ CSCs within the PTS, with ACE localized to the endothelium of the tumor microvessels within the PTS.

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Expression of Components of the Renin-Angiotensin System by Cancer Stem Cells in Renal Clear Cell Carcinoma

Biomolecules ◽

10.3390/biom11040537 ◽

2021 ◽

Vol 11 (4) ◽

pp. 537

Author(s):

Sam Siljee ◽

Bridget Milne ◽

Helen D. Brasch ◽

Nicholas Bockett ◽

Josie Patel ◽

...

Keyword(s):

Immunohistochemical Staining ◽

Clear Cell ◽

Clear Cell Carcinoma ◽

Renin Angiotensin System ◽

Renal Clear Cell Carcinoma ◽

Converting Enzyme ◽

Angiotensin Ii Receptor ◽

Tissue Samples ◽

Angiotensin System ◽

Double Immunohistochemical Staining

This study investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cells (CSCs) we have recently demonstrated in renal clear cell carcinoma (RCCC). Fifteen RCCC tissue samples underwent immunohistochemical staining for components of the RAS: renin, pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), and angiotensin II receptor 2 (AT2R). Immunofluorescence co-staining or double immunohistochemical staining of these components of the RAS with stemness-associated markers OCT4 or KLF4 was performed on two of the samples. Protein and transcript expression of these components of the RAS in six RCCC tissue samples was investigated using western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. In addition, angiotensin II receptor 1 (AT1R) was investigated using RT-qPCR only. Immunohistochemical staining demonstrated expression of renin, PRR, and ACE2 in 11, 13, and 13 out of 15 RCCC samples, respectively, while AT2R was expressed in all 15 samples. ACE was detected in the endothelium of normal vasculature only. Double immunohistochemical staining demonstrated localization of ACE2, but not renin, to the KLF4+ CSCs. Immunofluorescence staining showed localization of PRR and AT2R to the OCT4+ CSCs. Western blotting confirmed protein expression of all components of the RAS except renin. RT-qPCR demonstrated transcript expression of all components of the RAS including AT1R, but not AT2R, in all six RCCC tissue samples. This study demonstrated expression of PRR, ACE2, and AT2R by the CSCs within RCCC. Further studies may lead to novel therapeutic targeting of CSCs by manipulation of the RAS in the treatment of this aggressive cancer.

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A Review of Angiotensin Receptor Blocker-based Therapies at all Levels of Cardiovascular Risk

European Cardiology Review ◽

10.15420/ecr.2011.7.4.254 ◽

2011 ◽

Vol 7 (4) ◽

pp. 254 ◽

Cited By ~ 1

Author(s):

Giuliano Tocci ◽

Lorenzo Castello ◽

Massimo Volpe ◽

◽

...

Keyword(s):

Angiotensin Ii ◽

Ventricular Hypertrophy ◽

Renin Angiotensin System ◽

Left Ventricular ◽

Clinical Settings ◽

Angiotensin Ii Receptor ◽

Angiotensin System ◽

Receptor Blockers ◽

Artery Disease

The renin–angiotensin system (RAS) has a key role in the maintenance of cardiovascular homeostasis, and water and electrolyte metabolism in healthy subjects, as well as in several diseases including hypertension, left ventricular hypertrophy and dysfunction, coronary artery disease, renal disease and congestive heart failure. These conditions are all characterised by abnormal production and activity of angiotensin II, which represents the final effector of the RAS. Over the last few decades, accumulating evidence has demonstrated that antihypertensive therapy based on angiotensin II receptor blockers (ARBs) has a major role in the selective antagonism of the main pathological activities of angiotensin II. Significant efforts have been made to demonstrate that blocking the angiotensin II receptor type 1 (AT1) subtype receptors through ARB-based therapy results in proven benefits in different clinical settings. In this review, we discuss the main benefits of antihypertensive strategies based on ARBs in terms of their efficacy, safety and tolerability.

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The renin-angiotensin system and volume overload-induced cardiac hypertrophy in rats. Effects of angiotensin converting enzyme inhibitor versus angiotensin II receptor blocker.

Circulation ◽

10.1161/01.cir.87.3.921 ◽

1993 ◽

Vol 87 (3) ◽

pp. 921-930 ◽

Cited By ~ 63

Author(s):

M Ruzicka ◽

B Yuan ◽

E Harmsen ◽

F H Leenen

Keyword(s):

Angiotensin Ii ◽

Angiotensin Converting Enzyme ◽

Cardiac Hypertrophy ◽

Enzyme Inhibitor ◽

Renin Angiotensin System ◽

Volume Overload ◽

Angiotensin Ii Receptor Blocker ◽

Converting Enzyme ◽

Angiotensin Ii Receptor ◽

Angiotensin System

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Renin and prorenin have no direct effect on aldosterone synthesis in the human adrenocortical cell lines H295R and HAC15

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320312438792 ◽

2012 ◽

Vol 13 (3) ◽

pp. 360-366 ◽

Cited By ~ 9

Author(s):

Pieter M Jansen ◽

Johannes Hofland ◽

Anton H van den Meiracker ◽

Frank H de Jong ◽

AH Jan Danser

Keyword(s):

Angiotensin Ii ◽

Cell Lines ◽

Renin Angiotensin System ◽

Adrenocortical Cell ◽

Transgenic Rats ◽

Angiotensin System ◽

Extracellular Signal Regulated Kinase ◽

Erk Phosphorylation ◽

Extracellular Signal ◽

Aldosterone Production

Introduction: Transgenic rats expressing the human (pro)renin receptor (h(P)RR) have elevated plasma aldosterone levels despite unaltered levels, in plasma and adrenal, of renin and angiotensin II. Materials and methods: To investigate whether renin/prorenin–(P)RR interaction underlies these elevated aldosterone levels, the effect of (pro)renin on steroidogenesis was compared with that of angiotensin II in two (P)RR-expressing human adrenocortical cell lines, H295R and HAC15. Angiotensin II rapidly induced extracellular signal-regulated kinase (ERK) phosphorylation and increased the expression of STAR, CYP21A2, CYP11B2, and CYP17A1 at 6 and 24 hours, whereas the expression of CYP11A1 and HSD3B2 remained unaltered. Incubation with renin or prorenin at nanomolar concentrations had no effect on the expression of any of the steroidogenic enzymes tested, nor resulted in ERK phosphorylation. Angiotensin II, but not renin or prorenin, induced aldosterone production. Conclusion: Although the (P)RR is present in adrenocortical cells, renin and prorenin do not elicit ERK phosphorylation nor directly affect steroid production via this receptor at nanomolar concentrations. Thus, direct (pro)renin–(P)RR interaction is unlikely to contribute to the elevated aldosterone levels in human (P)RR transgenic rats. This conclusion also implies that the aldosterone rise that often occurs during prolonged renin–angiotensin system blockade is rather due to the angiotensin II ‘escape’ during such blockade.

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