Renin-angiotensin-system and clear cell renal carcinoma: research advances and future perspectives

Abstract

Hypertension is a known risk factor for clear cell renal cell carcinoma (ccRCC), yet the underlying mechanisms remain elusive. Studies have confirmed that the renin-angiotensin system (RAS) plays a role beyond regulating blood pressure, influencing various aspects of tumor development and metastasis. Generally, activation of the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/angiotensin type 1 receptor (AT1R) axis elevates blood pressure and promotes tumor progression, while the activation of the angiotensin-converting enzyme 2 (ACE2)/[Ang-(1-7)]/Mas receptor (MasR) axis antagonizes these effects. Consequently, many cardiovascular drugs targeting the RAS may possess both hypotensive and antitumor properties. However, the role of RAS in ccRCC is controversial. To explore this, we reviewed the relevant literature. Surprisingly, apart from ACE2, the activation of RAS may facilitate the progression and metastasis of ccRCC. This unexpected finding suggests caution when using RAS inhibitors in ccRCC patients. This review provides an overview of the RAS, highlights research advances in RAS for ccRCC, elucidates the current status of RAS-targeted drugs in the treatment of ccRCC, and discusses the current challenges and future research directions in this field. In conclusion, the upregulation of other effector peptides and the activation of receptors in the RAS, apart from ACE2, may expedite ccRCC progression. Therefore, careful consideration is needed when using relevant drugs in ccRCC patients with hypertension. This synthesis of available evidence is crucial for informing the clinical management of ccRCC and guiding the development of novel therapeutic strategies.

Keywords

Renin-angiotensin-system / ccRCC / hypertension / kidney / macrophage / cancer / tumor microenvironment

References

[1] Moch H,Humphrey PA,Ulbright TM.The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.Eur Urol2016;70:93-105

[2] Feng X,Tu W.Frequency, incidence and survival outcomes of clear cell renal cell carcinoma in the United States from 1973 to 2014: a SEER-based analysis.Medicine (Baltimore)2019;98:e16684 PMCID:PMC6708618

[3] Schiavoni V,Pozzi V.Recent advances in the management of clear cell renal cell carcinoma: novel biomarkers and targeted therapies.Cancers (Basel)2023;15:3207 PMCID:PMC10296504

[4] Kim SH,Hwang EC.Retrospective multicenter long-term follow-up analysis of prognostic risk factors for recurrence-free, metastasis-free, cancer-specific, and overall survival after curative nephrectomy in non-metastatic renal cell carcinoma.Front Oncol2019;9:859 PMCID:PMC6738012

[5] Wang C,Liao X.Hypertension promotes the proliferation and migration of ccRCC cells by downregulation of TIMP3 in tumor endothelial cells through the miR-21-5p/TGFBR2/P38/EGR1 Axis.Mol Cancer Res2023;21:62-75

[6] Hammer A,Friedrich J.Role of the receptor Mas in macrophage-mediated inflammation in vivo.Proc Natl Acad Sci U S A2016;113:14109-14 PMCID:PMC5150410

[7] Temme S,Bouvain P.Beyond vessel diameters: non-invasive monitoring of flow patterns and immune cell recruitment in murine abdominal aortic disorders by multiparametric MRI.Front Cardiovasc Med2021;8:750251 PMCID:PMC8572976

[8] Yang G,Rump LC,Stegbauer J.ACE2 and the homolog collectrin in the modulation of nitric oxide and oxidative stress in blood pressure homeostasis and vascular injury.Antioxid Redox Signal2017;26:645-59

[9] Yang G,Höges S.Angiotensin-(1-7)-induced Mas receptor activation attenuates atherosclerosis through a nitric oxide-dependent mechanism in apolipoproteinE-KO mice.Pflugers Arch2018;470:661-7

[10] Tan WSD,Zhou S,Wong WF.Targeting the renin-angiotensin system as novel therapeutic strategy for pulmonary diseases.Curr Opin Pharmacol2018;40:9-17

[11] Perlot T.ACE2 - from the renin-angiotensin system to gut microbiota and malnutrition.Microbes Infect2013;15:866-73 PMCID:PMC7110844

[12] Bosnyak S,Christopoulos A,Thomas WG.Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors.Clin Sci (Lond)2011;121:297-303

[13] Matysiak-Burzyńska ZE,Domińska K,Płuciennik E.Silencing of angiotensin receptor 1 interferes with angiotensin II oncogenic activity in endometrial cancer.J Cell Biochem2018;119:9110-21

[14] Daugherty A,Cassis LA.Antagonism of AT2 receptors augments angiotensin II-induced abdominal aortic aneurysms and atherosclerosis.Br J Pharmacol2001;134:865-70 PMCID:PMC1573019

[15] O'Connor AT,Alanazi AZ.Roles of angiotensin III in the brain and periphery.Peptides2022;153:170802

[16] Tipnis SR,Hyde R,Christie G.A human homolog of angiotensin-converting enzyme. cloning and functional expression as a captopril-insensitive carboxypeptidase.J Biol Chem2000;275:33238-43

[17] Donoghue M,Baronas E.A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9.Circ Res2000;87:E1-9

[18] Nakagawasai O,Koyama T,Nemoto W.Activation of angiotensin-converting enzyme 2 produces an antidepressant-like effect via MAS receptors in mice.Mol Brain2023;16:52 PMCID:PMC10262141

[19] Qaradakhi T,McSweeney KR.The potential actions of angiotensin-converting enzyme II (ACE2) activator diminazene aceturate (DIZE) in various diseases.Clin Exp Pharmacol Physiol2020;47:751-8

[20] Rushworth CA,Turner AJ.Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting enzymes (ACE and ACE2) identified by site-directed mutagenesis.FEBS J2008;275:6033-42 PMCID:PMC7163990

[21] Santos RAS,Alzamora AC.The ACE2/Angiotensin-(1-7)/MAS axis of the renin-angiotensin system: focus on Angiotensin-(1-7).Physiol Rev2018;98:505-53 PMCID:PMC7203574

[22] Santos RA,Verano-Braga T.Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system.J Endocrinol2013;216:R1-R17

[23] Chappell MC.Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute?.Am J Physiol Heart Circ Physiol2016;310:H137-52 PMCID:PMC4796631

[24] Santos RA,Maric C.Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas.Proc Natl Acad Sci U S A2003;100:8258-63 PMCID:PMC166216

[25] Hassani B,Firouzabadi N.The renin-angiotensin-aldosterone system (RAAS) signaling pathways and cancer: foes versus allies.Cancer Cell Int2023;23:254 PMCID:PMC10604988

[26] O'Rawe M,Mantamadiotis T,Tan ST.The renin-angiotensin system in the tumor microenvironment of glioblastoma.Cancers (Basel)2021;13:4004 PMCID:PMC8392691

[27] Perini MV,Nero TL.Evaluating the benefits of renin-angiotensin system inhibitors as cancer treatments.Pharmacol Ther2020;211:107527

[28] Imai N,Kihara M.Roles for host and tumor angiotensin II type 1 receptor in tumor growth and tumor-associated angiogenesis.Lab Invest2007;87:189-98

[29] Nguyen L,Neo J.Regulation of colorectal cancer cell epithelial to mesenchymal transition by the renin angiotensin system.J Gastroenterol Hepatol2016;31:1773-82

[30] Singh N,Rajguru JP,Thakkannavar SS.Inflammation and cancer.Ann Afr Med2019;18:121-6 PMCID:PMC6704802

[31] Klaunig JE.Oxidative stress and cancer.Curr Pharm Des2018;24:4771-8

[32] Liu Y,Wang X.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 Med2015;21:626-36 PMCID:PMC4656199

[33] Murphy KT,Swiderski K.Mas receptor activation slows tumor growth and attenuates muscle wasting in cancer.Cancer Res2019;79:706-19 PMCID:PMC6377850

[34] Larrinaga G,Sanz B.Angiotensin-converting enzymes (ACE and ACE2) are downregulated in renal tumors.Regul Pept2010;165:218-23

[35] Errarte P,Perez I.Expression and activity of angiotensin-regulating enzymes is associated with prognostic outcome in clear cell renal cell carcinoma patients.PLoS One2017;12:e0181711 PMCID:PMC5557356

[36] Bai S,Yan Y.Construct a circRNA/miRNA/mRNA regulatory network to explore potential pathogenesis and therapy options of clear cell renal cell carcinoma.Sci Rep2020;10:13659 PMCID:PMC7423896

[37] Rehman A,Wang Y.Unveiling the multi-target compounds of Rhazya stricta: discovery and inhibition of novel target genes for the treatment of clear cell renal cell carcinoma.Comput Biol Med2023;165:107424

[38] Kim K,Ko DS.Prognostic significance of COVID-19 receptor ACE2 and recommendation for antihypertensive drug in renal cell carcinoma.Biomed Res Int2020;2020:2054376 PMCID:PMC7695994

[39] Khanna P,Chen CH.ACE2 abrogates tumor resistance to VEGFR inhibitors suggesting angiotensin-(1-7) as a therapy for clear cell renal cell carcinoma.Sci Transl Med2021;13:eabc0170

[40] Uhlen M,Lee S.A pathology atlas of the human cancer transcriptome.Science2017;357:eaan2507

[41] Javorhazy A,Beothe T,Szanto A.Lack of TMEM27 expression is associated with postoperative progression of clinically localized conventional renal cell carcinoma.J Cancer Res Clin Oncol2016;142:1947-53

[42] Grewal R,Roberts LL.TMEM27 expression and clinical characteristics and survival in clear cell renal cell carcinoma.Acta Oncol2022;61:1507-11

[43] Dolley-Hitze T,Martin B.Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma?.Br J Cancer2010;103:1698-705 PMCID:PMC2994218

[44] Verhoest G,Jouan F.Sunitinib combined with angiotensin-2 type-1 receptor antagonists induces more necrosis: a murine xenograft model of renal cell carcinoma.Biomed Res Int2014;2014:901371 PMCID:PMC4054801

[45] Zheng S,Song R.Ang-(1-7) promotes the migration and invasion of human renal cell carcinoma cells via Mas-mediated AKT signaling pathway.Biochem Biophys Res Commun2015;460:333-40

[46] Sobczuk P,Koperski L,Cudnoch-Jedrzejewska A.Angiotensin-(1-7) can promote cell migration and tumor growth of clear cell renal cell carcinoma.J Physiol Pharmacol2022;73

[47] Yang Y,Zhao C.NHERF4 hijacks Mas-mediated PLC/AKT signaling to suppress the invasive potential of clear cell renal cell carcinoma cells.Cancer Lett2021;519:130-40

[48] Larrinaga G,Arrieta-Aguirre I.The expression of Alamandine receptor MrgD in clear cell renal cell carcinoma is associated with a worse prognosis and unfavorable response to antiangiogenic therapy.Int J Mol Sci2024;25:1499 PMCID:PMC10855800

[49] Cui H,Li Z.Integrated bioinformatics analysis for the identification of potential key genes affecting the pathogenesis of clear cell renal cell carcinoma.Oncol Lett2020;20:1573-84 PMCID:PMC7377202

[50] Solano-Iturri JD,Unda M.Clinical implications of (Pro)renin receptor (PRR) expression in renal tumours.Diagnostics (Basel)2021;11:272 PMCID:PMC7916453

[51] Yoon HE,Kim MY.Age-associated changes in the vascular renin-angiotensin system in mice.Oxid Med Cell Longev2016;2016:6731093 PMCID:PMC4855022

[52] Costa-Fraga FP,Souza-Neto FP.Age-related changes in vascular responses to angiotensin-(1-7) in female mice.J Renin Angiotensin Aldosterone Syst2018;19:1470320318789332 PMCID:PMC6053867

[53] Chauhan VP,Liu H.Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels.Nat Commun2013;4:2516 PMCID:PMC3806395

[54] Diop-Frimpong B,Krane S,Jain RK.Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors.Proc Natl Acad Sci U S A2011;108:2909-14 PMCID:PMC3041115

[55] Rhodes DR,Cao Q.AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist.Proc Natl Acad Sci U S A2009;106:10284-9 PMCID:PMC2689309

[56] Alhusban A,Goc A,Fagan SC.Clinically relevant doses of candesartan inhibit growth of prostate tumor xenografts in vivo through modulation of tumor angiogenesis.J Pharmacol Exp Ther2014;350:635-45 PMCID:PMC4152877

[57] Ishiguro H,Kubota Y.Regulation of prostate cancer cell growth and PSA expression by angiotensin II receptor blocker with peroxisome proliferator-activated receptor gamma ligand like action.Prostate2007;67:924-32

[58] Takahashi S,Seeni A.Therapeutic targeting of angiotensin II receptor type 1 to regulate androgen receptor in prostate cancer.Prostate2012;72:1559-72

[59] Neo JH,Muralidharan V.Effect of ACE inhibitors and angiotensin II receptor antagonists in a mouse model of colorectal cancer liver metastases.J Gastroenterol Hepatol2007;22:577-84

[60] Morris ZS,Magnuson WJ.Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.Cancer2016;122:2487-95 PMCID:PMC4998053

[61] Li XY,Hu SQ.The renin-angiotensin system blockers as adjunctive therapy for cancer: a meta-analysis of survival outcome.Eur Rev Med Pharmacol Sci2017; 21:1375-83

[62] Sun H,Zhuang R,Zheng Y.Do renin-angiotensin system inhibitors influence the recurrence, metastasis, and survival in cancer patients?.Medicine (Baltimore)2017;96:e6394 PMCID:PMC5380250

[63] Datzmann T,Andree D,Schmitt J.Systematic review and meta-analysis of randomised controlled clinical trial evidence refutes relationship between pharmacotherapy with angiotensin-receptor blockers and an increased risk of cancer.Eur J Intern Med2019;64:1-9

[64] Shen J,Wang M.Renin-angiotensin system blockade for the risk of cancer and death.J Renin Angiotensin Aldosterone Syst2016;17:1470320316656679 PMCID:PMC5843874

[65] Reichhart N,Skosyrski S.Control of the retinal local RAS by the RPE: an interface to systemic RAS activity.Exp Eye Res2019;189:107838

[66] Cruz-López EO,Danser AHJ.Perivascular adipose tissue in vascular function: does locally synthesized angiotensinogen play a role?.J Cardiovasc Pharmacol2021;78:S53-62

[67] Cao W,Wang L.A salt-induced reno-cerebral reflex activates renin-angiotensin systems and promotes CKD progression.J Am Soc Nephrol2015;26:1619-33 PMCID:PMC4483588

[68] Liu Y,Qiu M.Renal and cerebral RAS interaction contributes to diabetic kidney disease.Am J Transl Res2019; 11:2925-39 PMCID:PMC6556645

[69] Ren L,Danser AHJ.Revisiting the brain renin-angiotensin system-focus on novel therapies.Curr Hypertens Rep2019;21:28 PMCID:PMC6449495

[70] Li J,Zeng T.Silencing of central (Pro)renin receptor ameliorates salt-induced renal injury in chronic kidney disease.Antioxid Redox Signal2021;35:93-112

[71] Atkinson AJ Jr.Intracerebroventricular drug administration.Transl Clin Pharmacol2017;25:117-24 PMCID:PMC7033376

[72] Cohen-Pfeffer JL,Lester T.Intracerebroventricular delivery as a safe, long-term route of drug administration.Pediatr Neurol2017;67:23-35

[73] Chen J,Zhang J.Pathological changes in the brain after peripheral burns.Burns Trauma2023;11:tkac061 PMCID:PMC9972189

[74] Yang G,Wang C,Li Z.Exosomes and their bioengineering strategies in the cutaneous wound healing and related complications: current knowledge and future perspectives.Int J Biol Sci2023;19:1430-54 PMCID:PMC10086759

[75] Wang J,Yang M.Inflammatory tumor microenvironment responsive neutrophil exosomes-based drug delivery system for targeted glioma therapy.Biomaterials2021;273:120784

[76] Huang Z,Huang L,Liang J.Baicalin-loaded macrophage-derived exosomes ameliorate ischemic brain injury via the antioxidative pathway.Mater Sci Eng C Mater Biol Appl2021;126:112123

[77] Li F,Shi Y.Edaravone-loaded macrophage-derived exosomes enhance neuroprotection in the rat permanent middle cerebral artery occlusion model of stroke.Mol Pharm2020;17:3192-201

[78] Tao B,Zhang X.Engineering CAR-NK cell derived exosome disguised nano-bombs for enhanced HER2 positive breast cancer brain metastasis therapy.J Control Release2023;363:692-706

[79] Tian T,He CP.Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy.Biomaterials2018;150:137-49

[80] Wu T,Cao Y.Engineering macrophage exosome disguised biodegradable nanoplatform for enhanced sonodynamic therapy of glioblastoma.Adv Mater2022;34:e2110364

[81] Jia G,An Y.NRP-1 targeted and cargo-loaded exosomes facilitate simultaneous imaging and therapy of glioma in vitro and in vivo.Biomaterials2018;178:302-16

[82] Li B,Qiu W.Synchronous disintegration of ferroptosis defense axis via engineered exosome-conjugated magnetic nanoparticles for glioblastoma therapy.Adv Sci (Weinh)2022;9:e2105451 PMCID:PMC9189685

[83] Liu J,Zeng X.Engineering and characterization of an artificial drug-carrying vesicles nanoplatform for enhanced specifically targeted therapy of glioblastoma.Adv Mater2023;35:e2303660

[84] Wang R,Zhao H.Targeted delivery of hybrid nanovesicles for enhanced brain penetration to achieve synergistic therapy of glioma.J Control Release2024;365:331-47

[85] Xu W,Liu W.Tumor-associated macrophage-derived chemokine CCL5 facilitates the progression and immunosuppressive tumor microenvironment of clear cell renal cell carcinoma.Int J Biol Sci2022;18:4884-900 PMCID:PMC9379407

[86] Vallejo-Ardila DL,Burrell LM,Christophi C.Renin-angiotensin inhibitors reprogram tumor immune microenvironment: a comprehensive view of the influences on anti-tumor immunity.Oncotarget2018;9:35500-11 PMCID:PMC6231452

[87] Maniotis AJ,Hess A.Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry.Am J Pathol1999;155:739-52 PMCID:PMC1866899

[88] Xu K,Luo Y,Lin H.The angiotensin-converting enzyme inhibitory state promotes the transformation of non-small cell lung cancer blood supply pattern toward vasculogenic mimicry formation.Front Oncol2021;11:663671 PMCID:PMC8242235

[89] Geng B,Wang J.The categorizations of vasculogenic mimicry in clear cell renal cell carcinoma unveil inherent connections with clinical and immune features.Front Pharmacol2023;14:1333507 PMCID:PMC10765515

[90] Wang X,Wang Q,Ci H.Aberrant expression of vasculogenic mimicry, PRRX1, and CIP2A in clear cell renal cell carcinoma and its clinicopathological significance.Medicine (Baltimore)2019;98:e17028 PMCID:PMC6738984

[91] Liu Q,Geng B.Tumor-associated macrophage-derived exosomes transmitting miR-193a-5p promote the progression of renal cell carcinoma via TIMP2-dependent vasculogenic mimicry.Cell Death Dis2022;13:382 PMCID:PMC9021253

[92] Yan L,Li D,Lv Z.Development of a novel vasculogenic mimicry-associated gene signature for the prognostic assessment of osteosarcoma patients.Clin Transl Oncol2023;25:3501-18

[93] Peliky Fontes MA, Kangussu LM, Simões-e-Silva AC. Chapter 24 - the renin-angiotensin system, emotional stress and anxiety. In: Pilowsky PM, editors. Angiotensin from the kidney to coronavirus. Academic Press; 2023. p. 623-40.

[94] Eckerling A,Sorski L,Ben-Eliyahu S.Stress and cancer: mechanisms, significance and future directions.Nat Rev Cancer2021;21:767-85

[95] Cui Y,Huang Z.An antihypertensive drug-AT1 inhibitor attenuated BRCA development promoted by chronic psychological stress via Ang II/PARP1/FN1 pathway.Biochim Biophys Acta Mol Basis Dis2024;1870:167031

[96] Baffour-Awuah B,Goessler KF.Effect of exercise training on the renin-angiotensin-aldosterone system: a meta-analysis.J Hum Hypertens2024;38:89-101 PMCID:PMC10844078

[97] Kaschina E.Cross-talk between exercises and renin-angiotensin-aldosterone-system blockade in hypertension.Hypertens Res2024;47:1981-3 PMCID:PMC11224010

[98] Wang Q.Roles and molecular mechanisms of physical exercise in cancer prevention and treatment.J Sport Health Sci2021;10:201-10 PMCID:PMC7987556

[99] McTiernan A,Katzmarzyk PT.2018 PHYSICAL ACTIVITY GUIDELINES ADVISORY COMMITTEE^*Physical activity in cancer prevention and survival: a systematic review.Med Sci Sports Exerc2019;51:1252-61 PMCID:PMC6527123

[100] Fiuza-Luces C,Gálvez BG.The effect of physical exercise on anticancer immunity.Nat Rev Immunol2024;24:282-93