Hypoxia-induced inhibin promotes tumor growth and vascular permeability in ovarian cancers.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
02 06 2022
02 06 2022
Historique:
received:
15
10
2021
accepted:
17
05
2022
entrez:
2
6
2022
pubmed:
3
6
2022
medline:
7
6
2022
Statut:
epublish
Résumé
Hypoxia, a driver of tumor growth and metastasis, regulates angiogenic pathways that are targets for vessel normalization and ovarian cancer management. However, toxicities and resistance to anti-angiogenics can limit their use making identification of new targets vital. Inhibin, a heteromeric TGFβ ligand, is a contextual regulator of tumor progression acting as an early tumor suppressor, yet also an established biomarker for ovarian cancers. Here, we find that hypoxia increases inhibin levels in ovarian cancer cell lines, xenograft tumors, and patients. Inhibin is regulated primarily through HIF-1, shifting the balance under hypoxia from activins to inhibins. Hypoxia regulated inhibin promotes tumor growth, endothelial cell invasion and permeability. Targeting inhibin in vivo through knockdown and anti-inhibin strategies robustly reduces permeability in vivo and alters the balance of pro and anti-angiogenic mechanisms resulting in vascular normalization. Mechanistically, inhibin regulates permeability by increasing VE-cadherin internalization via ACVRL1 and CD105, a receptor complex that we find to be stabilized directly by inhibin. Our findings demonstrate direct roles for inhibins in vascular normalization via TGF-β receptors providing new insights into the therapeutic significance of inhibins as a strategy to normalize the tumor vasculature in ovarian cancer.
Identifiants
pubmed: 35654828
doi: 10.1038/s42003-022-03495-6
pii: 10.1038/s42003-022-03495-6
pmc: PMC9163327
doi:
Substances chimiques
Activins
104625-48-1
Inhibins
57285-09-3
ACVRL1 protein, human
EC 2.7.11.30
Activin Receptors, Type II
EC 2.7.11.30
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
536Subventions
Organisme : NCI NIH HHS
ID : R01 CA219495
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Cancers (Basel). 2019 Nov 02;11(11):
pubmed: 31684072
J Biol Chem. 2009 Mar 20;284(12):7843-52
pubmed: 19147499
Mol Biol Cell. 2015 Sep 1;26(17):3117-27
pubmed: 26157163
Exp Mol Med. 2012 Jan 31;44(1):1-9
pubmed: 22228176
J Am Coll Surg. 2004 Jun;198(6):999-1011
pubmed: 15194082
Cancer Res. 2007 Apr 1;67(7):3441-9
pubmed: 17409455
Vitam Horm. 2011;85:149-84
pubmed: 21353880
Mol Cancer Ther. 2021 Jan;20(1):85-95
pubmed: 33037137
J Biol Chem. 2012 Mar 9;287(11):8060-70
pubmed: 22267736
Endocrinology. 2004 Aug;145(8):3739-45
pubmed: 15117880
Cancer Lett. 2007 Apr 28;249(1):14-7
pubmed: 17320281
Crit Rev Biochem Mol Biol. 2014 Jan-Feb;49(1):1-15
pubmed: 24099156
Comput Methods Programs Biomed. 2009 Apr;94(1):58-65
pubmed: 18950895
J Biol Chem. 2004 May 7;279(19):19431-40
pubmed: 14982927
J Cell Mol Med. 2018 Jan;22(1):173-184
pubmed: 28834227
J Cell Sci. 2016 Jan 1;129(1):206-18
pubmed: 26598555
Br J Cancer. 2010 Jan 19;102(2):428-35
pubmed: 20087356
Elife. 2020 Jun 09;9:
pubmed: 32515349
Trends Mol Med. 2017 Sep;23(9):850-868
pubmed: 28811171
Cancer Lett. 2016 Oct 1;380(2):534-544
pubmed: 25449784
Mol Reprod Dev. 2014 Nov;81(11):1009-18
pubmed: 25358080
J Biol Chem. 2005 Jul 29;280(30):27800-8
pubmed: 15923183
Nat Rev Mol Cell Biol. 2004 Apr;5(4):261-70
pubmed: 15071551
PLoS One. 2014 Mar 05;9(3):e90575
pubmed: 24599287
Science. 2016 Apr 8;352(6282):175-80
pubmed: 27124451
Int J Mol Sci. 2021 Mar 28;22(7):
pubmed: 33800554
Cell Res. 2009 Jan;19(1):116-27
pubmed: 19114994
Mol Cancer Ther. 2010 Feb;9(2):379-88
pubmed: 20124460
Cancer Res. 2006 Aug 15;66(16):7983-90
pubmed: 16912173
Exp Hematol Oncol. 2020 Nov 24;9(1):32
pubmed: 33292604
Angiogenesis. 2017 Nov;20(4):409-426
pubmed: 28660302
Nat Protoc. 2014 Feb;9(2):457-63
pubmed: 24481272
Sci Rep. 2017 Aug 31;7(1):10121
pubmed: 28860539
Br J Cancer. 2009 Jun 2;100(11):1784-93
pubmed: 19436293
Hypoxia (Auckl). 2017 Apr 11;5:21-32
pubmed: 28443291
Methods Enzymol. 2008;443:137-53
pubmed: 18772015
Cancer Cell. 2014 Nov 10;26(5):605-22
pubmed: 25517747
Endocr Rev. 2014 Oct;35(5):747-94
pubmed: 25051334
PLoS One. 2014 Aug 11;9(8):e104944
pubmed: 25111790
Ann Oncol. 2016 Apr;27 Suppl 1:i33-i39
pubmed: 27141068
J Cell Biol. 1994 Jul;126(1):139-54
pubmed: 8027173
Cancer Res. 1991 May 15;51(10):2655-69
pubmed: 2021944
Sci Rep. 2017 Sep 6;7(1):10592
pubmed: 28878214
Histopathology. 1997 Jun;30(6):518-22
pubmed: 9205855
J Biol Chem. 2003 Jun 27;278(26):24200-8
pubmed: 12695522
Mol Cancer Ther. 2018 Oct;17(10):2248-2256
pubmed: 29997150
J Cell Mol Med. 2011 Jun;15(6):1239-53
pubmed: 21251211
Clin Endocrinol (Oxf). 1994 Jun;40(6):717-23
pubmed: 8033361
Acta Obstet Gynecol Scand. 2005 Mar;84(3):281-5
pubmed: 15715537
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
J Biol Chem. 2003 May 2;278(18):15911-6
pubmed: 12606543
Genes Cancer. 2011 Dec;2(12):1085-96
pubmed: 22866200
Cells. 2018 Dec 19;7(12):
pubmed: 30572633
Cancer Cell Int. 2011 Feb 14;11:3
pubmed: 21320311
J Endocrinol. 2000 May;165(2):223-9
pubmed: 10810286
J Mol Endocrinol. 2004 Feb;32(1):55-67
pubmed: 14765992
EMBO J. 2006 Nov 15;25(22):5270-83
pubmed: 17082774
PLoS One. 2021 Apr 5;16(4):e0249558
pubmed: 33819300
Cancer Res. 2005 Mar 1;65(5):1877-86
pubmed: 15753386
J Endocrinol. 1987 Mar;112(3):R11-4
pubmed: 3559445
Mol Oncol. 2016 Dec;10(10):1603-1620
pubmed: 28949445
PLoS One. 2015 Mar 13;10(3):e0120071
pubmed: 25769037
Clin Cancer Res. 2012 Sep 1;18(17):4820-9
pubmed: 22767667
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
Front Oncol. 2013 Sep 25;3:256
pubmed: 24093089
Front Immunol. 2018 Oct 08;9:2327
pubmed: 30349543
Cell Commun Signal. 2015 Jun 06;13:27
pubmed: 26047946
Mol Biol Cell. 2009 Oct;20(20):4362-70
pubmed: 19726563
Mol Hum Reprod. 2017 Mar 1;23(3):199-209
pubmed: 28115494
Mol Cell Endocrinol. 2001 Jun 30;180(1-2):79-86
pubmed: 11451575
Genome Biol. 2020 Jul 27;21(1):182
pubmed: 32718321
Mol Cell Biol. 2007 Mar;27(6):2092-102
pubmed: 17220275
Annu Rev Physiol. 1990;52:807-21
pubmed: 2184777
Int J Oncol. 2019 Jul;55(1):179-190
pubmed: 31059002
Cancer Res. 2018 Jun 1;78(11):2978-2989
pubmed: 29535220
J Cell Biol. 1998 Feb 23;140(4):767-77
pubmed: 9472030
Proc Natl Acad Sci U S A. 1988 Jan;85(1):247-51
pubmed: 2829170
Br J Cancer. 1985 Jun;51(6):877-82
pubmed: 4005143