Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions

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Abstract

The mechanistic involvement of the renin-angiotensin system (RAS) reaches beyond cardiovascular physiopathology. Recent knowledge pinpoints a pleiotropic role for this system, particularly in the lung, and mainly through locally regulated alternative molecules and secondary pathways. Angiotensin peptides play a role in cell proliferation, immunoinflammatory response, hypoxia and angiogenesis, which are critical biological processes in lung cancer. This manuscript reviews the literature supporting a role for the renin-angiotensin system in the lung tumor microenvironment and discusses whether blockade of this pathway in clinical settings may serve as an adjuvant therapy in lung cancer.

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Most cited references 133

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Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System

Mahmoud Gheblawi, Kaiming Wang, Anissa Viveiros … (2020)

ACE2 (angiotensin-converting enzyme 2) has a multiplicity of physiological roles that revolve around its trivalent function: a negative regulator of the renin-angiotensin system, facilitator of amino acid transport, and the severe acute respiratory syndrome-coronavirus (SARS-CoV) and SARS-CoV-2 receptor. ACE2 is widely expressed, including, in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 has recently been identified as the SARS-CoV-2 receptor, the infective agent responsible for coronavirus disease 2019, providing a critical link between immunity, inflammation, ACE2, and cardiovascular disease. Although sharing a close evolutionary relationship with SARS-CoV, the receptor-binding domain of SARS-CoV-2 differs in several key amino acid residues, allowing for stronger binding affinity with the human ACE2 receptor, which may account for the greater pathogenicity of SARS-CoV-2. The loss of ACE2 function following binding by SARS-CoV-2 is driven by endocytosis and activation of proteolytic cleavage and processing. The ACE2 system is a critical protective pathway against heart failure with reduced and preserved ejection fraction including, myocardial infarction and hypertension, and against lung disease and diabetes mellitus. The control of gut dysbiosis and vascular permeability by ACE2 has emerged as an essential mechanism of pulmonary hypertension and diabetic cardiovascular complications. Recombinant ACE2, gene-delivery of Ace2, Ang 1–7 analogs, and Mas receptor agonists enhance ACE2 action and serve as potential therapies for disease conditions associated with an activated renin-angiotensin system. rhACE2 (recombinant human ACE2) has completed clinical trials and efficiently lowered or increased plasma angiotensin II and angiotensin 1-7 levels, respectively. Our review summarizes the progress over the past 20 years, highlighting the critical role of ACE2 as the novel SARS-CoV-2 receptor and as the negative regulator of the renin-angiotensin system, together with implications for the coronavirus disease 2019 pandemic and associated cardiovascular diseases.

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Revisiting the hallmarks of cancer.

Yousef Fouad, Carmen M Aanei (2017)

The hallmarks of cancer described by Hanahan and Weinberg have proved seminal in our understanding of cancer's common traits and in rational drug design. Not free of critique and with understanding of different aspects of tumorigenesis coming into clearer focus in the recent years, we attempt to draw a more organized and updated picture of the cancer hallmarks. We define seven hallmarks of cancer: selective growth and proliferative advantage, altered stress response favoring overall survival, vascularization, invasion and metastasis, metabolic rewiring, an abetting microenvironment, and immune modulation, while highlighting some considerations for the future of the field.

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International union of pharmacology. XXIII. The angiotensin II receptors.

M de Gasparo, K Catt, T Inagami … (2000)

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.

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Journal

Journal ID (nlm-ta): Cancers (Basel)

Journal ID (iso-abbrev): Cancers (Basel)

Journal ID (publisher-id): cancers

Title: Cancers

Publisher: MDPI

ISSN (Electronic): 2072-6694

Publication date (Electronic): 03 June 2020

Publication date Collection: June 2020

Volume: 12

Issue: 6

Electronic Location Identifier: 1457

Affiliations

[1 ]Tumour & Microenvironment Interactions Group, I3S-Institute for Health Research & Innovation, University of Porto, 4200-135 Porto, Portugal; ricardo.ribeiro@ 123456i3s.up.pt (R.R.); mariajo@ 123456ineb.up.pt (M.J.O.)

[2 ]Tumour & Microenvironment Interactions Group, INEB-Biomedical Engineering Institute, University of Porto, 4200-135 Porto, Portugal

[3 ]Department of Pulmonology, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal; carlos.crobalo@ 123456gmail.com

[4 ]Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal; ruimedei@ 123456ipoporto.min-saude.pt

[5 ]Molecular Oncology and Viral Pathology Group-Research Centre, Portuguese Institute of Oncology, 4200-072 Porto, Portugal

[6 ]Laboratory of Genetics, Faculty of Medicine, University of Lisbon, 1649-028 Lisboa, Portugal

[7 ]Department of Clinical Pathology, Centro Hospitalar e Universitário de Coimbra, 3000-075 Coimbra, Portugal

[8 ]Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal

Author notes

[* ]Correspondence: mjcatarata@ 123456gmail.com ; Tel.: +351-22-607-4900

Author information

Maria Joana Catarata https://orcid.org/0000-0001-8027-6979

Ricardo Ribeiro https://orcid.org/0000-0001-9785-857X

Maria José Oliveira https://orcid.org/0000-0002-0724-0272

Rui Medeiros https://orcid.org/0000-0003-3010-8373

Article

Publisher ID: cancers-12-01457

DOI: 10.3390/cancers12061457

PMC ID: 7352181

PubMed ID: 32503281

SO-VID: 13ea9adb-48c8-4f51-8ebf-bea5196f1b50

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Renin-Angiotensin System in Lung Tumor and Microenvironment Interactions

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Abstract

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Inflamed lung in vitro co-culture models

Most cited references 133

Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System

Revisiting the hallmarks of cancer.

International union of pharmacology. XXIII. The angiotensin II receptors.

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