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PMID: 22013079 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Autocrine endothelin-3/endothelin receptor B signaling maintains cellular and molecular properties of glioblastoma stem cells.

Molecular cancer research : MCR ·Vol. 9 ·No. 12 ·2011-12-00 ·Pages 1668-85

Liu Y, Ye F, Yamada K, Tso JL, Zhang Y, Nguyen DH, Dong Q, Soto H, Choe J, Dembo A, Wheeler H, Eskin A, Schmid I, Yong WH, Mischel PS, Cloughesy TF, Kornblum HI, Nelson SF, Liau LM, Tso CL

Abstract

Glioblastoma stem cells (GSC) express both radial glial cell and neural crest cell (NCC)-associated genes. We report that endothelin 3 (EDN3), an essential mitogen for NCC development and migration, is highly produced by GSCs. Serum-induced proliferative differentiation rapidly decreased EDN3 production and downregulated the expression of stemness-associated genes, and reciprocally, two glioblastoma markers, EDN1 and YKL-40 transcripts, were induced. Correspondingly, patient glioblastoma tissues express low levels of EDN3 mRNA and high levels of EDN1 and YKL-40 mRNA. Blocking EDN3/EDN receptor B (EDNRB) signaling by an EDNRB antagonist (BQ788), or EDN3 RNA interference (siRNA), leads to cell apoptosis and functional impairment of tumor sphere formation and cell spreading/migration in culture and loss of tumorigenic capacity in animals. Using exogenous EDN3 as the sole mitogen in culture does not support GSC propagation, but it can rescue GSCs from undergoing cell apoptosis. Molecular analysis by gene expression profiling revealed that most genes downregulated by EDN3/EDNRB blockade were those involved in cytoskeleton organization, pause of growth and differentiation, and DNA damage response, implicating the involvement of EDN3/EDNRB signaling in maintaining GSC migration, undifferentiation, and survival. These data suggest that autocrine EDN3/EDNRB signaling is essential for maintaining GSCs. Incorporating END3/EDNRB-targeted therapies into conventional cancer treatments may have clinical implication for the prevention of tumor recurrence.

MeSH Terms
Animals Apoptosis Autocrine Communication/genetics Brain Neoplasms/genetics,metabolism Cell Differentiation Cell Movement Cell Transformation, Neoplastic Endothelin-3/genetics,metabolism Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Gene Regulatory Networks Genome, Human Glioblastoma/genetics,metabolism Humans Mice Mice, SCID Neoplastic Stem Cells Neural Crest/cytology,growth & development,metabolism RNA, Small Interfering Receptor, Endothelin B/genetics,metabolism
Chemicals
Endothelin-3 RNA, Small Interfering Receptor, Endothelin B
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Liu Yue
Department of Surgery/Surgical Oncology, University of California Los Angeles, Los Angeles, California 90095, USA.
Ye Fei
Yamada Kazunari
Tso Jonathan L
Zhang Yibei
Nguyen David H
Dong Qinghua
Soto Horacio
Choe Jinny
Dembo Anna
Wheeler Hayley
Eskin Ascia
Schmid Ingrid
Yong William H
Mischel Paul S
Cloughesy Timothy F
Kornblum Harley I
Nelson Stanley F
Liau Linda M
Tso Cho-Lea
References (50)
50 references, click to expand
  1. SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult.
    Dev Neurosci. 2004 Mar-Aug;26(2-4):148-65 PMID: 15711057
  2. Molecular properties of CD133+ glioblastoma stem cells derived from treatment-refractory recurrent brain tumors.
    J Neurooncol. 2009 Aug;94(1):1-19 PMID: 19468690
  3. Endothelin 3 selectively promotes survival and proliferation of neural crest-derived glial and melanocytic precursors in vitro.
    Proc Natl Acad Sci U S A. 1998 Nov 24;95(24):14214-9 PMID: 9826680
  4. Endothelin B receptor antagonists block proliferation and induce apoptosis in glioma cells.
    Pharmacol Res. 2010 Apr;61(4):306-15 PMID: 19931393
  5. Epistatic connections between microphthalmia-associated transcription factor and endothelin signaling in Waardenburg syndrome and other pigmentary disorders.
    FASEB J. 2008 Apr;22(4):1155-68 PMID: 18039926
  6. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts.
    Stem Cells. 2010 Jan;28(1):5-16 PMID: 19904829
  7. Expression of endothelin 3 by mesenchymal cells of embryonic mouse caecum.
    Gut. 1999 Feb;44(2):246-52 PMID: 9895385
  8. The neural crest population responding to endothelin-3 in vitro includes multipotent cells.
    J Cell Sci. 1997 Jul;110 ( Pt 14):1673-82 PMID: 9247201
  9. YKL-40 expression is associated with poorer response to radiation and shorter overall survival in glioblastoma.
    Clin Cancer Res. 2005 May 1;11(9):3326-34 PMID: 15867231
  10. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma.
    Cancer Res. 2004 Oct 1;64(19):7011-21 PMID: 15466194
  11. Inhibition of in vitro enteric neuronal development by endothelin-3: mediation by endothelin B receptors.
    Development. 1999 Mar;126(6):1161-73 PMID: 10021336
  12. Endothelins.
    N Engl J Med. 1995 Aug 10;333(6):356-63 PMID: 7609754
  13. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.
    Nature. 2006 Dec 7;444(7120):756-60 PMID: 17051156
  14. Endothelin B receptor blockade inhibits dynamics of cell interactions and communications in melanoma cell progression.
    Cancer Res. 2004 Feb 15;64(4):1436-43 PMID: 14973117
  15. Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria.
    Oncogene. 2008 May 1;27(20):2897-909 PMID: 18037961
  16. Maintenance of mammalian enteric nervous system progenitors by SOX10 and endothelin 3 signalling.
    Development. 2006 May;133(10):2075-86 PMID: 16624853
  17. Endothelin-3 regulates neural crest cell proliferation and differentiation in the hindgut enteric nervous system.
    Dev Biol. 2006 May 1;293(1):203-17 PMID: 16519884
  18. Ontogeny of endothelins-1 and -3, their receptors, and endothelin converting enzyme-1 in the early human embryo.
    J Clin Invest. 1998 Feb 1;101(3):549-59 PMID: 9449687
  19. Effects of TNF-alpha on hemodynamic changes and circulating endothelium-derived vasoactive factors in dogs.
    Am J Physiol. 1994 Oct;267(4 Pt 2):H1530-6 PMID: 7943398
  20. Direct isolation of human central nervous system stem cells.
    Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14720-5 PMID: 11121071
  21. Stimulation of endothelin B receptors in astrocytes induces cAMP response element-binding protein phosphorylation and c-fos expression via multiple mitogen-activated protein kinase signaling pathways.
    J Neurosci. 2001 Nov 15;21(22):8842-53 PMID: 11698596
  22. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines.
    Cancer Cell. 2006 May;9(5):391-403 PMID: 16697959
  23. The endothelin system in human glioblastoma.
    Lab Invest. 2000 Nov;80(11):1681-9 PMID: 11092528
  24. Pulmonary expression of preproET-1 and preproET-3 mRNAs is altered reciprocally in rats after inhalation of air pollutants.
    Exp Biol Med (Maywood). 2006 Jun;231(6):979-84 PMID: 16741034
  25. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology.
    Pharmacol Rev. 1994 Sep;46(3):325-415 PMID: 7831383
  26. Stem cell-related "self-renewal" signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma.
    J Clin Oncol. 2008 Jun 20;26(18):3015-24 PMID: 18565887
  27. SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity.
    Stem Cells. 2009 Jan;27(1):40-8 PMID: 18948646
  28. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome).
    Nat Genet. 1996 Apr;12(4):442-4 PMID: 8630502
  29. Cloning and functional expression of human endothelin-converting enzyme cDNA.
    Biochem Biophys Res Commun. 1995 Feb 15;207(2):807-12 PMID: 7864876
  30. Gi2 signaling enhances proliferation of neural progenitor cells in the developing brain.
    J Biol Chem. 2004 Sep 24;279(39):41141-8 PMID: 15272018
  31. Identification of human brain tumour initiating cells.
    Nature. 2004 Nov 18;432(7015):396-401 PMID: 15549107
  32. Endothelin receptor antagonism and cancer.
    Eur J Clin Invest. 2009 Jun;39 Suppl 2:74-7 PMID: 19335749
  33. Isolation of cancer stem cells from adult glioblastoma multiforme.
    Oncogene. 2004 Dec 16;23(58):9392-400 PMID: 15558011
  34. Identification of p90RSK as the probable CREB-Ser133 kinase in human melanocytes.
    Cell Growth Differ. 1995 Mar;6(3):291-302 PMID: 7540859
  35. CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles.
    Cancer Res. 2007 May 1;67(9):4010-5 PMID: 17483311
  36. Endothelin-3 stimulates survival of goblet cells in organotypic cultures of fetal human colonic epithelium.
    Am J Physiol Gastrointest Liver Physiol. 2008 Dec;295(6):G1182-9 PMID: 18832450
  37. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
    Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 PMID: 16199517
  38. EDNRB/EDN3 and Hirschsprung disease type II.
    Pigment Cell Res. 2001 Jun;14(3):161-9 PMID: 11434563
  39. Id4 regulates neural progenitor proliferation and differentiation in vivo.
    Development. 2004 Nov;131(21):5441-8 PMID: 15469968
  40. Enhanced expression of an endothelin ETA receptor in capillaries from human glioblastoma: a quantitative receptor autoradiographic analysis using a radioluminographic imaging plate system.
    J Neurochem. 1994 Dec;63(6):2240-7 PMID: 7964744
  41. Cancerous stem cells can arise from pediatric brain tumors.
    Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15178-83 PMID: 14645703
  42. Frequent loss of endothelin-3 (EDN3) expression due to epigenetic inactivation in human breast cancer.
    Breast Cancer Res. 2009;11(3):R34 PMID: 19527488
  43. Malignant glioma: genetics and biology of a grave matter.
    Genes Dev. 2001 Jun 1;15(11):1311-33 PMID: 11390353
  44. CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells.
    Int J Cancer. 2008 Feb 15;122(4):761-8 PMID: 17955491
  45. Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor.
    BMC Cancer. 2008 Nov 28;8:354 PMID: 19040731
  46. Endothelin-3 growth factor levels decreased in cervical cancer compared with normal cervical epithelial cells.
    Hum Pathol. 2007 Jul;38(7):1047-1056 PMID: 17445867
  47. The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells.
    Hum Mol Genet. 2001 Apr 15;10(9):903-10 PMID: 11309363
  48. The expression pattern of a novel gene encoding brain-fatty acid binding protein correlates with neuronal and glial cell development.
    Development. 1994 Sep;120(9):2637-49 PMID: 7956838
  49. Endothelins as autocrine regulators of tumor cell growth.
    Trends Endocrinol Metab. 1998 Nov;9(9):378-83 PMID: 18406309
  50. Failure to express GAP-43 leads to disruption of a multipotent precursor and inhibits astrocyte differentiation.
    Mol Cell Neurosci. 2004 Jul;26(3):390-405 PMID: 15234344
Article Info
Journal
Molecular cancer research : MCR
Abbr.
Mol Cancer Res
ISSN
1557-3125
DOI
10.1158/1541-7786.MCR-10-0563
Published
2011-12-00
Epub
2011-00-19
Pages
1668-85
Language
English
Region
United States
NLM ID
101150042
PMCID
PMC3245317
Subset
IM
Grants
NCI NIH HHS · 1 R21 CA140912-01 · United States
NCI NIH HHS · R21 CA140912-02 · United States
NINDS NIH HHS · R01 NS052563 · United States
NIH HHS · 1DP2OD006444-01 · United States
NCI NIH HHS · R21 CA140912-01 · United States
NCI NIH HHS · R21 CA140912 · United States
NIH HHS · DP2 OD006444-01 · United States
NIH HHS · DP2 OD006444 · United States
External Links
PubMed source DOI: 10.1158/1541-7786.MCR-10-0563 PMC Full Text View journal details
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