Update from the laboratory: mechanistic studies of pathways of cancer-associated venous thrombosis using mouse models.
Journal
Hematology. American Society of Hematology. Education Program
ISSN: 1520-4383
Titre abrégé: Hematology Am Soc Hematol Educ Program
Pays: United States
ID NLM: 100890099
Informations de publication
Date de publication:
06 12 2019
06 12 2019
Historique:
entrez:
7
12
2019
pubmed:
7
12
2019
medline:
11
6
2020
Statut:
ppublish
Résumé
Cancer patients have an increased risk of venous thromboembolism (VTE). The rate of VTE varies with cancer type, with pancreatic cancer having one of the highest rates, suggesting that there are cancer type-specific mechanisms of VTE. Risk assessment scores, such as the Khorana score, have been developed to identify ambulatory cancer patients at high risk of VTE. However, the Khorana score performed poorly in discriminating pancreatic cancer patients at risk of VTE. Currently, thromboprophylaxis is not recommended for cancer outpatients. Recent clinical trials showed that factor Xa (FXa) inhibitors reduced VTE in high-risk cancer patients but also increased major bleeding. Understanding the mechanisms of cancer-associated thrombosis should lead to the development of safer antithrombotic drugs. Mouse models can be used to study the role of different prothrombotic pathways in cancer-associated thrombosis. Human and mouse studies support the notion that 2 prothrombotic pathways contribute to VTE in pancreatic cancer patients: tumor-derived, tissue factor-positive (TF+) extracellular vesicles (EVs), and neutrophils and neutrophil extracellular traps (NETs). In pancreatic cancer patients, elevated levels of plasma EVTF activity and citrullinated histone H3 (H3Cit), a NET biomarker, are independently associated with VTE. We observed increased levels of circulating tumor-derived TF+ EVs, neutrophils, cell-free DNA, and H3Cit in nude mice bearing human pancreatic tumors. Importantly, inhibition of tumor-derived human TF, depletion of neutrophils, or administration of DNAse I to degrade cell-free DNA (including NETs) reduced venous thrombosis in tumor-bearing mice. These studies demonstrate that tumor-derived TF+ EVs, neutrophils, and cell-free DNA contribute to venous thrombosis in a mouse model of pancreatic cancer.
Identifiants
pubmed: 31808871
pii: 422598
doi: 10.1182/hematology.2019000025
pmc: PMC6913477
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
182-186Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL007149
Pays : United States
Informations de copyright
© 2019 by The American Society of Hematology. All rights reserved.
Déclaration de conflit d'intérêts
Conflict-of-interest disclosure: Y.H. and N.M. declare no competing financial interests.
Références
Blood. 2010 Dec 9;116(24):5377-82
pubmed: 20829374
Thromb J. 2016 Jan 19;14:2
pubmed: 26793031
J Thromb Haemost. 2008 Nov;6(11):1983-5
pubmed: 18795992
Oncoimmunology. 2016 Feb 18;5(5):e1134073
pubmed: 27467952
J Thromb Haemost. 2016 Jan;14(1):153-66
pubmed: 26516108
Oncogene. 2012 Aug 23;31(34):3889-900
pubmed: 22139075
Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13076-81
pubmed: 22826226
Thromb Res. 2013 Aug;132(2):180-4
pubmed: 23856554
J Clin Oncol. 2015 Feb 20;33(6):654-6
pubmed: 25605844
Lancet Haematol. 2018 Jul;5(7):e289-e298
pubmed: 29885940
Thromb Haemost. 2016 Jan;115(2):299-310
pubmed: 26446354
Thromb Haemost. 2014 Apr 1;111(4):647-55
pubmed: 24258684
Am J Med. 2006 Jan;119(1):60-8
pubmed: 16431186
Cell Mol Life Sci. 2011 Aug;68(16):2667-88
pubmed: 21560073
J Thromb Haemost. 2012 Jul;10(7):1363-70
pubmed: 22520016
Thromb Res. 2018 May;165:1-5
pubmed: 29539580
J Thromb Haemost. 2014 Feb;12(2):186-96
pubmed: 24298933
Arterioscler Thromb Vasc Biol. 2012 Mar;32(3):556-62
pubmed: 22345593
J Thromb Haemost. 2017 Nov;15(11):2208-2217
pubmed: 28834179
Haematologica. 2020 Jan;105(1):218-225
pubmed: 31048354
Circ Res. 2017 May 12;120(10):1632-1648
pubmed: 28495994
Blood. 2008 May 15;111(10):4902-7
pubmed: 18216292
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8674-9
pubmed: 23650392
Nat Rev Immunol. 2013 Jan;13(1):34-45
pubmed: 23222502
J Thromb Haemost. 2015 Jul;13(7):1310-9
pubmed: 25955268
Thromb Res. 2018 Apr;164 Suppl 1:S48-S53
pubmed: 29306575
J Vasc Surg. 2016 Nov;64(5):1450-1458.e1
pubmed: 26482993
N Engl J Med. 2019 Feb 21;380(8):711-719
pubmed: 30511879
N Engl J Med. 2019 Feb 21;380(8):720-728
pubmed: 30786186
Thromb Res. 2016 Sep;145:51-3
pubmed: 27485998
J Thromb Haemost. 2007 Mar;5(3):520-7
pubmed: 17166244
J Exp Med. 2009 Aug 31;206(9):1913-27
pubmed: 19667060
Science. 2004 Mar 5;303(5663):1532-5
pubmed: 15001782
Thromb Res. 2018 Jun;166:54-59
pubmed: 29656167
Oncotarget. 2017 Oct 26;8(57):97394-97406
pubmed: 29228619
Blood. 2005 Feb 15;105(4):1734-41
pubmed: 15494427
Oncology. 2019;96(4):217-222
pubmed: 30844808
Sci Rep. 2017 Jul 25;7(1):6438
pubmed: 28743887
Exp Mol Pathol. 2007 Feb;82(1):12-24
pubmed: 16919266
Blood. 2012 Jun 7;119(23):5543-52
pubmed: 22547577
Arterioscler Thromb Vasc Biol. 2012 Aug;32(8):1777-83
pubmed: 22652600
J Thromb Haemost. 2018 Mar;16(3):508-518
pubmed: 29325226
Blood. 2013 Sep 5;122(10):1712-23
pubmed: 23908465
Clin Transl Oncol. 2014 Oct;16(10):927-30
pubmed: 24643701