The Tumor Coagulome as a Transcriptional Target and a Potential Effector of Glucocorticoids in Human Cancers.
glucocorticoids
tumor coagulome
tumor microenvironment
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
28 Feb 2023
28 Feb 2023
Historique:
received:
27
01
2023
revised:
13
02
2023
accepted:
25
02
2023
entrez:
11
3
2023
pubmed:
12
3
2023
medline:
12
3
2023
Statut:
epublish
Résumé
The coagulome, defined as the repertoire of genes that locally regulate coagulation and fibrinolysis, is a key determinant of vascular thromboembolic complications of cancer. In addition to vascular complications, the coagulome may also regulate the tumor microenvironment (TME). Glucocorticoids are key hormones that mediate cellular responses to various stresses and exert anti-inflammatory effects. We addressed the effects of glucocorticoids on the coagulome of human tumors by investigating interactions with Oral Squamous Cell Carcinoma, Lung Adenocarcinoma, and Pancreatic Adenocarcinoma tumor types. We analyzed the regulation of three essential coagulome components, i.e., the tissue factor (TF), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) in cancer cell lines exposed to specific agonists of the glucocorticoid receptor (GR) (dexamethasone and hydrocortisone). We used QPCR, immunoblots, small-interfering RNA, Chromatin immunoprecipitation sequencing (ChIPseq) and genomic data from whole tumor and single-cell analyses. Glucocorticoids modulate the coagulome of cancer cells through a combination of indirect and direct transcriptional effects. Dexamethasone directly increased PAI-1 expression in a GR-dependent manner. We confirmed the relevance of these findings in human tumors, where high GR activity/high The transcriptional regulation of the coagulome by glucocorticoids that we report may have vascular consequences and account for some of the effects of glucocorticoids on the TME.
Sections du résumé
BACKGROUND
BACKGROUND
The coagulome, defined as the repertoire of genes that locally regulate coagulation and fibrinolysis, is a key determinant of vascular thromboembolic complications of cancer. In addition to vascular complications, the coagulome may also regulate the tumor microenvironment (TME). Glucocorticoids are key hormones that mediate cellular responses to various stresses and exert anti-inflammatory effects. We addressed the effects of glucocorticoids on the coagulome of human tumors by investigating interactions with Oral Squamous Cell Carcinoma, Lung Adenocarcinoma, and Pancreatic Adenocarcinoma tumor types.
METHODS
METHODS
We analyzed the regulation of three essential coagulome components, i.e., the tissue factor (TF), urokinase-type plasminogen activator (uPA), and plasminogen activator inhibitor-1 (PAI-1) in cancer cell lines exposed to specific agonists of the glucocorticoid receptor (GR) (dexamethasone and hydrocortisone). We used QPCR, immunoblots, small-interfering RNA, Chromatin immunoprecipitation sequencing (ChIPseq) and genomic data from whole tumor and single-cell analyses.
RESULTS
RESULTS
Glucocorticoids modulate the coagulome of cancer cells through a combination of indirect and direct transcriptional effects. Dexamethasone directly increased PAI-1 expression in a GR-dependent manner. We confirmed the relevance of these findings in human tumors, where high GR activity/high
CONCLUSION
CONCLUSIONS
The transcriptional regulation of the coagulome by glucocorticoids that we report may have vascular consequences and account for some of the effects of glucocorticoids on the TME.
Identifiants
pubmed: 36900323
pii: cancers15051531
doi: 10.3390/cancers15051531
pmc: PMC10001343
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : Dutch Cancer Society
ID : 12128
Références
Comp Hepatol. 2007 May 02;6:5
pubmed: 17474984
Lancet Oncol. 2019 Oct;20(10):e566-e581
pubmed: 31492632
Cancer Treat Res. 2019;179:11-36
pubmed: 31317478
Mol Cell Endocrinol. 2018 May 5;466:38-50
pubmed: 28687451
Cell Rep. 2018 Nov 20;25(8):2177-2191.e7
pubmed: 30463014
Oncotarget. 2016 Aug 30;7(35):57351-57366
pubmed: 27385000
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Commun. 2015 Sep 16;6:8323
pubmed: 26374485
Nat Commun. 2021 Aug 16;12(1):4960
pubmed: 34400618
Bone. 2020 May;134:115310
pubmed: 32142912
Front Immunol. 2022 Mar 16;13:845956
pubmed: 35371006
Int J Mol Sci. 2021 Aug 31;22(17):
pubmed: 34502382
Int J Mol Sci. 2022 Jan 01;23(1):
pubmed: 35008904
J Bone Miner Metab. 2018 Mar;36(2):148-156
pubmed: 28321652
Cancers (Basel). 2022 Jan 17;14(2):
pubmed: 35053621
Nat Rev Mol Cell Biol. 2017 Mar;18(3):159-174
pubmed: 28053348
Cancer Res. 2011 Oct 15;71(20):6360-70
pubmed: 21868756
N Engl J Med. 2020 Jan 2;382(1):60-72
pubmed: 31893516
Mol Cancer Res. 2010 Aug;8(8):1116-25
pubmed: 20647330
Cancers (Basel). 2021 Sep 05;13(17):
pubmed: 34503285
Nucleic Acids Res. 1988 Apr 11;16(7):2805-24
pubmed: 3130610
Cancer Cell. 2008 Oct 7;14(4):324-34
pubmed: 18835034
ESMO Open. 2020 Nov;5(6):e000948
pubmed: 33229505
Cancer Res. 2006 Nov 15;66(22):10643-6
pubmed: 17108099
Trends Cancer. 2022 May;8(5):369-383
pubmed: 35027336
Nucleic Acids Res. 2013 Jan;41(Database issue):D377-86
pubmed: 23193289
Nat Commun. 2021 Jul 16;12(1):4360
pubmed: 34272384
Placenta. 2002 Nov;23(10):727-34
pubmed: 12398812
Cancer Treat Rev. 2022 Jan;102:102322
pubmed: 34922151
Clin Cancer Res. 2018 Jul 15;24(14):3433-3446
pubmed: 29636357
Breast Cancer Res Treat. 2015 Apr;150(2):335-46
pubmed: 25762479
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
J Immunother Cancer. 2018 Jun 11;6(1):51
pubmed: 29891009
Trends Pharmacol Sci. 2013 Sep;34(9):518-30
pubmed: 23953592
BMC Cancer. 2021 Feb 5;21(1):122
pubmed: 33546637
Genome Biol. 2016 Oct 20;17(1):218
pubmed: 27765066
Immunity. 2018 Apr 17;48(4):812-830.e14
pubmed: 29628290
Curr Biol. 2020 Aug 17;30(16):R921-R925
pubmed: 32810447
Int J Mol Sci. 2019 Jun 11;20(11):
pubmed: 31212608
Br J Cancer. 2009 Jan 13;100(1):200-5
pubmed: 19034275
Endocr Relat Cancer. 2021 May 11;28(6):R157-R171
pubmed: 33852423
Cancer Immunol Immunother. 2021 Apr;70(4):923-933
pubmed: 33057845
Cell. 2017 Dec 14;171(7):1611-1624.e24
pubmed: 29198524
Cancer Res. 2012 Jul 15;72(14):3499-511
pubmed: 22802077
Cell. 2013 Dec 5;155(6):1309-22
pubmed: 24315100
Sci Signal. 2013 Apr 02;6(269):pl1
pubmed: 23550210
J Cell Physiol. 2016 Nov;231(11):2368-73
pubmed: 27115293
J Cell Mol Med. 2019 Apr;23(4):2984-2994
pubmed: 30734495
Nature. 2019 Mar;567(7749):540-544
pubmed: 30867597