Review Article

ACE2/Angiotensin-(1-7)/Mas Receptor Axis in Human Cancer: Potential Role for Pediatric Tumors

Author(s): Ana Luiza Ataide Carneiro de Paula Gonzaga , Vitória Andrade Palmeira , Thomas Felipe Silva Ribeiro , Larissa Braga Costa , Karla Emília de Sá Rodrigues and Ana Cristina Simões-e-Silva *

Volume 21, Issue 9, 2020

Page: [892 - 901] Pages: 10

DOI: 10.2174/1389450121666200210124217

Price: $65


Background: Pediatric tumors remain the highest cause of death in developed countries. Research on novel therapeutic strategies with lesser side effects is of utmost importance. In this scenario, the role of Renin-Angiotensin System (RAS) axes, the classical one formed by angiotensinconverting enzyme (ACE), Angiotensin II and AT1 receptor and the alternative axis composed by ACE2, Angiotensin-(1-7) and Mas receptor, have been investigated in cancer.

Objective: This review aimed to summarize the pathophysiological role of RAS in cancer, evidence for anti-tumor effects of ACE2/Angiotensin-(1-7)/Mas receptor axis and future therapeutic perspectives for pediatric cancer.

Methods: Pubmed, Scopus and Scielo were searched in regard to RAS molecules in human cancer and pediatric patients. The search terms were “RAS”, “ACE”, “Angiotensin-(1-7)”, “ACE2”, “Angiotensin II”, “AT1 receptor”, “Mas receptor”, “Pediatric”, “Cancer”.

Results: Experimental studies have shown that Angiotensin-(1-7) inhibits the growth of tumor cells and reduces local inflammation and angiogenesis in several types of cancer. Clinical trials with Angiotensin-( 1-7) or TXA127, a pharmaceutical grade formulation of the naturally occurring peptide, have reported promising findings, but not enough to recommend medical use in human cancer. In regard to pediatric cancer, only three articles that marginally investigated RAS components were found and none of them evaluated molecules of the alternative RAS axis.

Conclusion: Despite the potential applicability of Angiotensin-(1-7) in pediatric tumors, the role of this molecule was never tested. Further clinical trials are necessary, also including pediatric patients, to confirm safety and efficiency and to define therapeutic targets.

Keywords: Renin-angiotensin system, cancer, pediatric tumor, angiotensin II, angiotensin-(1-7), angiotensin-converting enzyme, ACE2, angiogenesis.

Graphical Abstract
World Health Organization. Definition of key terms: Age groups and populations. terms/en/ (Accessed September 15, 2019)
Jeanquartier F, Jean-Quartier C, Holzinger A. Use case driven evaluation of open databases for pediatric cancer research BioData Min 2019 12(1): 2.
[] [PMID: 30675185]
Martins HTG, Balmant NV, de Paula Silva N, Santos MO, Reis RS, de Camargo B. Who cares for adolescents and young adults with cancer in Brazil? J Pediatr (Rio J) 2018; 94(4): 440-5.
[] [PMID: 28888615]
Burdach SEG, Westhoff MA, Steinhauser MF, Debatin KM. Precision medicine in pediatric oncology. Mol Cell Pediatr 2018; 5(1): 6.
[] [PMID: 30171420]
Jankowski M, Dresse MF, Forget P, Piette C, Florkin B, Hoyoux C. [Epidemiology of childhood cancer, a single-center study (1985- 2016)]. Rev Med Liege 2019 74(3): 146-51.
[PMID: 30897314]
Downing JR, Wilson RK, Zhang J, et al. The Pediatric Cancer Genome Project. Nat Genet 2012; 44(6): 619-22.
[] [PMID: 22641210]
Wedekind MF, Denton NL, Chen CY, Cripe TP. Pediatric Cancer Immunotherapy: Opportunities and Challenges. Paediatr Drugs 2018; 20(5): 395-408.
[] [PMID: 29948928]
Lam CG, Howard SC, Bouffet E, Pritchard-Jones K. Science and health for all children with cancer. Science 2019; 15(363(6432)): 1182-6.
LeBaron S, Zeltzer LK, LeBaron C, Scott SE, Zeltzer PM. Chemotherapy side effects in pediatric oncology patients: drugs, age, and sex as risk factors. Med Pediatr Oncol 1988; 16(4): 263-8.
[] [PMID: 3419392]
Ruggiero A, Ferrara P, Attinà G, Rizzo D, Riccardi R. Renal toxicity and chemotherapy in children with cancer. Br J Clin Pharmacol 2017; 83(12): 2605-14.
[] [PMID: 28758697]
Gallagher PE, Arter AL, Deng G, Tallant EA. Angiotensin-(1-7): a peptide hormone with anti-cancer activity. Curr Med Chem 2014; 21(21): 2417-23.
[] [PMID: 24524765]
Simões E Silva AC, Flynn JT. The renin-angiotensin-aldosterone system in 2011: role in hypertension and chronic kidney disease. Pediatr Nephrol 2012; 27(10): 1835-45.
[] [PMID: 21947887]
Simões E Silva AC, Teixeira MM. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis. Pharmacol Res 2016; 107: 154-62.
[] [PMID: 26995300]
Fountain JH, Lappin SL. Physiology, Renin Angiotensin System. [Updated 2019 May 5] StatPearls [Internet] Treasure Island (FL): StatPearls Publishing; 2019.Available from:. https://
Sanjuliani AF, Torres MRSG, Paula LV, Bassan FB. Eixo Renina-Angiotensina-Aldosterona: Fisiolóficas e Fisiopatológicas. Brazilian Journal of Health and Biomedical Sciences 2011; 10(3): 20-30.
Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000; 275(43): 33238-43.
[] [PMID: 10924499]
Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000; 87(5): E1-9.
[] [PMID: 10969042]
Santos RA, Simoes e Silva AC, Maric C, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 2003; 100(14): 8258-63.
[] [PMID: 12829792]
Lever AF, Hole DJ, Gillis CR, et al. Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet 1998; 352(9123): 179-84.
[] [PMID: 9683206]
Luque M, Martin P, Martell N, Fernandez C, Brosnihan KB, Ferrario CM. Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension. J Hypertens 1996; 14(6): 799-805.
[] [PMID: 8793704]
Simões e Silva AC, Diniz JS, Pereira RM, Pinheiro SV, Santos RAS. Circulating renin Angiotensin system in childhood chronic renal failure: marked increase of Angiotensin-(1-7) in end-stage renal disease. Pediatr Res 2006; 60(6): 734-9.
[] [PMID: 17065573]
Rodrigues Prestes TR, Rocha NP, Miranda AS, Teixeira AL, Simoes E-Silva AC. The anti-inflammatory potential of ACE2/ angiotensin-(1-7)/Mas receptor axis: evidence from basic and clinical research. Curr Drug Targets 2017; 18(11): 1301-13.
[] [PMID: 27469342]
Machado RDP, Santos RAS, Andrade SP. Opposing actions of angiotensins on angiogenesis. Life Sci 2000; 66(1): 67-76.
[] [PMID: 10658925]
Simões e Silva AC, Sampaio WO. The Role of Angiotensin–(1-7) in Cancer.Angiotensin-. 219-29.
Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005; 23(5): 1011-27.
[] [PMID: 15585754]
Ma TK, Kam KK, Yan BP, Lam YY. Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol 2010; 160(6): 1273-92.
[] [PMID: 20590619]
Xie X, Liu Y, Perkovic V, et al. Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials. Am J Kidney Dis 2016; 67(5): 728-41.
[] [PMID: 26597926]
Sobczuk P, Szczylik C, Porta C, Czarnecka AM. Renin angiotensin system deregulation as renal cancer risk factor. Oncol Lett 2017 14(5): 5059-68. [Review]
[] [PMID: 29098020]
Hallas J, Christensen R, Andersen M, Friis S, Bjerrum L. Long term use of drugs affecting the renin-angiotensin system and the risk of cancer: a population-based case-control study. Br J Clin Pharmacol 2012; 74(1): 180-8.
[] [PMID: 22243442]
Shen J, Huang Y-M, Wang M, et al. Zhu. M-H.; Zhang, X-X.; Sui, Y.; Zhao, H-L. Renin–angiotensin system blockade for the risk of cancer and death. J Renin Angiotensin Aldosterone Syst 2016; 1-14.
Forrester SJ, Booz GW, Sigmund CD, et al. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev 2018; 98(3): 1627-738.
[] [PMID: 29873596]
Escobar E, Rodríguez-Reyna TS, Arrieta O, Sotelo J, Angiotensin II. Angiotensin II, cell proliferation and angiogenesis regulator: biologic and therapeutic implications in cancer. Curr Vasc Pharmacol 2004; 2(4): 385-99.
[] [PMID: 15320819]
Pupilli C, Lasagni L, Romagnani P, et al. Angiotensin II stimulates the synthesis and secretion of vascular permeability factor/vascular endothelial growth factor in human mesangial cells. J Am Soc Nephrol 1999; 10(2): 245-55.
[PMID: 10215323]
Fernandez LA, Twickler J, Mead A. Neovascularization produced by angiotensin II. J Lab Clin Med 1985; 105(2): 141-5.
[PMID: 2579174]
Amaral SL, Linderman JR, Morse MM, Greene AS. Angiogenesis Induced by Electrical Stimulation Is Mediated by Angiotensin II and VEGF. Microcirculation (New York, NY : 1994) 2001; 8: 57-67.
Goel S, Duda DG, Xu L, et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol Rev 2011; 91(3): 1071-121.
[] [PMID: 21742796]
Viallard C, Larrivée B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis 2017; 20(4): 409-26.
[] [PMID: 28660302]
Kohara K, Brosnihan KB, Ferrario CM. Angiotensin(1-7) in the spontaneously hypertensive rat. Peptides 1993; 14(5): 883-91.
[] [PMID: 8284265]
Montana V, Sontheimer H. Bradykinin promotes the chemotactic invasion of primary brain tumors. J Neurosci 2011; 31(13): 4858-67.
[] [PMID: 21451024]
Domińska K, Okła P, Kowalska K, et al. Influence and mechanism of Angiotensin 1-7 on biological properties of normal prostate epithelial cells. Biochem Biophys Res Commun 2018; 502(1): 152-9.
[] [PMID: 29802847]
Gallagher PE, Tallant EA. Inhibition of human lung cancer cell growth by angiotensin-(1-7). Carcinogenesis 2004; 25(11): 2045-52.
[] [PMID: 15284177]
Forte BL, Slosky LM, Zhang H, Arnold MR, Staatz WD. Hay. M.; Largent-Milnes, T.M.; Vanderah, T.W. Angiotensin-(1-7)/Mas receptor as an anti nociceptive agent in cancer-induced bone pain. Pain 2016; 157: 2709-21.
[] [PMID: 27541850]
Willey JS, Bracey DN, Gallagher PE, et al. Angiotensin-(1-7) Attenuates Skeletal Muscle Fibrosis and Stiffening in a Mouse Model of Extremity Sarcoma Radiation Therapy. J Bone Joint Surg Am 2016; 98(1): 48-55.
[] [PMID: 26738903]
Ahmad I, Ahmed MM, Ahsraf MF, et al. Pain Management in Metastatic Bone Disease: A Literature Review. Cureus 2018 10(9) e3286
[] [PMID: 30443456]
Straub JM, New J, Hamilton CD, Lominska C, Shnayder Y, Thomas SM. Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol 2015; 141(11): 1985-94.
[] [PMID: 25910988]
George AJ, Thomas WG, Hannan RD. The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer 2010; 10(11): 745-59.
[] [PMID: 20966920]
Rodgers KE, Xiong S, diZerega GS. Accelerated recovery from irradiation injury by angiotensin peptides. Cancer Chemother Pharmacol 2002; 49(5): 403-11.
[] [PMID: 11976835]
Rodgers K, Xiong S, DiZerega GS. Effect of angiotensin II and angiotensin(1-7) on hematopoietic recovery after intravenous chemotherapy. Cancer Chemother Pharmacol 2003; 51(2): 97-106.
[] [PMID: 12647010]
Menon J, Soto-Pantoja DR, Callahan MF, et al. Angiotensin-(1-7) inhibits growth of human lung adenocarcinoma xenografts in nude mice through a reduction in cyclooxygenase-2. Cancer Res 2007; 67(6): 2809-15.
[] [PMID: 17363603]
Hida T, Yatabe Y, Achiwa H, et al. Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 1998; 58(17): 3761-4.
[PMID: 9731479]
Lee EO, Lee HJ, Hwang HS, et al. Potent inhibition of Lewis lung cancer growth by heyneanol A from the roots of Vitis amurensis through apoptotic and anti-angiogenic activities. Carcinogenesis 2006; 27(10): 2059-69.
[] [PMID: 16675471]
Harris RE, Beebe-Donk J, Schuller HM. Chemoprevention of lung cancer by non-steroidal anti-inflammatory drugs among cigarette smokers. Oncol Rep 2002; 9(4): 693-5.
[] [PMID: 12066194]
Mukherjee D, Topol EJ. Cox-2: where are we in 2003? - Cardiovascular risk and Cox-2 inhibitors. Arthritis Res Ther 2003; 5(1): 8-11.
[] [PMID: 12716442]
Soto-Pantoja DR, Menon J, Gallagher PE, Tallant EA. Angiotensin-(1-7) inhibits tumor angiogenesis in human lung cancer xenografts with a reduction in vascular endothelial growth factor. Mol Cancer Ther 2009; 8(6): 1676-83.
[] [PMID: 19509262]
Silva BOD, Lima KF, Gonçalves LR, Silveira MBD, Moraes KCM. MicroRNA profiling of the effect of the heptapeptide Angiotensin-( 1-7) in A549 lung tumor cells reveals a role for miRNA149- 3p in cellular migration processes. PLoS One 2017 12(12) e0190204
[] [PMID: 29261785]
da Silveira MB, Lima KF, da Silva AR, Dos Santos RAS, Moraes KCM. Mir-513a-3p contributes to the controlling of cellular migration processes in the A549 lung tumor cells by modulating integrin β-8 expression. Mol Cell Biochem 2018 444(1-2): 43-52.
[] [PMID: 29204818]
Cook KL, Metheny-Barlow LJ, Tallant EA, Gallagher PE. Angiotensin-(1-7) reduces fibrosis in orthotopic breast tumors. Cancer Res 2010; 70(21): 8319-28.
[] [PMID: 20837666]
Yu C, Tang W, Wang Y, et al. Downregulation of ACE2/Ang-(1-7)/Mas axis promotes breast cancer metastasis by enhancing store-operated calcium entry. Cancer Lett 2016; 376(2): 268-77.
[] [PMID: 27063099]
Cambados N, Walther T, Nahmod K, et al. Angiotensin-(1-7) counteracts the transforming effects triggered by angiotensin II in breast cancer cells. Oncotarget 2017; 8(51): 88475-87.
[] [PMID: 29179450]
Krishnan B, Torti FM, Gallagher PE, Tallant EA. Angiotensin-(1-7) reduces proliferation and angiogenesis of human prostate cancer xenografts with a decrease in angiogenic factors and an increase in sFlt-1. Prostate 2013; 73(1): 60-70.
[] [PMID: 22644934]
Krishnan B, Smith TL, Dubey P, et al. Angiotensin-(1-7) attenuates metastatic prostate cancer and reduces osteoclastogenesis. Prostate 2013; 73(1): 71-82.
[] [PMID: 22644942]
Liu Y, Li B, Wang X, et al. Angiotensin-(1-7) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor. Mol Med 2015; 21: 626-36.
[] [PMID: 26225830]
Mao Y, Pei N, Chen X, et al. Angiotensin 1-7 Overexpression Mediated by a Capsid-optimized AAV8 Vector Leads to Significant Growth Inhibition of Hepatocellular Carcinoma In vivo. Int J Biol Sci 2018; 14(1): 57-68.
[] [PMID: 29483825]
Liu B, Liu Y, Jiang Y. Podocalyxin promotes glioblastoma multiforme cell invasion and proliferation by inhibiting angiotensin-(1-7)/Mas signaling. Oncol Rep 2015; 33(5): 2583-91.
[] [PMID: 25708368]
Li X, Wang X, Xie J, Liang B, Wu J. Suppression of Angiotensin-(1-7) on the Disruption of Blood-Brain Barrier in Rat of Brain Glioma. Pathol Oncol Res 2019; 25(1): 429-35.
[] [PMID: 30229380]
Petty WJ, Miller AA, McCoy TP, Gallagher PE, Tallant EA, Torti FM. Phase I and pharmacokinetic study of angiotensin-(1-7), an endogenous antiangiogenic hormone. Clin Cancer Res 2009; 15(23): 7398-404.
[] [PMID: 19920106]
Rodgers KE, Oliver J, diZerega GS. Phase I/II dose escalation study of angiotensin 1-7 [A(1-7)] administered before and after chemotherapy in patients with newly diagnosed breast cancer. Cancer Chemother Pharmacol 2006; 57(5): 559-68.
[] [PMID: 16096787]
Pham H, Schwartz BM, Delmore JE, et al. Pharmacodynamic stimulation of thrombogenesis by angiotensin (1-7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy. Cancer Chemother Pharmacol 2013; 71(4): 965-72.
[] [PMID: 23370663]
Maas MH, Cransberg K, van Grotel M, Pieters R, van den Heuvel-Eibrink MM. Renin-induced hypertension in Wilms tumor patients. Pediatr Blood Cancer 2007; 48(5): 500-3.
[] [PMID: 16794999]
Zaher H, Rasheed H, El-Komy MM, et al. Propranolol versus captopril in the treatment of infantile hemangioma (IH): A randomized controlled trial. J Am Acad Dermatol 2016; 74(3): 499-505.
[] [PMID: 26685718]
Kaslow AM, Riquier-Brison A, Peti-Peterdi J, et al. An ectopic renin-secreting adrenal corticoadenoma in a child with malignant hypertension. Physiol Rep 2016; 4(5): 1-5.
[] [PMID: 26997629]
Sukarochana K, Tolentino W, Kiesewetter WB. Wilms’ tumor and hypertension. J Pediatr Surg 1972; 7(5): 573-6.
[] [PMID: 4343314]
Bradley J, Pincoffs M. The association of adeno-sarcoma of the kidney (Wilms’ tumor) with arterial hypertension. Ann Intern Med 1938; 11(9): 1613-28.
Galambos C. Vasculogenesis in infantile hemangioma. Yearbook of Pathology and Laboratory Medicine 2010 234-5.
Itinteang T, Brasch HD, Tan ST, Day DJ. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution. J Plast Reconstr Aesthet Surg 2011; 64(6): 759-65.
[] [PMID: 20870476]
Tan ST, Itinteang T, Day DJ, O’Donnell C, Mathy JA, Leadbitter P. Treatment of infantile haemangioma with captopril. Br J Dermatol 2012; 167(3): 619-24.
[] [PMID: 22533490]
Ji Y, Chen S, Xu C, Li L, Xiang B. The use of propranolol in the treatment of infantile haemangiomas: An update on potential mechanisms of action. Br J Dermatol 2014; 172-6.
[PMID: 25196392]
Kurtz A. Renin release: sites, mechanisms, and control. Annu Rev Physiol 2011; 73: 377-99.
[] [PMID: 20936939]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy