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. 1995 Oct;96(4):2017–2025. doi: 10.1172/JCI118249

Expression and localization of endothelin-1 and endothelin receptors in human meningiomas. Evidence for a role in tumoral growth.

U Pagotto 1, T Arzberger 1, U Hopfner 1, J Sauer 1, U Renner 1, C J Newton 1, M Lange 1, E Uhl 1, A Weindl 1, G K Stalla 1
PMCID: PMC185840  PMID: 7560095

Abstract

In addition to its well-known homoeostatic actions in the cardiovascular system, ET-1 has been shown to constitute a potent growth regulatory peptide in various tissues. We have studied the expression of ET-1 and its receptors (ET-Ar and ET-Br) in human meningiomas (n = 35) as well as their involvement in cellular growth. By PCR of reverse-transcribed RNA we detected ET-1 mRNA in 91% (32 of 35), ET-Ar mRNA in 82% (29 of 35), and ET-Br mRNA in 42% (15 of 35) of human meningiomas examined. The localization of ET-1 mRNA, ET-Ar mRNA, and ET-1 peptide in tumoral cells was observed by in situ hybridization and immunohistochemistry, whereas ET-Br mRNA was expressed at low level only in cells belonging to blood vessels. In addition, we found that ET-1 stimulated [3H] thymidine incorporation in primary cell cultures of 20 meningiomas and that this effect could be blocked by BQ-123, a specific antagonist for ET-Ar. In contrast, RES-701-3, an antagonist of ET-Br, did not block the proliferative effect of ET-1. In conclusion, our data provide evidence that ET-1 constitutes an important growth factor for meningiomas acting via ET-Ar. We can hypothesize that ET-1, acting in concert with other growth factors and cytokines, is involved in the meningioma tumorigenesis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antoniades H. N., Galanopoulos T., Neville-Golden J., Maxwell M. Expression of insulin-like growth factors I and II and their receptor mRNAs in primary human astrocytomas and meningiomas; in vivo studies using in situ hybridization and immunocytochemistry. Int J Cancer. 1992 Jan 21;50(2):215–222. doi: 10.1002/ijc.2910500210. [DOI] [PubMed] [Google Scholar]
  2. Battistini B., Chailler P., D'Orléans-Juste P., Brière N., Sirois P. Growth regulatory properties of endothelins. Peptides. 1993 Mar-Apr;14(2):385–399. doi: 10.1016/0196-9781(93)90057-n. [DOI] [PubMed] [Google Scholar]
  3. Bloch K. D., Friedrich S. P., Lee M. E., Eddy R. L., Shows T. B., Quertermous T. Structural organization and chromosomal assignment of the gene encoding endothelin. J Biol Chem. 1989 Jun 25;264(18):10851–10857. [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Cross M., Dexter T. M. Growth factors in development, transformation, and tumorigenesis. Cell. 1991 Jan 25;64(2):271–280. doi: 10.1016/0092-8674(91)90638-f. [DOI] [PubMed] [Google Scholar]
  6. Davenport A. P., O'Reilly G., Molenaar P., Maguire J. J., Kuc R. E., Sharkey A., Bacon C. R., Ferro A. Human endothelin receptors characterized using reverse transcriptase-polymerase chain reaction, in situ hybridization, and subtype-selective ligands BQ123 and BQ3020: evidence for expression of ETB receptors in human vascular smooth muscle. J Cardiovasc Pharmacol. 1993;22 (Suppl 8):S22–S25. doi: 10.1097/00005344-199322008-00008. [DOI] [PubMed] [Google Scholar]
  7. Economos K., MacDonald P. C., Casey M. L. Endothelin-1 gene expression and biosynthesis in human endometrial HEC-1A cancer cells. Cancer Res. 1992 Feb 1;52(3):554–557. [PubMed] [Google Scholar]
  8. Ehrenreich H., Kehrl J. H., Anderson R. W., Rieckmann P., Vitkovic L., Coligan J. E., Fauci A. S. A vasoactive peptide, endothelin-3, is produced by and specifically binds to primary astrocytes. Brain Res. 1991 Jan 4;538(1):54–58. doi: 10.1016/0006-8993(91)90375-6. [DOI] [PubMed] [Google Scholar]
  9. Ekstrand A. J., James C. D., Cavenee W. K., Seliger B., Pettersson R. F., Collins V. P. Genes for epidermal growth factor receptor, transforming growth factor alpha, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 1991 Apr 15;51(8):2164–2172. [PubMed] [Google Scholar]
  10. Giaid A., Hamid Q. A., Springall D. R., Yanagisawa M., Shinmi O., Sawamura T., Masaki T., Kimura S., Corrin B., Polak J. M. Detection of endothelin immunoreactivity and mRNA in pulmonary tumours. J Pathol. 1990 Sep;162(1):15–22. doi: 10.1002/path.1711620105. [DOI] [PubMed] [Google Scholar]
  11. Hosoda K., Nakao K., Hiroshi-Arai, Suga S., Ogawa Y., Mukoyama M., Shirakami G., Saito Y., Nakanishi S., Imura H. Cloning and expression of human endothelin-1 receptor cDNA. FEBS Lett. 1991 Aug 5;287(1-2):23–26. doi: 10.1016/0014-5793(91)80007-p. [DOI] [PubMed] [Google Scholar]
  12. Ihara M., Noguchi K., Saeki T., Fukuroda T., Tsuchida S., Kimura S., Fukami T., Ishikawa K., Nishikibe M., Yano M. Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci. 1992;50(4):247–255. doi: 10.1016/0024-3205(92)90331-i. [DOI] [PubMed] [Google Scholar]
  13. Inoue A., Yanagisawa M., Kimura S., Kasuya Y., Miyauchi T., Goto K., Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2863–2867. doi: 10.1073/pnas.86.8.2863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Ishibashi M., Fujita M., Nagai K., Kako M., Furue H., Haku E., Osamura Y., Yamaji T. Production and secretion of endothelin by hepatocellular carcinoma. J Clin Endocrinol Metab. 1993 Feb;76(2):378–383. doi: 10.1210/jcem.76.2.7679399. [DOI] [PubMed] [Google Scholar]
  15. Johnson M. D., Federspiel C. F., Gold L. I., Moses H. L. Transforming growth factor-beta and transforming growth factor beta-receptor expression in human meningioma cells. Am J Pathol. 1992 Sep;141(3):633–642. [PMC free article] [PubMed] [Google Scholar]
  16. Komuro I., Kurihara H., Sugiyama T., Yoshizumi M., Takaku F., Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett. 1988 Oct 10;238(2):249–252. doi: 10.1016/0014-5793(88)80489-7. [DOI] [PubMed] [Google Scholar]
  17. Kurihara M., Ochi A., Kawaguchi T., Niwa M., Kataoka Y., Mori K. Localization and characterization of endothelin receptors in human gliomas: a growth factor? Neurosurgery. 1990 Aug;27(2):275–281. doi: 10.1097/00006123-199008000-00017. [DOI] [PubMed] [Google Scholar]
  18. Kurihara Y., Kurihara H., Suzuki H., Kodama T., Maemura K., Nagai R., Oda H., Kuwaki T., Cao W. H., Kamada N. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature. 1994 Apr 21;368(6473):703–710. doi: 10.1038/368703a0. [DOI] [PubMed] [Google Scholar]
  19. Kusuhara M., Yamaguchi K., Nagasaki K., Hayashi C., Suzaki A., Hori S., Handa S., Nakamura Y., Abe K. Production of endothelin in human cancer cell lines. Cancer Res. 1990 Jun 1;50(11):3257–3261. [PubMed] [Google Scholar]
  20. Ladenheim R. G., Lacroix I., Foignant-Chaverot N., Strosberg A. D., Couraud P. O. Endothelins stimulate c-fos and nerve growth factor expression in astrocytes and astrocytoma. J Neurochem. 1993 Jan;60(1):260–266. doi: 10.1111/j.1471-4159.1993.tb05846.x. [DOI] [PubMed] [Google Scholar]
  21. Lange M., Pagotto U., Hopfner U., Ehrenreich H., Oeckler R., Sinowatz F., Stalla G. K. Endothelin expression in normal human anterior pituitaries and pituitary adenomas. J Clin Endocrinol Metab. 1994 Dec;79(6):1864–1870. doi: 10.1210/jcem.79.6.7527415. [DOI] [PubMed] [Google Scholar]
  22. Lee M. E., de la Monte S. M., Ng S. C., Bloch K. D., Quertermous T. Expression of the potent vasoconstrictor endothelin in the human central nervous system. J Clin Invest. 1990 Jul;86(1):141–147. doi: 10.1172/JCI114677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. MacCumber M. W., Ross C. A., Glaser B. M., Snyder S. H. Endothelin: visualization of mRNAs by in situ hybridization provides evidence for local action. Proc Natl Acad Sci U S A. 1989 Sep;86(18):7285–7289. doi: 10.1073/pnas.86.18.7285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. MacCumber M. W., Ross C. A., Snyder S. H. Endothelin in brain: receptors, mitogenesis, and biosynthesis in glial cells. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2359–2363. doi: 10.1073/pnas.87.6.2359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Maiuri F., Montagnani S., Gallicchio B., Carandente M., Lanza G. G., D'Andrea F. Oestrogen and progesterone sensitivity in cultured meningioma cells. Neurol Res. 1989 Mar;11(1):9–13. doi: 10.1080/01616412.1989.11739853. [DOI] [PubMed] [Google Scholar]
  26. Maxwell M., Naber S. P., Wolfe H. J., Galanopoulos T., Hedley-Whyte E. T., Black P. M., Antoniades H. N. Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance. J Clin Invest. 1990 Jul;86(1):131–140. doi: 10.1172/JCI114675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Maxwell M., Naber S. P., Wolfe H. J., Hedley-Whyte E. T., Galanopoulos T., Neville-Golden J., Antoniades H. N. Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression. Cancer Res. 1991 Feb 15;51(4):1345–1351. [PubMed] [Google Scholar]
  28. Ogawa Y., Nakao K., Arai H., Nakagawa O., Hosoda K., Suga S., Nakanishi S., Imura H. Molecular cloning of a non-isopeptide-selective human endothelin receptor. Biochem Biophys Res Commun. 1991 Jul 15;178(1):248–255. doi: 10.1016/0006-291x(91)91806-n. [DOI] [PubMed] [Google Scholar]
  29. Pribnow D., Muldoon L. L., Fajardo M., Theodor L., Chen L. Y., Magun B. E. Endothelin induces transcription of fos/jun family genes: a prominent role for calcium ion. Mol Endocrinol. 1992 Jul;6(7):1003–1012. doi: 10.1210/mend.6.7.1508217. [DOI] [PubMed] [Google Scholar]
  30. Renner U., Mojto J., Arzt E., Lange M., Stalla J., Müller O. A., Stalla G. K. Secretion of polypeptide growth factors by human nonfunctioning pituitary adenoma cells in culture. Neuroendocrinology. 1993 May;57(5):825–834. doi: 10.1159/000126441. [DOI] [PubMed] [Google Scholar]
  31. Rubanyi G. M., Polokoff M. A. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev. 1994 Sep;46(3):325–415. [PubMed] [Google Scholar]
  32. Shichiri M., Hirata Y., Nakajima T., Ando K., Imai T., Yanagisawa M., Masaki T., Marumo F. Endothelin-1 is an autocrine/paracrine growth factor for human cancer cell lines. J Clin Invest. 1991 May;87(5):1867–1871. doi: 10.1172/JCI115210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Shyamala V., Moulthrop T. H., Stratton-Thomas J., Tekamp-Olson P. Two distinct human endothelin B receptors generated by alternative splicing from a single gene. Cell Mol Biol Res. 1994;40(4):285–296. [PubMed] [Google Scholar]
  34. Sporn M. B., Roberts A. B. Autocrine growth factors and cancer. 1985 Feb 28-Mar 6Nature. 313(6005):745–747. doi: 10.1038/313745a0. [DOI] [PubMed] [Google Scholar]
  35. Stalla G. K., Stalla J., Huber M., Loeffler J. P., Höllt V., von Werder K., Müller O. A. Ketoconazole inhibits corticotropic cell function in vitro. Endocrinology. 1988 Feb;122(2):618–623. doi: 10.1210/endo-122-2-618. [DOI] [PubMed] [Google Scholar]
  36. Takahashi J. A., Mori H., Fukumoto M., Igarashi K., Jaye M., Oda Y., Kikuchi H., Hatanaka M. Gene expression of fibroblast growth factors in human gliomas and meningiomas: demonstration of cellular source of basic fibroblast growth factor mRNA and peptide in tumor tissues. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5710–5714. doi: 10.1073/pnas.87.15.5710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Takahashi K., Satoh F., Murakami O., Totsune K., Sone M., Itoi K., Ohneda M., Mouri T. Endothelin in ectopic ACTH-secreting bronchial carcinoid tumors. J Cardiovasc Pharmacol. 1993;22 (Suppl 8):S288–S290. doi: 10.1097/00005344-199322008-00075. [DOI] [PubMed] [Google Scholar]
  38. Tanaka T., Tsukuda E., Nozawa M., Nonaka H., Ohno T., Kase H., Yamada K., Matsuda Y. RES-701-1, a novel, potent, endothelin type B receptor-selective antagonist of microbial origin. Mol Pharmacol. 1994 Apr;45(4):724–730. [PubMed] [Google Scholar]
  39. Tilemans D., Andries M., Denef C. Luteinizing hormone-releasing hormone and neuropeptide Y influence deoxyribonucleic acid replication in three anterior pituitary cell types. Evidence for mediation by growth factors released from gonadotrophs. Endocrinology. 1992 Feb;130(2):882–894. doi: 10.1210/endo.130.2.1310281. [DOI] [PubMed] [Google Scholar]
  40. Todo T., Adams E. F., Rafferty B., Fahlbusch R., Dingermann T., Werner H. Secretion of interleukin-6 by human meningioma cells: possible autocrine inhibitory regulation of neoplastic cell growth. J Neurosurg. 1994 Sep;81(3):394–401. doi: 10.3171/jns.1994.81.3.0394. [DOI] [PubMed] [Google Scholar]
  41. Vigne P., Marsault R., Breittmayer J. P., Frelin C. Endothelin stimulates phosphatidylinositol hydrolysis and DNA synthesis in brain capillary endothelial cells. Biochem J. 1990 Mar 1;266(2):415–420. doi: 10.1042/bj2660415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Weisman A. S., Raguet S. S., Kelly P. A. Characterization of the epidermal growth factor receptor in human meningioma. Cancer Res. 1987 Apr 15;47(8):2172–2176. [PubMed] [Google Scholar]
  43. Yanagisawa M., Kurihara H., Kimura S., Tomobe Y., Kobayashi M., Mitsui Y., Yazaki Y., Goto K., Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988 Mar 31;332(6163):411–415. doi: 10.1038/332411a0. [DOI] [PubMed] [Google Scholar]
  44. Zava D. T., Markwalder T. M., Markwalder R. V. Biological expression of steroid hormone receptors in primary meningioma cells in monolayer culture. Clin Neuropharmacol. 1984;7(4):382–388. doi: 10.1097/00002826-198412000-00019. [DOI] [PubMed] [Google Scholar]

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