Abstract

Endothelins are a family of four endogenous peptides (ET-1, ET-2, ET-3, ET-4) secreted primarily in an inactive form by the endothelium. They are activated with the participation of converting enzyme. Numerous studies have described their pleiotropic biological activity. These peptides are involved, inter alia, in the regulation of processes such as cell proliferation, migration, angiogenesis and apoptosis. Their important role in the regulation of blood pressure, tissue perfusion (especially in the central nervous system), and myocardial systolic function is also known. Moreover, changes in transcriptional activity of endothelin and its receptors may be involved, with the participation of a number of signaling pathways, in carcinogenesis, and the pathogenesis of numerous diseases (heart, kidney, lung and skin disorders, especially with the component of fibrosis). Their role has been documented in the development of breast, prostatic, colorectal, ovarian, lung, kidney, and endometrial cancer, and in melanoma. In this article we present a brief description of the endothelin group and the participation of them and their receptors in carcinogenesis. We also try to show their role as prognostic and predictive factors in human malignant tumors. The article also refers to clinical trials on the use of preparations of endothelin receptor antagonists in the design of molecular therapeutic strategies in human malignancies.

References

• 1. Bagnato A., Natali P.G.: Endothelin receptors as novel targets intumor therapy. J. Transl. Med., 2004; 2: 16
  Google Scholar
• 2. Bagnato A., Spinella F., Rosanò L.: Emerging role of the endothelinaxis in ovarian tumor progression. Endocr. Relat. Cancer, 2005;12: 761-772
  Google Scholar
• 3. Bagnato A., Spinella F., Rosanò L.: The endothelin axis in cancer:the promise and the challenges of molecularly targeted therapy.Can. J. Physiol. Pharmacol., 2008; 86: 473-484
  Google Scholar
• 4. Barton M., Yanagisawa M.: Endothelin: 20 years from discoveryto therapy. Can. J. Physiol. Pharmacol., 2008; 86: 485-498
  Google Scholar
• 5. Battistini B., Berthiaume N., Kelland N.F., Webb D.J., Kohan D.E.:Profile of past and current clinical trials involving endothelin receptorantagonists: the novel “-sentan” class of drug. Exp. Biol. Med.,2006; 231: 653-695
  Google Scholar
• 6. Bianchi M., Adur J., Izaguirre M.F., Viale S., Cesar C.L., Casco V.H.:Endothelin-2 differential expression in normal and early-stages ofcolon cancer development. J. Cancer Ther., 2013; 4: 26-33
  Google Scholar
• 7. Bianchi M., Adur J., Takizawa S., Saida K., Casco V.H.: Endothelinsystem in intestinal villi: a possible role of endothelin-2/vasoactiveintestinal contractor in the maintenance of intestinal architecture.Biochem. Biophys. Res. Commun., 2012; 417: 1113-1118
  Google Scholar
• 8. Braczkowski R., Romanawsky W., Danikiewicz A., Muc-WierzgońM., Błażelonis A., Zubelewicz B.: Decrease of erythropoietinlevel by human recombinant tumor necrosis factor α (TNF-α) in patientswith advanced cancer. J. Biol. Regul. Homeost. Agents, 2001;15: 366-369
  Google Scholar
• 9. Castañares C., Redondo-Horcajo M., Magán-Marchal N., ten DijkeP., Lamas S., Rodríguez-Pascual F.: Signaling by ALK5 mediates TGF-β-induced ET-1 expression in endothelial cells: a role for migrationand proliferation. J. Cell Sci., 2007; 120: 1256-1266
  Google Scholar
• 10. Davenport A.P.: International Union of Pharmacology. XXIX.Update on endothelin receptor nomenclature. Pharmacol. Rev.,2002; 54: 219-226
  Google Scholar
• 11. Del Bufalo D., Di Castro V., Biroccio A.: Endothelin-1 protectsovarian carcinoma cells against paclitaxel-induced apoptosis: requirementfor Akt activation. Mol. Pharmacol., 2002; 61: 524-532
  Google Scholar
• 12. Dobrek Ł., Thor P.: Endotelina w patofizjologii chorób sercowo–naczyniowych. Pol. Merkur. Lek., 2010; 28: 289-292
  Google Scholar
• 13. Domeier T.L., Zima A.V., Maxwell J.T., Huke S., Mignery G.A.,Blatter L.A.: IP3 receptor-dependent Ca2+ release modulates excitation-contractioncoupling in rabbit ventricular myocytes. Am. J.Physiol. Heart Circ. Physiol., 2008; 294: 596-604
  Google Scholar
• 14. Duan X.L., Zhang X.S., Li G.W.: Clinical relationship betweenEDN-3 gene, EDNRB gene and Hirschsprung’s disease. World J. Gastroenterol.,2003; 9: 2839-2842
  Google Scholar
• 15. Folberg R., Hendrix M.J., Maniotis A.J.: Vasculogenic mimicryand tumor angiogenesis. Am. J. Pathol., 2000; 156: 361-381
  Google Scholar
• 16. Grimshaw M.J.: Endothelins and hypoxia-inducible factor incancer. Endocr. Relat. Cancer, 2007; 14: 233-244
  Google Scholar
• 17. Grimshaw M.J., Hagemann T., Ayhan A., Gillett C.E., Binder C.,Balkwill F.R.: A role for endothelin-2 and its receptors in breast tumorcell invasion. Cancer Res., 2004; 64: 2461-2468
  Google Scholar
• 18. Grimshaw M.J., Naylor S., Balkwill F.R.: Endothelin-2 is a hypoxia-inducedautocrine survival factor for breast tumor cells. Mol.Cancer Ther., 2002; 1: 1273-1281
  Google Scholar
• 19. Groenewegen G., Walraven M., Vermaat J., de Gast B., WitteveenE., Giles R., Haanen J., Voest E.: Targeting the endothelin axis withatrasentan, in combination with IFN-α, in metastatic renal cell carcinoma.Br. J. Cancer, 2012; 106: 284-289
  Google Scholar
• 20. Haque S.U., Dashwood M.R., Heetun M., Shiwen X., FarooquiN., Ramesh B., Welch H., Savage F.J., Ogunbiyi O., Abraham D.J., LoizidouM.: Efficacy of the specific endothelin A receptor antagonistzibotentan (ZD4054) in colorectal cancer: a preclinical study. Mol.Cancer Ther., 2013; 12; 1556-1567
  Google Scholar
• 21. Harłozińska-Szmyrka A., Sobańska E.: Przerzuty nowotworowe– terrorysta XXI wieku. Przegl. Lek., 2008; 1: 19-27
  Google Scholar
• 22. Harris A.K., Hutchinson J.R., Sachidanandam K., Johnson M.H.,Dorrance A.M., Stepp D.W., Fagan S.C., Ergul A.: Type 2 diabetes causesremodeling of cerebrovasculature via differential regulation ofmatrix metalloproteinases and collagen synthesis: role of endothelin-1.Diabetes, 2005; 54: 2638-2644
  Google Scholar
• 23. Haynes W.G., Webb D.J.: Contribution of endogenous generationof endothelin 1 to basal vascular tone. Lancet, 1994; 344: 852-854
  Google Scholar
• 24. He S., Prasanna G., Yorio T.: Endothelin-1-mediated signaling inthe expression of matrix metalloproteinases and tissue inhibitorsof metalloproteinases in astrocytes. Invest. Ophthalmol. Vis. Sci.,2007; 48: 3737-3745
  Google Scholar
• 25. Horstmeyer A., Licht C., Scherr G., Eckes B., Krieg T.: Signallingand regulation of collagen I synthesis by ET-1 and TGF-β1. FEBS J.,2005; 272: 6297-6309
  Google Scholar
• 26. Ikeda K., Emoto N., Raharjo S.B., Nurhantari Y., Saiki K., YokoyamaM., Matsuo M.: Molecular identification and characterizationof novel membrane-bound metalloprotease, the soluble secretedform of which hydrolyzes a variety of vasoactive peptides. J. Biol.Chem., 1999; 274: 32469-32477
  Google Scholar
• 27. Inoue A., Yanagisawa M., Kimura S., Kasuqy Y., Mayauchi T., GotoK., Masaki T.: The human endothelin family: three structurally andpharmacologically distinct isopeptides predicted by three separategenes. Proc. Natl. Acad. Sci. USA, 1989; 86: 2863-2867
  Google Scholar
• 28. Kalabis J., Li G., Fukunaga-Kalabis M., Rustgi A.K., Herlyn M.:Endothelin-3 stimulates survival of goblet cells in organotypic culturesof fetal human colonic epithelium. Am. J. Physiol. Gastrointest.Liver Physiol., 2008; 295: 1182-1189
  Google Scholar
• 29. Kalles V., Zografos G.C., Provatopoulou X., Kalogera E., Liakou P.,Georgiou G., Sagkriotis A., Nonni A., Gounaris A.: Circulating levelsof endothelin-1 (ET-1) and its precursor (Big ET-1) in breast cancerearly diagnosis. Tumour Biol., 2012, 33: 1231-1236
  Google Scholar
• 30. Kedzierski R.M., Yanagisawa M.: Endothelin system: the double–edged sword in health and disease. Annu. Rev. Pharmacol. Toxicol.,2001; 41: 851-876
  Google Scholar
• 31. Khodorova A., Montmayeur J.P., Strichartz G.: Endothelin receptorsand pain. J. Pain, 2009; 10: 4-28
  Google Scholar
• 32. Kim S.J., Kim J.S., Kim S.W., Brantley E., Yun S.J., He J., Maya M.,Zhang F., Wu Q., Lehembre F., Regenass U., Fidler I.J.: Macitentan(ACT-064992), a tissue-targeting endothelin receptor antagonist,enhances therapeutic efficacy of paclitaxel by modulating survivalpathways in orthotopic models of metastatic human ovarian cancer.Neoplasia, 2011; 13: 167-179
  Google Scholar
• 33. Kleinz M.J., Davenport A.P.: Immunocytochemical localization ofendogenous vasoactive peptide apelin to human vascular and endocardialendothelial cells. Regul. Pept., 2004; 118: 119-125
  Google Scholar
• 34. Kleniewska P., Michalski Ł., Skibska B., Goraca A.: The influenceof endothelin-1 and endothelin receptor blocker on the content ofwhite blood cells in the peripheral blood of rat. Pol. Merkur. Lek.,2012; 32: 225-227
  Google Scholar
• 35. Komatsu K., Buchanan F.G., Otaka M., Jin M., Odashima M., HorikawaY., Watanabe S., Dubois R.N.: Gene expression profiling followingconstitutive activation of MEK1 and transformation of ratintestinal epithelial cells. Mol. Cancer, 2006; 5: 63
  Google Scholar
• 36. Kotake-Nara E., Saida K.: Endothelin-2/vasoactive intestinal contractor:regulation of expression via reactive oxygen species inducedby CoCl22, and biological activities including neurite outgrowth inPC12 cells. Sci. World J., 2006; 6: 176-186
  Google Scholar
• 37. Kowalczyk A., Kołodziejczyk M., Gorąca A.: Antagoniści receptorówendotelinowych (ERA)– krótka charakterystyka nowej grupyleków. Postępy Hig. Med. Dośw., 2014; 68: 1076-1080
  Google Scholar
• 38. Kozakai T., Zhao H., Sakate M., Masuo Y., Uchide T., Saida K.:Effect of aging on gene expression rates of endothelin-1 and endothelin-2/vasoactiveintestinal contractor in ethanol-induced gastricmucosal injury of the mouse. Clin. Sci., 2002; 103: 455-458
  Google Scholar
• 39. Kun T., Dąbrowski R.: Endoteliny w regulacji funkcji układu krą-żenia. Pol. Przegl. Kardiol., 2002; 4: 149-155
  Google Scholar
• 40. Küry S., Buecher B., Robiou-du-Pont S., Scoul C., Colman H., LeNeel T., Le Horuérou C., Faroux R., Ollivry J., Lafraise B., Chupin L.D.,Sébille V., Bézieau S.: Low-penetrance alleles predisposing to sporadiccolorectal cancers: a French case-controlled genetic associationstudy. BMC Cancer, 2008; 8: 326
  Google Scholar
• 41. Kusuhara M., Yamaguchi K., Nagasaki K.: Production of endothelinin human cancer cell lines. Cancer Res., 1990; 50: 3257-3261
  Google Scholar
• 42. Lee S., Lin M., Mele A., Cao Y., Farmar J., Russo D., Redman C.:Proteolytic processing of big endothelin-3 by the kell blood groupprotein. Blood, 1999; 94: 1440-1450
  Google Scholar
• 43. Lewandowicz A.M., Kowalski M.L., Pawliczak R.: Białka regulująceprzekazywanie sygnału przez białka G (białka RGS) i ich znaczeniew regulacji odpowiedzi immunologicznej. Postępy Hig. Med.Dośw., 2004; 58: 312-320
  Google Scholar
• 44. Liu L., Heneghan J.F., Mitra-Ganguli T., Roberts-Crowley M.L.,Rittenhouse A.R.: Role of PIP2 in regulating versus modulating Ca2+channel activity. J. Physiol., 2007; 583: 1165-1166
  Google Scholar
• 45. Lorenzo M.N., Khan R.Y., Wang Y., Tai S.C., Chan G.C., CheungA.H., Marsden P.A.: Human endothelin converting enzyme-2 (ECE2):characterization of mRNA species and chromosomal localization.Biochim. Biophys. Acta, 2001; 1522: 46-52
  Google Scholar
• 46. Makita T., Sucov H.M., Gariepy C.E., Yanagisawa M., Ginty D.D.:Endothelins are vascular-derived axonal guidance cues for developingsympathetic neurons. Nature, 2008; 452: 759-763
  Google Scholar
• 47. Nelson J.B., Fizazi K., Miller K., Higano C., Moul J.W., Akaza H.,Morris T., McIntosh S., Pemberton K., Gleave M.: Phase 3, randomized,placebo-controlled study of zibotentan (ZD4054) in patientswith castration-resistant prostate cancer metastatic to bone. Cancer,2012; 118: 5709-5718
  Google Scholar
• 48. Nelson J.B., Udan M.S., Guruli G., Pflug B.R.: Endothelin-1 inhibitsapoptosis in prostate cancer. Neoplasia, 2005; 7: 631-637
  Google Scholar
• 49. Oppenheimer S.B.: Cellular basis of cancer metastasis: a reviewof fundamentals and new advances. Acta Histochem., 2006;108: 327-334
  Google Scholar
• 50. Ortmann J., Nett P.C., Celeiro J., Hofmann-Lehmann R., TornilloR., Terracciano L.M., Barton M.: Downregulation of renal endothelin-convertingenzyme 2 expression in early autoimmune diabetes.Exp. Biol. Med., 2006; 231: 1030 1033
  Google Scholar
• 51. Paasche J.D., Attramadal T., Sandberg C., Johansen H.K., Attramadal H.: Mechanisms of endothelin receptor subtype-specific targetingto distinct intracellular trafficking pathways. J. Biol. Chem.,2001; 276: 34041-34050
  Google Scholar
• 52. Park S., Lim S., Chang W., Song H., Lee S., Song B.W., Kim H.J.,Cha M.J., Choi E., Jang Y., Chung N., Cho S.Y., Hwang K.C.: The inhibitionof insulin-stimulated proliferation of vascular smooth musclecells by rosiglitazone is mediated by the Akt-mTOR-P70S6K pathway.Yonsei Med. J., 2008; 49: 592-600
  Google Scholar
• 53. Rauh A., Windischhofer W., Kovacevic A., DeVaney T., Huber E.,Semlitsch M., Leis H.J., Sattler W., Malle E.: Endothelin (ET)-1 andET-3 promote expression of c-fos and c-jun in human choriocarcinomavia ETB receptor-mediated Gi- and Gq-pathways and MAP kinaseactivation. Br. J. Pharmacol., 2008; 154: 13-24
  Google Scholar
• 54. Ribatti D., Conconi M.T., Nussdorfer G.G.: Nonclassic endogenousnovel regulators of angiogenesis. Pharmacol. Rev., 2007; 59: 185-205
  Google Scholar
• 55. Rosano L., Di Castro V., Spinella F., Tortora G., Nicotra M.R., NataliP.G., Bagnato A.: Combined targeting of endothelin A receptor andepidermal growth factor receptor in ovarian cancer shows enhancedantitumor activity. Cancer Res., 2007; 67: 6351-6359
  Google Scholar
• 56. Rozengurt E.: Mitogenic signaling pathways induced by G protein-coupledreceptors. J. Cell Physiol., 2007; 213: 589-602
  Google Scholar
• 57. Sacewicz I., Wiktorska M., Wysocki T., Niewiarowska J.: Mechanizmyangiogenezy nowotworowej. Postępy Hig. Med. Dośw.,2009; 63: 159-168
  Google Scholar
• 58. Saida K., Gao X., Matsui M., Mitsui Y.: Vasoactive intestinal contractor(VIC)/mouse ET-2 and VIC receptor: biological activity, geneexpression, and specific receptor. Nihon Rinsho, 1996; 54: 1115-1121
  Google Scholar
• 59. Salani D., Di Castro V., Nicotra M.R., Rosano L., Tecce R., VenutiA., Natali P.G., Bagnato A.: Role of endothelin-1 in neovascularizationof ovarian carcinoma. Am. J. Pathol., 2000; 157: 1537-1547
  Google Scholar
• 60. Secchi M.E., Sulli A., Pizzorni C., Cutolo M.: Endothelin-1 in systemicsclerosis. Reumatismo, 2007; 59: 129-134
  Google Scholar
• 61. Shahbazian A., Holzer P.: Regulation of guinea pig intestinalperistalsis by endogenous endothelin acting at ETB receptors. Gastroenterology,2000; 119: 80-88
  Google Scholar
• 62. Shan Y., Yu L., Li Y., Pan Y., Zhang Q., Wang F., Chen J., Zhu X.:Nudel and FAK as antagonizing strength modulators of nascent adhesionsthrough paxillin. PLoS Biol., 2009; 7: e1000116
  Google Scholar
• 63. Shephard P., Hinz B., Smola-Hess S., Meister J.J., Krieg T., SmolaH.: Dissecting the roles of endothelin, TGF-β and GM-CSF on myofibroblastdifferentiation by keratinocytes. Thromb. Haemost., 2004;92: 262-274
  Google Scholar
• 64. Shi-Wen X., Denton C.P., Dashwood M.R., Holmes A.M., Bou-GhariosG., Pearson J.D., Black C.M., Abraham D.J.: Fibroblast matrix geneexpression and connective tissue remodeling: role of endothelin-1.J. Invest. Dermatol., 2001; 116: 417-425
  Google Scholar
• 65. Spinella F., Rosano L., Di Castro V., Decandia S., Nicotra M.R.,Natali P.G., Bagnato A.: Endothelin-1 and endothelin-3 promote invasivebehavior via hypoxia-inducible factor-1α in human melanomacells. Cancer Res., 2007; 67: 1725-1734
  Google Scholar
• 66. Spinella F., Rosanò L., Di Castro V., Natali P.G., Bagnato A.: Endothelin-1induces vascular endothelial growth factor by increasinghypoxia-inducible factor-1α in ovarian carcinoma cells. J. Biol.Chem., 2002; 277: 27850-27855
  Google Scholar
• 67. Spinella F., Rosanò L., Di Castro V., Nicotra M.R., Natali P.G., BagnatoA.: Endothelin 1 decreases gap junctional intercellular communicationby inducing phosphorylation of connexin 43 in humanovarian carcinoma cells. J. Biol. Chem., 2003; 278: 41294-41301
  Google Scholar
• 68. Sticherling M.: The role of endothelin in connective tissue diseases.Rheumatology, 2006; 45 Suppl. 3: 8-10. Erratum in: Rheumatology,2008; 47: 234-235
  Google Scholar
• 69. Swigris J.J., Brown K.K.: The role of endothelin-1 in the pathogenesisof idiopathic pulmonary fibrosis. BioDrugs, 2010; 24: 49-54
  Google Scholar
• 70. Śliwowska I., Kopczyński Z.: Metaloproteinazy macierzy zewną-trzkomórkowej – charakterystyka biochemiczna i kliniczna wartośćoznaczania u chorych na raka piersi. Współ. Onkol., 2005; 9: 327-335
  Google Scholar
• 71. Takuwa N., Takuwa Y., Yanagisawa M., Yamashita K., Masaki T.:A novel vasoactive peptide endothelin stimulates mitogenesis throughinositol lipid turnover in Swiss 3T3 fibroblasts. J. Biol. Chem.,1989; 264: 7856-7861
  Google Scholar
• 72. Uchide T., Fujimori Y., Sasaki T., Temma K., Adur J., Masuo Y.,Kozakai T., Lee Y.S., Saida K.: Expression of endothelin-1 and vasoactiveintestinal contractor genes in mouse organs during the perinatalperiod. Clin. Sci., 2002; 103: 167-170
  Google Scholar
• 73. Valdenaire O., Barret A., Schweizer A., Rohrbacher E., Mongiat F.,Pinet F., Corvol P., Tougard C.: Two di-leucine-based motifs accountfor the different subcellular localizations of the human endothelin–converting enzyme (ECE-1) isoforms. J. Cell Sci., 1999; 112: 3115-3125
  Google Scholar
• 74. Van Harmelen V., Eriksson A., Aström G., Wahlén K., Näslund E.,Karpe F., Frayn K., Olsson T., Andersson J., Rydén M., Arner P.: Vascularpeptide endothelin-1 links fat accumulation with alterations ofvisceral adipocyte lipolysis. Diabetes, 2008; 57: 378-386
  Google Scholar
• 75. Wanecek M., Weitzberg E., Rudehill A., Oldner A.: The endothelinsystem in septic and endotoxin shock. Eur. J. Pharmacol.,2000; 407: 1-15
  Google Scholar
• 76. Wenger R.H.: Mammalian oxygen sensing, signalling and generegulation. J. Exp. Biol., 2000; 203: 1253-1263
  Google Scholar
• 77. Wiesmann F., Veeck J., Galm O., Hartmann A., Esteller M.,Knüchel R., Dahl E.: Frequent loss of endothelin-3 (EDN3) expressiondue to epigenetic inactivation in human breast cancer. BreastCancer Res., 2009; 11: R34
  Google Scholar
• 78. Witz I.P.: The tumor microenvironment: the making of a paradigm.Cancer Microenviron., 2009; 2: 9-17
  Google Scholar
• 79. Wnuczko K., Szczepański M.: Śródbłonek – charakterystykai funkcje. Pol. Merkur. Lek., 2007; 23: 60-65
  Google Scholar

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