Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy.
Angiogenesis Inhibitors
/ pharmacology
Animals
Apelin
/ antagonists & inhibitors
Apelin Receptors
/ antagonists & inhibitors
Cell Line, Tumor
Cell Movement
/ drug effects
Drug Resistance, Neoplasm
Endothelial Cells
/ drug effects
Female
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
/ drug therapy
Mammary Neoplasms, Experimental
/ drug therapy
Mice
Mice, Inbred C57BL
Mice, Knockout
Mouse Embryonic Stem Cells
/ drug effects
Neoplasm Metastasis
Neovascularization, Pathologic
Protein Kinase Inhibitors
/ pharmacology
Signal Transduction
Sunitinib
/ pharmacology
Tumor Burden
/ drug effects
Tumor Microenvironment
Apelin-Apelin receptor
VEGF-VEGFR
anti-angiogenic therapy
therapy-induced resistance
tumor angiogenesis
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
25
04
2018
revised:
22
05
2019
accepted:
28
05
2019
pubmed:
4
7
2019
medline:
6
5
2020
entrez:
4
7
2019
Statut:
ppublish
Résumé
Angiogenesis is a hallmark of cancer, promoting growth and metastasis. Anti-angiogenic treatment has limited efficacy due to therapy-induced blood vessel alterations, often followed by local hypoxia, tumor adaptation, progression, and metastasis. It is therefore paramount to overcome therapy-induced resistance. We show that Apelin inhibition potently remodels the tumor microenvironment, reducing angiogenesis, and effectively blunting tumor growth. Functionally, targeting Apelin improves vessel function and reduces polymorphonuclear myeloid-derived suppressor cell infiltration. Importantly, in mammary and lung cancer, Apelin prevents resistance to anti-angiogenic receptor tyrosine kinase (RTK) inhibitor therapy, reducing growth and angiogenesis in lung and breast cancer models without increased hypoxia in the tumor microenvironment. Apelin blockage also prevents RTK inhibitor-induced metastases, and high Apelin levels correlate with poor prognosis of anti-angiogenic therapy patients. These data identify a druggable anti-angiogenic drug target that reduces tumor blood vessel densities and normalizes the tumor vasculature to decrease metastases.
Identifiants
pubmed: 31267692
doi: 10.15252/emmm.201809266
pmc: PMC6685079
doi:
Substances chimiques
Angiogenesis Inhibitors
0
Apelin
0
Apelin Receptors
0
Apln protein, mouse
0
Aplnr protein, mouse
0
Protein Kinase Inhibitors
0
Sunitinib
V99T50803M
Banques de données
GEO
['GSE100293']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e9266Subventions
Organisme : EMBO Long-term Fellowship
Pays : International
Organisme : Era of Hope Innovator award
Pays : International
Organisme : Marie Curie Fellowship
Pays : International
Organisme : Hungarian National Research, Development and Innovation Office
ID : PD111656
Pays : International
Organisme : Hungarian National Research, Development and Innovation Office
ID : K109626
Pays : International
Organisme : Hungarian National Research, Development and Innovation Office
ID : KNN121510
Pays : International
Organisme : Janos Bolyai Research Scholarship
Pays : International
Organisme : IMBA
Pays : International
Organisme : Austrian Ministry of Sciences
Pays : International
Organisme : Austrian Academy of Sciences
Pays : International
Organisme : ERC Advanced Grant
Pays : International
Organisme : T. von Zastrow Foundation
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
Références
J Mol Histol. 2008 Feb;39(1):121-4
pubmed: 17823846
Cell Stem Cell. 2011 Dec 2;9(6):563-74
pubmed: 22136931
Endocrinology. 2005 Jan;146(1):231-6
pubmed: 15486224
Lancet. 2016 Jul 30;388(10043):518-29
pubmed: 26853587
Cancer Cell. 2012 Aug 14;22(2):263-77
pubmed: 22897855
J Clin Pathol. 2004 Jul;57(7):675-81
pubmed: 15220356
Cancer Cell. 2017 Jan 9;31(1):157-158
pubmed: 28073001
Anticancer Res. 2005 Nov-Dec;25(6B):3905-15
pubmed: 16312045
Nat Cell Biol. 2010 Oct;12(10):943-53
pubmed: 20871601
Cancer Res. 2005 Nov 15;65(22):10280-8
pubmed: 16288016
J Biochem. 2012 Aug;152(2):125-31
pubmed: 22745157
J Clin Invest. 2015 Sep;125(9):3356-64
pubmed: 26168215
Mech Dev. 2002 Jan;110(1-2):183-6
pubmed: 11744380
Nat Protoc. 2014 Jan;9(1):171-81
pubmed: 24385147
Nat Cell Biol. 2011 Oct 23;13(12):1443-9
pubmed: 22020439
Cancer Cell. 2009 Mar 3;15(3):232-9
pubmed: 19249681
EMBO Mol Med. 2019 Aug;11(8):e9266
pubmed: 31267692
Cell. 2011 Sep 16;146(6):873-87
pubmed: 21925313
Cancer Lett. 1992 Jul 10;64(3):203-9
pubmed: 1322235
Nat Rev Drug Discov. 2011 Jun;10(6):417-27
pubmed: 21629292
Oncogene. 2000 Feb 21;19(8):968-88
pubmed: 10713680
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
J Pathol. 2012 Aug;227(4):417-30
pubmed: 22611036
Blood. 2010 Nov 11;116(19):4025-33
pubmed: 20705756
Sci Transl Med. 2017 Apr 12;9(385):
pubmed: 28404866
Oncologist. 2007 Jan;12(1):107-13
pubmed: 17227905
BMC Med Genomics. 2009 Apr 24;2:18
pubmed: 19393097
Nature. 1998 Jul 16;394(6690):287-91
pubmed: 9685160
Cell. 1988 Jul 1;54(1):105-15
pubmed: 2898299
Oncotarget. 2017 Jun 27;8(26):42949-42961
pubmed: 28487489
Cancer Res. 2019 May 1;79(9):2298-2313
pubmed: 30718358
Cancer Cell. 2010 Aug 9;18(2):171-84
pubmed: 20708158
Toxicol Pathol. 2012 Aug;40(6 Suppl):7S-39S
pubmed: 22949413
Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2182-7
pubmed: 20705920
Front Immunol. 2018 May 03;9:978
pubmed: 29774034
Nat Med. 2001 Sep;7(9):987-9
pubmed: 11533692
PLoS One. 2013 Dec 18;8(12):e82241
pubmed: 24367507
Biochemistry. 2003 Sep 2;42(34):10163-8
pubmed: 12939143
EMBO Mol Med. 2015 Dec 14;8(1):39-57
pubmed: 26666269
Science. 2005 Jan 7;307(5706):58-62
pubmed: 15637262
Cancer Cell. 2014 Nov 10;26(5):605-22
pubmed: 25517747
Nat Rev Cancer. 2008 Aug;8(8):592-603
pubmed: 18650835
Biochem Biophys Res Commun. 2004 Dec 10;325(2):395-400
pubmed: 15530405
Nat Rev Gastroenterol Hepatol. 2012 Feb 07;9(4):199-208
pubmed: 22310917
Nature. 2011 May 19;473(7347):298-307
pubmed: 21593862
Nat Protoc. 2009;4(7):1064-72
pubmed: 19561589
Cancer Cell. 2009 Mar 3;15(3):220-31
pubmed: 19249680
Brain. 2017 Nov 1;140(11):2939-2954
pubmed: 29053791
Breast Cancer Res Treat. 2010 Oct;123(3):725-31
pubmed: 20020197
Gynecol Oncol. 1998 Nov;71(2):270-7
pubmed: 9826471
Sci Transl Med. 2011 Dec 21;3(114):114rv3
pubmed: 22190240
Nature. 2017 Oct 5;550(7674):114-118
pubmed: 28953874
J Thorac Oncol. 2010 Aug;5(8):1120-9
pubmed: 20581707
Cancer Immunol Res. 2017 Jan;5(1):3-8
pubmed: 28052991
Science. 2014 Feb 14;343(6172):1248636
pubmed: 24407481
Cell. 2015 Jan 29;160(3):393-406
pubmed: 25601461
Cancer Cell. 2005 Oct;8(4):299-309
pubmed: 16226705
Science. 2015 Aug 14;349(6249):694-5
pubmed: 26273044
Oral Oncol. 2012 Jun;48(6):500-6
pubmed: 22285858
Oncotarget. 2016 Jun 21;7(25):37931-37943
pubmed: 27177328
AJNR Am J Neuroradiol. 2006 Apr;27(4):859-67
pubmed: 16611779
Cancer Cell. 2007 Jun;11(6):539-54
pubmed: 17560335
J Neurochem. 2003 Mar;84(5):1162-72
pubmed: 12603839
Annu Rev Med. 2015;66:97-110
pubmed: 25341012
Dev Biol. 2006 Aug 1;296(1):177-89
pubmed: 16750822
Cancer Cell. 2014 Aug 11;26(2):190-206
pubmed: 25117709
Nat Commun. 2015 Jan 19;6:6020
pubmed: 25597280
Sci Transl Med. 2017 Apr 12;9(385):
pubmed: 28404865
ChemMedChem. 2011 Jun 6;6(6):1017-23
pubmed: 21560248
EMBO J. 2008 Feb 6;27(3):522-34
pubmed: 18200044
Mol Cancer Ther. 2010 Jan;9(1):145-56
pubmed: 20053776
Cancer Res. 2001 Dec 15;61(24):8924-9
pubmed: 11751418
Genes Dev. 2001 Dec 15;15(24):3243-8
pubmed: 11751630
Clin Cancer Res. 2013 Dec 15;19(24):6730-40
pubmed: 24097868
Cell. 2009 Mar 6;136(5):839-851
pubmed: 19217150
Onco Targets Ther. 2014 May 12;7:719-28
pubmed: 24872713
Biochem Biophys Res Commun. 1998 Oct 20;251(2):471-6
pubmed: 9792798
Circ Res. 2007 Aug 17;101(4):e32-42
pubmed: 17673668
Oncogene. 2007 Dec 6;26(55):7692-9
pubmed: 17563744
Dev Biol. 2007 May 15;305(2):599-614
pubmed: 17412318
Cell Rep. 2014 Aug 7;8(3):696-706
pubmed: 25088418