Skip to main content

Advertisement

Log in

Renin angiotensin system and its role in biomarkers and treatment in gliomas

  • Topic Review
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Gliomas are the most common primary intrinsic tumor in the brain and are classified as low- or high-grade according to the World Health Organization (WHO). Patients with high-grade gliomas (HGG) who undergo surgical resection with adjuvant therapy have a mean overall survival of 15 months and 100% recurrence. The renin-angiotensin system (RAS), the primary regulator of cardiovascular circulation, exhibits local action and works as a paracrine system. In the context of this local regulation, the expression of RAS peptides and receptors has been detected in different kinds of tumors, including gliomas. The dysregulation of RAS components plays a significant role in the proliferation, angiogenesis, and invasion of these tumors, and therefore in their outcomes. The study and potential application of RAS peptides and receptors as biomarkers in gliomas could bring advantages against the limitations of current tumoral markers and should be considered in the future. The targeting of RAS components by RAS blockers has shown potential of being protective against cancer and improving immunotherapy. In gliomas, RAS blockers have shown a broad spectrum for beneficial effects and are being considered for use in treatment protocols. This review aims to summarize the background behind how RAS plays a role in gliomagenesis and explore the evidence that could lead to their use as biomarkers and treatment adjuvants.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Xavier-Magalhaes A, Nandhabalan M, Jones C, Costa BM (2013) Molecular prognostic factors in glioblastoma: state of the art and future challenges. CNS Oncol 2(6):495–510. https://doi.org/10.2217/cns.13.48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS (2015) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol 17(Suppl 4):iv1–iv62. https://doi.org/10.1093/neuonc/nov189

    Article  Google Scholar 

  3. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109. https://doi.org/10.1007/s00401-007-0243-4

    Article  PubMed  PubMed Central  Google Scholar 

  4. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820. https://doi.org/10.1007/s00401-016-1545-1

    Article  PubMed  Google Scholar 

  5. Daumas-Duport C, Scheithauer B, O’Fallon J, Kelly P (1988) Grading of astrocytomas. A simple and reproducible method. Cancer 62(10):2152–2165

    Article  CAS  PubMed  Google Scholar 

  6. de Groot JF (2015) High-grade gliomas. Continuum Neuro Oncol 21(2):332–344. https://doi.org/10.1212/01.CON.0000464173.58262.d9

    Article  Google Scholar 

  7. Komori T (2015) Pathology and genetics of diffuse gliomas in adults. Neurol Med Chirurg 55(1):28–37. https://doi.org/10.2176/nmc.ra.2014-0229

    Article  Google Scholar 

  8. Sahm F, Capper D, Jeibmann A, Habel A, Paulus W, Troost D, von Deimling A (2012) Addressing diffuse glioma as a systemic brain disease with single-cell analysis. Arch Neurol 69(4):523–526. https://doi.org/10.1001/archneurol.2011.2910

    Article  PubMed  Google Scholar 

  9. Ferris SP, Hofmann JW, Solomon DA, Perry A (2017) Characterization of gliomas: from morphology to molecules. Virchows Arch. https://doi.org/10.1007/s00428-017-2181-4

    Article  PubMed  Google Scholar 

  10. Aldape K, Zadeh G, Mansouri S, Reifenberger G, von Deimling A (2015) Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol 129(6):829–848. https://doi.org/10.1007/s00401-015-1432-1

    Article  CAS  PubMed  Google Scholar 

  11. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO, European Organisation for R, Treatment of Cancer Brain. Radiation Oncology T G, National Cancer Institute of Canada Clinical Trials G (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466. https://doi.org/10.1016/S1470-2045(09)70025-7

    Article  CAS  PubMed  Google Scholar 

  12. Karsy M, Neil JA, Guan J, Mahan MA, Colman H, Jensen RL (2015) A practical review of prognostic correlations of molecular biomarkers in glioblastoma. Neurosurg Focus 38(3):E4. https://doi.org/10.3171/2015.1.FOCUS14755

    Article  PubMed  Google Scholar 

  13. Preusser M (2014) Neuro-oncology: a step towards clinical blood biomarkers of glioblastoma. Nat Rev Neurol 10(12):681–682. https://doi.org/10.1038/nrneurol.2014.208

    Article  PubMed  Google Scholar 

  14. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  15. Wegman-Ostrosky T, Soto-Reyes E, Vidal-Millan S, Sanchez-Corona J (2015) The renin-angiotensin system meets the hallmarks of cancer. J Renin-Angiotensin-Aldosterone Syst 16(2):227–233. https://doi.org/10.1177/1470320313496858

    Article  CAS  PubMed  Google Scholar 

  16. Rivera E, Arrieta O, Guevara P, Duarte-Rojo A, Sotelo J (2001) AT1 receptor is present in glioma cells; its blockage reduces the growth of rat glioma. Br J Cancer 85(9):1396–1399. https://doi.org/10.1054/bjoc.2001.2102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Juillerat-Jeanneret L, Celerier J, Chapuis Bernasconi C, Nguyen G, Wostl W, Maerki HP, Janzer RC, Corvol P, Gasc JM (2004) Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma. Br J Cancer 90(5):1059–1068. https://doi.org/10.1038/sj.bjc.6601646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ager EI, Neo J, Christophi C (2008) The renin-angiotensin system and malignancy. Carcinogenesis 29(9):1675–1684. https://doi.org/10.1093/carcin/bgn171

    Article  CAS  PubMed  Google Scholar 

  19. Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, Meredith PA, Murray LS, Reid JL, Robertson JW (1998) Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet 352(9123):179–184. https://doi.org/10.1016/S0140-6736(98)03228-0

    Article  CAS  PubMed  Google Scholar 

  20. van der Knaap R, Siemes C, Coebergh JW, van Duijn CM, Hofman A, Stricker BH (2008) Renin-angiotensin system inhibitors, angiotensin I-converting enzyme gene insertion/deletion polymorphism, and cancer: the Rotterdam Study. Cancer 112(4):748–757. https://doi.org/10.1002/cncr.23215

    Article  PubMed  Google Scholar 

  21. Sun H, Li T, Zhuang R, Cai W, Zheng Y (2017) Do renin-angiotensin system inhibitors influence the recurrence, metastasis, and survival in cancer patients?: evidence from a meta-analysis including 55 studies. Medicine 96(13):e6394. https://doi.org/10.1097/MD.0000000000006394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wright JW, Harding JW (2011) Brain renin-angiotensin–a new look at an old system. Prog Neurobiol 95(1):49–67. https://doi.org/10.1016/j.pneurobio.2011.07.001

    Article  CAS  PubMed  Google Scholar 

  23. Crowley SD, Coffman TM (2012) Recent advances involving the renin-angiotensin system. Exp Cell Res 318(9):1049–1056. https://doi.org/10.1016/j.yexcr.2012.02.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Celerier J, Cruz A, Lamande N, Gasc JM, Corvol P (2002) Angiotensinogen and its cleaved derivatives inhibit angiogenesis. Hypertension 39(2):224–228

    Article  CAS  PubMed  Google Scholar 

  25. Albiston AL, Fernando RN, Yeatman HR, Burns P, Ng L, Daswani D, Diwakarla S, Pham V, Chai SY (2010) Gene knockout of insulin-regulated aminopeptidase: loss of the specific binding site for angiotensin IV and age-related deficit in spatial memory. Neurobiol Learn Mem 93(1):19–30. https://doi.org/10.1016/j.nlm.2009.07.011

    Article  CAS  PubMed  Google Scholar 

  26. Santos RA, Ferreira AJ, Verano-Braga T, Bader M (2013) Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin-angiotensin system. J Endocrinol 216(2):R1–R17. https://doi.org/10.1530/JOE-12-0341

    Article  CAS  Google Scholar 

  27. Xu P, Sriramula S, Lazartigues E (2011) ACE2/ANG-(1–7)/Mas pathway in the brain: the axis of good. Am J Physiol Regul Integr Comp Physiol 300(4):R804-817. https://doi.org/10.1152/ajpregu.00222.2010

    Article  CAS  Google Scholar 

  28. Bickerton RK, Buckley JP (1961) Evidence for a central mechanism in angiotensin induced hypertension. Proc Soc Exp Biol Med 106(4):834–836. https://doi.org/10.3181/00379727-106-26492

    Article  CAS  Google Scholar 

  29. Harding JW, Sullivan MJ, Hanesworth JM, Cushing LL, Wright JW (1988) Inability of [125I]Sar1, Ile8-angiotensin II to move between the blood and cerebrospinal fluid compartments. J Neurochem 50(2):554–557

    Article  CAS  PubMed  Google Scholar 

  30. Wright JW, Harding JW (1994) Brain angiotensin receptor subtypes in the control of physiological and behavioral responses. Neurosci Biobehav Rev 18(1):21–53

    Article  CAS  PubMed  Google Scholar 

  31. Saavedra JM (2005) Brain angiotensin II: new developments, unanswered questions and therapeutic opportunities. Cell Mol Neurobiol 25(3–4):485–512. https://doi.org/10.1007/s10571-005-4011-5

    Article  CAS  PubMed  Google Scholar 

  32. Davisson RL (2003) Physiological genomic analysis of the brain renin-angiotensin system. Am J Physiol Regul Integr Comp Physiol 285(3):R498-511. https://doi.org/10.1152/ajpregu.00190.2003

    Article  PubMed  Google Scholar 

  33. und Halbach OV, Albrecht D (2006) The CNS renin-angiotensin system. Cell Tissue Res 326(2):599–616. https://doi.org/10.1007/s00441-006-0190-8

    Article  CAS  Google Scholar 

  34. Fry M, Ferguson AV (2007) The sensory circumventricular organs: brain targets for circulating signals controlling ingestive behavior. Physiol Behav 91(4):413–423. https://doi.org/10.1016/j.physbeh.2007.04.003

    Article  CAS  PubMed  Google Scholar 

  35. Ferguson AV, Washburn DLS, Bains JS (1999) Regulation of autonomic pathways by angiotensin. Curr Opin Endocrinol Diabet Obes 6(1):19

    Article  CAS  Google Scholar 

  36. Ferguson AV, Washburn DL, Latchford KJ (2001) Hormonal and neurotransmitter roles for angiotensin in the regulation of central autonomic function. Exp Biol Med 226(2):85–96

    Article  CAS  Google Scholar 

  37. Farag E, Sessler DI, Ebrahim Z, Kurz A, Morgan J, Ahuja S, Maheshwari K, John Doyle D (2017) The renin angiotensin system and the brain: New developments. J Clin Neurosci. https://doi.org/10.1016/j.jocn.2017.08.055

    Article  PubMed  Google Scholar 

  38. Barnes JM, Steward LJ, Barber PC, Barnes NM (1993) Identification and characterisation of angiotensin II receptor subtypes in human brain. Eur J Pharmacol 230(3):251–258

    Article  CAS  PubMed  Google Scholar 

  39. Tsutsumi K, Saavedra JM (1991) Characterization and development of angiotensin II receptor subtypes (AT1 and AT2) in rat brain. Am J Physiol 261(1 Pt 2):R209-216

    Google Scholar 

  40. Johren O, Saavedra JM (1996) Gene expression of angiotensin II receptor subtypes in the cerebellar cortex of young rats. Neuroreport 7(8):1349–1352

    Article  CAS  PubMed  Google Scholar 

  41. Wright JW, Harding JW (2013) The brain renin-angiotensin system: a diversity of functions and implications for CNS diseases. Pflugers Arch 465(1):133–151. https://doi.org/10.1007/s00424-012-1102-2

    Article  CAS  PubMed  Google Scholar 

  42. Lazaroni TL, Raslan AC, Fontes WR, de Oliveira ML, Bader M, Alenina N, Moraes MF, Dos Santos RA, Pereira GS (2012) Angiotensin-(1–7)/Mas axis integrity is required for the expression of object recognition memory. Neurobiol Learn Mem 97(1):113–123. https://doi.org/10.1016/j.nlm.2011.10.003

    Article  CAS  PubMed  Google Scholar 

  43. George AJ, Thomas WG, Hannan RD (2010) The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer 10(11):745–759. https://doi.org/10.1038/nrc2945

    Article  CAS  PubMed  Google Scholar 

  44. Vincent F, Bonnin P, Clemessy M, Contreres JO, Lamande N, Gasc JM, Vilar J, Hainaud P, Tobelem G, Corvol P, Dupuy E (2009) Angiotensinogen delays angiogenesis and tumor growth of hepatocarcinoma in transgenic mice. Cancer Res 69(7):2853–2860. https://doi.org/10.1158/0008-5472.CAN-08-2484

    Article  CAS  PubMed  Google Scholar 

  45. Arrieta O, Pineda-Olvera B, Guevara-Salazar P, Hernandez-Pedro N, Morales-Espinosa D, Ceron-Lizarraga TL, Gonzalez-De la Rosa CH, Rembao D, Segura-Pacheco B, Sotelo J (2008) Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis. Br J Cancer 99(1):160–166. https://doi.org/10.1038/sj.bjc.6604431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li JM, Mogi M, Tsukuda K, Tomochika H, Iwanami J, Min LJ, Nahmias C, Iwai M, Horiuchi M (2007) Angiotensin II-induced neural differentiation via angiotensin II type 2 (AT2) receptor-MMS2 cascade involving interaction between AT2 receptor-interacting protein and Src homology 2 domain-containing protein-tyrosine phosphatase 1. Mol Endocrinol 21(2):499–511. https://doi.org/10.1210/me.2006-0005

    Article  PubMed  CAS  Google Scholar 

  47. Li H, Qi Y, Li C, Braseth LN, Gao Y, Shabashvili AE, Katovich MJ, Sumners C (2009) Angiotensin type 2 receptor-mediated apoptosis of human prostate cancer cells. Mol Cancer Ther 8(12):3255–3265. https://doi.org/10.1158/1535-7163.MCT-09-0237

    Article  CAS  PubMed  Google Scholar 

  48. Bouquet C, Lamande N, Brand M, Gasc JM, Jullienne B, Faure G, Griscelli F, Opolon P, Connault E, Perricaudet M, Corvol P (2006) Suppression of angiogenesis, tumor growth, and metastasis by adenovirus-mediated gene transfer of human angiotensinogen. Mol Ther 14(2):175–182. https://doi.org/10.1016/j.ymthe.2006.01.017

    Article  CAS  PubMed  Google Scholar 

  49. Smith GR, Missailidis S (2004) Cancer, inflammation and the AT1 and AT2 receptors. J Inflamm 1(1):3. https://doi.org/10.1186/1476-9255-1-3

    Article  CAS  Google Scholar 

  50. Rodriguez A, Gomez-Ambrosi J, Catalan V, Fortuno A, Fruhbeck G (2010) Leptin inhibits the proliferation of vascular smooth muscle cells induced by angiotensin II through nitric oxide-dependent mechanisms. Mediators Inflamm 2010:105489. https://doi.org/10.1155/2010/105489

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Gonzalez-Zuloeta Ladd AM, Arias Vasquez A, Siemes C, Yazdanpanah M, Coebergh JW, Hofman A, Stricker BH, van Duijn CM (2007) Differential roles of angiotensinogen and angiotensin receptor type 1 polymorphisms in breast cancer risk. Breast Cancer Res Treat 101(3):299–304. https://doi.org/10.1007/s10549-006-9290-0

    Article  CAS  PubMed  Google Scholar 

  52. Vasku A, Vokurka J, Bienertova-Vasku J (2009) Obesity-related genes variability in Czech patients with sporadic colorectal cancer: preliminary results. Int J Colorectal Dis 24(3):289–294. https://doi.org/10.1007/s00384-008-0553-6

    Article  PubMed  Google Scholar 

  53. Sugimoto M, Furuta T, Shirai N, Kodaira C, Nishino M, Ikuma M, Sugimura H, Hishida A (2007) Role of angiotensinogen gene polymorphism on Helicobacter pylori infection-related gastric cancer risk in Japanese. Carcinogenesis 28(9):2036–2040. https://doi.org/10.1093/carcin/bgm074

    Article  CAS  PubMed  Google Scholar 

  54. Andreotti G, Boffetta P, Rosenberg PS, Berndt SI, Karami S, Menashe I, Yeager M, Chanock SJ, Zaridze D, Matteev V, Janout V, Kollarova H, Bencko V, Navratilova M, Szeszenia-Dabrowska N, Mates D, Rothman N, Brennan P, Chow WH, Moore LE (2010) Variants in blood pressure genes and the risk of renal cell carcinoma. Carcinogenesis 31(4):614–620. https://doi.org/10.1093/carcin/bgp321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pringle KG, Delforce SJ, Wang Y, Ashton KA, Proietto A, Otton G, Blackwell CC, Scott RJ, Lumbers ER (2016) Renin-angiotensin system gene polymorphisms and endometrial cancer. Endocr Connect 5(3):128–135. https://doi.org/10.1530/EC-15-0112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Deckers IA, van den Brandt PA, van Engeland M, van Schooten FJ, Godschalk RW, Keszei AP, Schouten LJ (2015) Polymorphisms in genes of the renin-angiotensin-aldosterone system and renal cell cancer risk: interplay with hypertension and intakes of sodium, potassium and fluid. Int J Cancer 136(5):1104–1116. https://doi.org/10.1002/ijc.29060

    Article  CAS  PubMed  Google Scholar 

  57. Tamarat R, Silvestre JS, Durie M, Levy BI (2002) Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. Lab Invest 82(6):747–756

    Article  CAS  PubMed  Google Scholar 

  58. Wolf G, Wenzel U, Burns KD, Harris RC, Stahl RA, Thaiss F (2002) Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney Int 61(6):1986–1995. https://doi.org/10.1046/j.1523-1755.2002.00365.x

    Article  CAS  PubMed  Google Scholar 

  59. Leung PS, Suen PM, Ip SP, Yip CK, Chen G, Lai PB (2003) Expression and localization of AT1 receptors in hepatic Kupffer cells: its potential role in regulating a fibrogenic response. Regul Pept 116(1–3):61–69

    Article  CAS  PubMed  Google Scholar 

  60. Arrieta O, Villarreal-Garza C, Vizcaino G, Pineda B, Hernandez-Pedro N, Guevara-Salazar P, Wegman-Ostrosky T, Villanueva-Rodriguez G, Gamboa-Dominguez A (2015) Association between AT1 and AT2 angiotensin II receptor expression with cell proliferation and angiogenesis in operable breast cancer. Tumour Biol 36(7):5627–5634. https://doi.org/10.1007/s13277-015-3235-3

    Article  CAS  PubMed  Google Scholar 

  61. Kawai T, Forrester SJ, O’Brien S, Baggett A, Rizzo V, Eguchi S (2017) AT1 receptor signaling pathways in the cardiovascular system. Pharmacol Res 125(Pt A):4–13. https://doi.org/10.1016/j.phrs.2017.05.008

    Article  CAS  PubMed  Google Scholar 

  62. Lanz TV, Ding Z, Ho PP, Luo J, Agrawal AN, Srinagesh H, Axtell R, Zhang H, Platten M, Wyss-Coray T, Steinman L (2010) Angiotensin II sustains brain inflammation in mice via TGF-beta. J Clin Invest 120(8):2782–2794. https://doi.org/10.1172/JCI41709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Levin VA, Chan J, Datta M, Yee JL, Jain RK (2017) Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab. J Neuro Oncol 134(2):325–330. https://doi.org/10.1007/s11060-017-2528-3

    Article  CAS  Google Scholar 

  64. Clere N, Corre I, Faure S, Guihot AL, Vessieres E, Chalopin M, Morel A, Coqueret O, Hein L, Delneste Y, Paris F, Henrion D (2010) Deficiency or blockade of angiotensin II type 2 receptor delays tumorigenesis by inhibiting malignant cell proliferation and angiogenesis. Int J Cancer 127(10):2279–2291. https://doi.org/10.1002/ijc.25234

    Article  CAS  PubMed  Google Scholar 

  65. Yoshida T, Kinoshita H, Fukui K, Matsuzaki T, Yoshida K, Mishima T, Yanishi M, Komai Y, Sugi M, Inoue T, Murota T, Matsuda T (2017) Prognostic impact of renin-angiotensin inhibitors in patients with bladder cancer undergoing radical cystectomy. Ann Surg Oncol 24(3):823–831. https://doi.org/10.1245/s10434-016-5534-3

    Article  PubMed  Google Scholar 

  66. Moreno-Munoz D, de la Haba-Rodriguez JR, Conde F, Lopez-Sanchez LM, Valverde A, Hernandez V, Martinez A, Villar C, Gomez-Espana A, Porras I, Rodriguez-Ariza A, Aranda E (2015) Genetic variants in the renin-angiotensin system predict response to bevacizumab in cancer patients. Eur J Clin Invest 45(12):1325–1332. https://doi.org/10.1111/eci.12557

    Article  CAS  PubMed  Google Scholar 

  67. Passos-Silva DG, Brandan E, Santos RA (2015) Angiotensins as therapeutic targets beyond heart disease. Trends Pharmacol Sci 36(5):310–320. https://doi.org/10.1016/j.tips.2015.03.001

    Article  CAS  PubMed  Google Scholar 

  68. Weller M, Pfister SM, Wick W, Hegi ME, Reifenberger G, Stupp R (2013) Molecular neuro-oncology in clinical practice: a new horizon. Lancet Oncol 14(9):e370–e379. https://doi.org/10.1016/s1470-2045(13)70168-2

    Article  Google Scholar 

  69. Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, Villano JL (2014) Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol 23(10):1985–1996. https://doi.org/10.1158/1055-9965.EPI-14-0275

    Article  CAS  Google Scholar 

  70. Bradshaw AR, Wickremesekera AC, Brasch HD, Chibnall AM, Davis PF, Tan ST, Itinteang T (2016) Glioblastoma multiforme cancer stem cells express components of the renin-angiotensin system. Front Surg 3:51. https://doi.org/10.3389/fsurg.2016.00051

    Article  PubMed  PubMed Central  Google Scholar 

  71. Urup T, Michaelsen SR, Olsen LR, Toft A, Christensen IJ, Grunnet K, Winther O, Broholm H, Kosteljanetz M, Issazadeh-Navikas S, Poulsen HS, Lassen U (2016) Angiotensinogen and HLA class II predict bevacizumab response in recurrent glioblastoma patients. Mol Oncol 10(8):1160–1168. https://doi.org/10.1016/j.molonc.2016.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Perdomo-Pantoja A, Mejia-Perez S, Gomez-Amador J, Wegman-Ostrosky T (2017) Serum rs5050 AGT polymorphism is related to poor prognosis in astrocytoma: potential biomarker in blood. Turk Neurosurg 27(5 Suppl):102–103

    Google Scholar 

  73. Wegman-Ostrosky T (2014) Identificación de variantes en el gen AGT en pacientes con astrocitoma (tesis de doctorado). Universidad de Guadalajara, Mexico

    Google Scholar 

  74. Medeiros R, Vasconcelos A, Costa S, Pinto D, Lobo F, Morais A, Oliveira J, Lopes C (2004) Linkage of angiotensin I-converting enzyme gene insertion/deletion polymorphism to the progression of human prostate cancer. J Pathol 202(3):330–335. https://doi.org/10.1002/path.1529

    Article  CAS  PubMed  Google Scholar 

  75. Sierra Diaz E, Sanchez Corona J, Rosales Gomez RC, Gutierrez Rubio SA, Vazquez Camacho JG, Solano Moreno H, Moran Moguel MC (2009) Angiotensin-converting enzyme insertion/deletion and angiotensin type 1 receptor A1166C polymorphisms as genetic risk factors in benign prostatic hyperplasia and prostate cancer. J Renin-Angiotensin-Aldosterone Syst 10(4):241–246. https://doi.org/10.1177/1470320309352800

    Article  PubMed  Google Scholar 

  76. Devic Pavlic S, Ristic S, Flego V, Kapovic M, Radojcic Badovinac A (2012) Angiotensin-converting enzyme insertion/deletion gene polymorphism in lung cancer patients. Genet Test Mol Biomark 16(7):722–725. https://doi.org/10.1089/gtmb.2011.0306

    Article  CAS  Google Scholar 

  77. Lukic S, Nikolic A, Alempijevic T, Popovic D, Sokic Milutinovic A, Ugljesic M, Knezevic S, Milicic B, Dinic D, Radojkovic D (2011) Angiotensin-converting enzyme gene insertion/deletion polymorphism in patients with chronic pancreatitis and pancreatic cancer. Dig Surg 28(4):258–262. https://doi.org/10.1159/000328666

    Article  CAS  PubMed  Google Scholar 

  78. Srivastava K, Srivastava A, Mittal B (2010) Angiotensin I-converting enzyme insertion/deletion polymorphism and increased risk of gall bladder cancer in women. DNA Cell Biol 29(8):417–422. https://doi.org/10.1089/dna.2010.1033

    Article  CAS  PubMed  Google Scholar 

  79. Alves Correa SA, Ribeiro de Noronha SM, Nogueira-de-Souza NC, Valleta de Carvalho C, Massad Costa AM, Juvenal Linhares J, Vieira Gomes MT, Guerreiro da Silva ID (2009) Association between the angiotensin-converting enzyme (insertion/deletion) and angiotensin II type 1 receptor (A1166C) polymorphisms and breast cancer among Brazilian women. J Renin-Angiotensin-Aldosterone Syst 10 (1):51–58. https://doi.org/10.1177/1470320309102317

    Article  PubMed  Google Scholar 

  80. Vairaktaris E, Yapijakis C, Tsigris C, Vassiliou S, Derka S, Nkenke E, Spyridonidou S, Vylliotis A, Vorris E, Ragos V, Neukam FW, Patsouris E (2007) Association of angiotensin-converting enzyme gene insertion/deletion polymorphism with increased risk for oral cancer. Acta Oncol 46(8):1097–1102. https://doi.org/10.1080/02841860701373579

    Article  CAS  PubMed  Google Scholar 

  81. Rigat B, Hubert C, Alhenc-Gelas F, Cambien F, Corvol P, Soubrier F (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86(4):1343–1346. https://doi.org/10.1172/JCI114844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Tiret L, Rigat B, Visvikis S, Breda C, Corvol P, Cambien F, Soubrier F (1992) Evidence, from combined segregation and linkage analysis, that a variant of the angiotensin I-converting enzyme (ACE) gene controls plasma ACE levels. Am J Hum Genet 51(1):197–205

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Lian M, Jiang H, Wang H, Guo S (2015) Angiotensin-converting enzyme insertion/deletion gene polymorphisms is associated with risk of glioma in a Chinese population. J Renin-Angiotensin-Aldosterone Syst 16(2):443–447. https://doi.org/10.1177/1470320313495910

    Article  CAS  PubMed  Google Scholar 

  84. Azevedo H, Fujita A, Bando SY, Iamashita P, Moreira-Filho CA (2014) Transcriptional network analysis reveals that AT1 and AT2 angiotensin II receptors are both involved in the regulation of genes essential for glioma progression. PLoS ONE 9(11):e110934. https://doi.org/10.1371/journal.pone.0110934

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Herrera M, Sparks MA, Alfonso-Pecchio AR, Harrison-Bernard LM, Coffman TM (2013) Response to lack of specificity of commercial antibodies leads to misidentification of angiotensin type-1 receptor protein. Hypertension 61(4):e32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ni L, Feng Y, Wan H, Ma Q, Fan L, Qian Y, Li Q, Xiang Y, Gao B (2012) Angiotensin-(1–7) inhibits the migration and invasion of A549 human lung adenocarcinoma cells through inactivation of the PI3K/Akt and MAPK signaling pathways. Oncol Rep 27(3):783–790. https://doi.org/10.3892/or.2011.1554

    Article  CAS  PubMed  Google Scholar 

  87. Liu B, Liu Y, Jiang Y (2015) Podocalyxin promotes glioblastoma multiforme cell invasion and proliferation by inhibiting angiotensin-(1–7)/Mas signaling. Oncol Rep 33(5):2583–2591. https://doi.org/10.3892/or.2015.3813

    Article  CAS  PubMed  Google Scholar 

  88. Ma TK, Kam KK, Yan BP, Lam YY (2010) Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol 160(6):1273–1292. https://doi.org/10.1111/j.1476-5381.2010.00750.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ronquist G, Rodriguez LA, Ruigomez A, Johansson S, Wallander MA, Frithz G, Svardsudd K (2004) Association between captopril, other antihypertensive drugs and risk of prostate cancer. Prostate 58(1):50–56. https://doi.org/10.1002/pros.10294

    Article  CAS  PubMed  Google Scholar 

  90. Friis S, Sorensen HT, Mellemkjaer L, McLaughlin JK, Nielsen GL, Blot WJ, Olsen JH (2001) Angiotensin-converting enzyme inhibitors and the risk of cancer: a population-based cohort study in Denmark. Cancer 92(9):2462–2470

    Article  CAS  PubMed  Google Scholar 

  91. Meier CR, Derby LE, Jick SS, Jick H (2000) Angiotensin-converting enzyme inhibitors, calcium channel blockers, and breast cancer. Arch Intern Med 160(3):349–353

    Article  CAS  PubMed  Google Scholar 

  92. Lund EL, Spang-Thomsen M, Skovgaard-Poulsen H, Kristjansen PE (1998) Tumor angiogenesis–a new therapeutic target in gliomas. Acta Neurol Scand 97(1):52–62

    Article  CAS  PubMed  Google Scholar 

  93. Wang D, Huang HJ, Kazlauskas A, Cavenee WK (1999) Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res 59(7):1464–1472

    CAS  PubMed  Google Scholar 

  94. Juillerat-Jeanneret L, Lohm S, Hamou MF, Pinet F (2000) Regulation of aminopeptidase A in human brain tumor vasculature: evidence for a role of transforming growth factor-beta. Lab Invest 80(6):973–980

    Article  CAS  PubMed  Google Scholar 

  95. Kakinuma Y, Hama H, Sugiyama F, Yagami K, Goto K, Murakami K, Fukamizu A (1998) Impaired blood-brain barrier function in angiotensinogen-deficient mice. Nat Med 4(9):1078–1080. https://doi.org/10.1038/2070

    Article  CAS  PubMed  Google Scholar 

  96. Egidy G, Eberl LP, Valdenaire O, Irmler M, Majdi R, Diserens AC, Fontana A, Janzer RC, Pinet F, Juillerat-Jeanneret L (2000) The endothelin system in human glioblastoma. Lab Invest 80(11):1681–1689

    Article  CAS  PubMed  Google Scholar 

  97. Arrieta O, Guevara P, Escobar E, Garcia-Navarrete R, Pineda B, Sotelo J (2005) Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma. Br J Cancer 92(7):1247–1252. https://doi.org/10.1038/sj.bjc.6602483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T (1995) The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 95(2):651–657. https://doi.org/10.1172/JCI117710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Fogarty DJ, Sanchez-Gomez MV, Matute C (2002) Multiple angiotensin receptor subtypes in normal and tumor astrocytes in vitro. Glia 39(3):304–313. https://doi.org/10.1002/glia.10117

    Article  PubMed  Google Scholar 

  100. Januel E, Ursu R, Alkhafaji A, Marantidou A, Doridam J, Belin C, Levy-Piedbois C, Carpentier AF (2015) Impact of renin-angiotensin system blockade on clinical outcome in glioblastoma. Eur J Neurol 22(9):1304–1309. https://doi.org/10.1111/ene.12746

    Article  CAS  PubMed  Google Scholar 

  101. Carpentier AF, Ferrari D, Bailon O, Ursu R, Banissi C, Dubessy AL, Belin C, Levy C (2012) Steroid-sparing effects of angiotensin-II inhibitors in glioblastoma patients. Eur J Neurol 19(10):1337–1342. https://doi.org/10.1111/j.1468-1331.2012.03766.x

    Article  CAS  PubMed  Google Scholar 

  102. Kourilsky A, Bertrand G, Ursu R, Doridam J, Barlog C, Faillot T, Mandonnet E, Belin C, Levy C, Carpentier AF (2016) Impact of angiotensin-II receptor blockers on vasogenic edema in glioblastoma patients. J Neurol 263(3):524–530. https://doi.org/10.1007/s00415-015-8016-9

    Article  CAS  PubMed  Google Scholar 

  103. Saavedra JM (2012) Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci 123(10):567–590. https://doi.org/10.1042/CS20120078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Saavedra JM (2017) Beneficial effects of angiotensin II receptor blockers in brain disorders. Pharmacol Res 125(Pt A):91–103. https://doi.org/10.1016/j.phrs.2017.06.017

    Article  CAS  PubMed  Google Scholar 

  105. Zhang M, Mao Y, Ramirez SH, Tuma RF, Chabrashvili T (2010) Angiotensin II induced cerebral microvascular inflammation and increased blood-brain barrier permeability via oxidative stress. Neuroscience 171(3):852–858. https://doi.org/10.1016/j.neuroscience.2010.09.029

    Article  CAS  PubMed  Google Scholar 

  106. Fleegal-DeMotta MA, Doghu S, Banks WA (2009) Angiotensin II modulates BBB permeability via activation of the AT(1) receptor in brain endothelial cells. J Cereb Blood Flow Metab 29(3):640–647. https://doi.org/10.1038/jcbfm.2008.158

    Article  CAS  PubMed  Google Scholar 

  107. Sano H, Hosokawa K, Kidoya H, Takakura N (2006) Negative regulation of VEGF-induced vascular leakage by blockade of angiotensin II type 1 receptor. Arterioscler Thromb Vasc Biol 26(12):2673–2680. https://doi.org/10.1161/01.ATV.0000245821.77155.c3

    Article  CAS  PubMed  Google Scholar 

  108. Lu-Emerson C, Duda DG, Emblem KE, Taylor JW, Gerstner ER, Loeffler JS, Batchelor TT, Jain RK (2015) Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J Clin Oncol 33(10):1197–1213. https://doi.org/10.1200/JCO.2014.55.9575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722. https://doi.org/10.1056/NEJMoa1308345

    Article  CAS  PubMed  Google Scholar 

  110. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708. https://doi.org/10.1056/NEJMoa1308573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Levin VA, Mendelssohn ND, Chan J, Stovall MC, Peak SJ, Yee JL, Hui RL, Chen DM (2015) Impact of bevacizumab administered dose on overall survival of patients with progressive glioblastoma. J Neuro Oncol 122(1):145–150. https://doi.org/10.1007/s11060-014-1693-x

    Article  CAS  Google Scholar 

  112. Lombardi G, Zustovich F, Farina P, Fiduccia P, Della Puppa A, Polo V, Bertorelle R, Gardiman MP, Banzato A, Ciccarino P, Denaro L, Zagonel V (2013) Hypertension as a biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs: a single-center experience and a critical review of the literature. Anticancer Drugs 24(1):90–97. https://doi.org/10.1097/CAD.0b013e32835aa5fd

    Article  CAS  PubMed  Google Scholar 

  113. Ranpura V, Pulipati B, Chu D, Zhu X, Wu S (2010) Increased risk of high-grade hypertension with bevacizumab in cancer patients: a meta-analysis. Am J Hypertens 23(5):460–468. https://doi.org/10.1038/ajh.2010.25

    Article  CAS  PubMed  Google Scholar 

  114. Emile G, Pujade-Lauraine E, Alexandre J (2014) Should we use the angiotensin-converting enzyme inhibitors for the treatment of anti-VEGF-induced hypertension? Ann Oncol 25(8):1669–1670. https://doi.org/10.1093/annonc/mdu197

    Article  CAS  PubMed  Google Scholar 

  115. Okwan-Duodu D, Landry J, Shen XZ, Diaz R (2013) Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis. Am J Physiol Regul Integr Comp Physiol 305(3):R205-215. https://doi.org/10.1152/ajpregu.00544.2012

    Article  CAS  Google Scholar 

  116. Tom B, Dendorfer A, de Vries R, Saxena PR, Jan Danser AH (2002) Bradykinin potentiation by ACE inhibitors: a matter of metabolism. Br J Pharmacol 137(2):276–284. https://doi.org/10.1038/sj.bjp.0704862

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Stylianopoulos T, Jain RK (2013) Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc Natl Acad Sci USA 110(46):18632–18637. https://doi.org/10.1073/pnas.1318415110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popovic Z, Huang P, Bawendi MG, Boucher Y, Jain RK (2013) Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 4:2516. https://doi.org/10.1038/ncomms3516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Harrison LB, Chadha M, Hill RJ, Hu K, Shasha D (2002) Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist 7(6):492–508

    Article  PubMed  Google Scholar 

  120. Clarke RH, Moosa S, Anzivino M, Wang Y, Floyd DH, Purow BW, Lee KS (2014) Sustained radiosensitization of hypoxic glioma cells after oxygen pretreatment in an animal model of glioblastoma and in vitro models of tumor hypoxia. PLoS ONE 9(10):e111199. https://doi.org/10.1371/journal.pone.0111199

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Pinter M, Jain RK (2017) Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aan5616

    Article  PubMed  PubMed Central  Google Scholar 

  122. Liu H, Naxerova K, Pinter M, Incio J, Lee H, Shigeta K, Ho WW, Crain JA, Jacobson A, Michelakos T, Dias-Santos D, Zanconato A, Hong TS, Clark JW, Murphy JE, Ryan DP, Deshpande V, Lillemoe KD, Fernandez-Del Castillo C, Downes M, Evans RM, Michaelson J, Ferrone CR, Boucher Y, Jain RK (2017) Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma. Clin Cancer Res 23(19):5959–5969. https://doi.org/10.1158/1078-0432.CCR-17-0256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Pinter M, Weinmann A, Worns MA, Hucke F, Bota S, Marquardt JU, Duda DG, Jain RK, Galle PR, Trauner M, Peck-Radosavljevic M, Sieghart W (2017) Use of inhibitors of the renin-angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. United Eur Gastroenterol J 5(7):987–996. https://doi.org/10.1177/2050640617695698

    Article  CAS  Google Scholar 

  124. Rosen EM, Day R, Singh VK (2014) New approaches to radiation protection. Front Oncol 4:381. https://doi.org/10.3389/fonc.2014.00381

    Article  PubMed  Google Scholar 

  125. Johnke RM, Sattler JA, Allison RR (2014) Radioprotective agents for radiation therapy: future trends. Future Oncol 10(15):2345–2357. https://doi.org/10.2217/fon.14.175

    Article  CAS  PubMed  Google Scholar 

  126. McLaughlin MF, Donoviel DB, Jones JA (2017) Novel indications for commonly used medications as radiation protectants in spaceflight. Aerosp Med Hum Perform 88(7):665–676. https://doi.org/10.3357/AMHP.4735.2017

    Article  PubMed  PubMed Central  Google Scholar 

  127. Robbins ME, Payne V, Tommasi E, Diz DI, Hsu FC, Brown WR, Wheeler KT, Olson J, Zhao W (2009) The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys 73(2):499–505. https://doi.org/10.1016/j.ijrobp.2008.09.058

    Article  CAS  PubMed  Google Scholar 

  128. Lee TC, Greene-Schloesser D, Payne V, Diz DI, Hsu FC, Kooshki M, Mustafa R, Riddle DR, Zhao W, Chan MD, Robbins ME (2012) Chronic administration of the angiotensin-converting enzyme inhibitor, ramipril, prevents fractionated whole-brain irradiation-induced perirhinal cortex-dependent cognitive impairment. Radiation Res 178(1):46–56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Jenrow KA, Brown SL, Liu J, Kolozsvary A, Lapanowski K, Kim JH (2010) Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus. Radiat Oncol 5:6. https://doi.org/10.1186/1748-717X-5-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Kast RE, Boockvar JA, Bruning A, Cappello F, Chang WW, Cvek B, Dou QP, Duenas-Gonzalez A, Efferth T, Focosi D, Ghaffari SH, Karpel-Massler G, Ketola K, Khoshnevisan A, Keizman D, Magne N, Marosi C, McDonald K, Munoz M, Paranjpe A, Pourgholami MH, Sardi I, Sella A, Srivenugopal KS, Tuccori M, Wang W, Wirtz CR, Halatsch ME (2013) A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the international initiative for accelerated improvement of glioblastoma care. Oncotarget 4(4):502–530. https://doi.org/10.18632/oncotarget.969

    Article  PubMed  PubMed Central  Google Scholar 

  131. Kast RE, Karpel-Massler G, Halatsch ME (2014) CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget 5(18):8052–8082. https://doi.org/10.18632/oncotarget.2408

    Article  PubMed  PubMed Central  Google Scholar 

  132. Assistance Publique – Hôpitaux de Paris. Angiotensin II Receptor Blockers, Steroids and Radiotherapy in Glioblastoma (ASTER). https://clinicaltrials.gov/ct2/show/NCT01805453 (Accessed 16 Jan 2018)

Download references

Acknowledgements

Special thanks to Alejandro Lafuente for his invaluable help with the figures of this review.

Funding

This project was funded by CONACYT (Salud-2013-01-202720).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Talia Wegman-Ostrosky.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors

Informed consent

This article does not require informed consent.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Perdomo-Pantoja, A., Mejía-Pérez, S.I., Gómez-Flores-Ramos, L. et al. Renin angiotensin system and its role in biomarkers and treatment in gliomas. J Neurooncol 138, 1–15 (2018). https://doi.org/10.1007/s11060-018-2789-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-018-2789-5

Keywords

Navigation