Role of Lymphatic Deficiency in the Pathogenesis and Progression of Inflammatory Bowel Disease to Colorectal Cancer in an Experimental Mouse Model.
Angiopoietin-2
/ blood
Animals
Azoxymethane
Biomarkers
/ blood
Colon
/ pathology
Colorectal Neoplasms
/ etiology
Dextran Sulfate
Disease Models, Animal
Disease Progression
Female
Inflammatory Bowel Diseases
/ blood
Lymphangiogenesis
/ genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Tumor Necrosis Factor-alpha
/ blood
Angiopoietin-2 mice
azoxymethane
colorectal carcinoma
dextran sodium sulfate
inflammatory bowel disease
lymphangiogenesis
lymphatic deficiency
Journal
Inflammatory bowel diseases
ISSN: 1536-4844
Titre abrégé: Inflamm Bowel Dis
Pays: England
ID NLM: 9508162
Informations de publication
Date de publication:
14 11 2019
14 11 2019
Historique:
received:
14
03
2019
pubmed:
8
6
2019
medline:
25
6
2020
entrez:
8
6
2019
Statut:
ppublish
Résumé
Inflammatory bowel disease (IBD) is characterized by chronic inflammation, which can progress to colorectal cancer, with duration of disease being the most important risk factor. Although many factors are involved, the pathogenic link between inflammation and cancer and the role played by the lymphatic system have not been fully investigated. This project uses lymphatic-deficient mice (Angiopoietin-2 [Ang2] knockout) to examine the lymphatic system in the progression of IBD to colorectal cancer. Angiopoietin-2 wild-type, heterozygote, and knockout mice received a single injection of the procarcinogen azoxymethane and had an IBD-promoting chemical irritant (dextran sodium sulfate) added to their drinking water over a 7-week period. We measured disease activity (weight loss, stool consistency, fecal occult blood) during the study and at sacrifice, collected blood for cytokine/biomarker (Ang2, interleukin [IL] 1-β, IL-6, tumor necrosis factor α [TNFα], and VEGF-C) enzyme-linked immunosorbent assay analysis, measured colon length, and assessed tumor burden. Ang2 knockout (KO) mice exhibited reduced (55%) survival vs wild-type (100%) and heterozygotes (91%; P < 0.01 and P < 0.0001, respectively). Most (>89%) mice developed tumors, and the incidence of colorectal cancer did not differ among the genotypes (P = 0.32). The tumor area was significantly increased in KO mice (P = 0.004). Of the biomarkers measured in the serum, Ang2 and TNF-α concentrations were significantly different among the genotypes (P = 3.35e-08 and P = 0.003 respectively). Disease activity was significantly increased in KO mice compared with wild-type and heterozygote mice (P = 0.033). Lymphatic deficiency, defective lymphangiogenesis, and impaired lymphatic-generated inflammation did not protect against clinical IBD or progression to colorectal cancer in this experimental model.
Sections du résumé
BACKGROUND
Inflammatory bowel disease (IBD) is characterized by chronic inflammation, which can progress to colorectal cancer, with duration of disease being the most important risk factor. Although many factors are involved, the pathogenic link between inflammation and cancer and the role played by the lymphatic system have not been fully investigated. This project uses lymphatic-deficient mice (Angiopoietin-2 [Ang2] knockout) to examine the lymphatic system in the progression of IBD to colorectal cancer.
METHODS
Angiopoietin-2 wild-type, heterozygote, and knockout mice received a single injection of the procarcinogen azoxymethane and had an IBD-promoting chemical irritant (dextran sodium sulfate) added to their drinking water over a 7-week period. We measured disease activity (weight loss, stool consistency, fecal occult blood) during the study and at sacrifice, collected blood for cytokine/biomarker (Ang2, interleukin [IL] 1-β, IL-6, tumor necrosis factor α [TNFα], and VEGF-C) enzyme-linked immunosorbent assay analysis, measured colon length, and assessed tumor burden.
RESULTS
Ang2 knockout (KO) mice exhibited reduced (55%) survival vs wild-type (100%) and heterozygotes (91%; P < 0.01 and P < 0.0001, respectively). Most (>89%) mice developed tumors, and the incidence of colorectal cancer did not differ among the genotypes (P = 0.32). The tumor area was significantly increased in KO mice (P = 0.004). Of the biomarkers measured in the serum, Ang2 and TNF-α concentrations were significantly different among the genotypes (P = 3.35e-08 and P = 0.003 respectively). Disease activity was significantly increased in KO mice compared with wild-type and heterozygote mice (P = 0.033).
CONCLUSIONS
Lymphatic deficiency, defective lymphangiogenesis, and impaired lymphatic-generated inflammation did not protect against clinical IBD or progression to colorectal cancer in this experimental model.
Identifiants
pubmed: 31173626
pii: 5512544
doi: 10.1093/ibd/izz112
pmc: PMC6855278
doi:
Substances chimiques
Angiopoietin-2
0
Angpt2 protein, mouse
0
Biomarkers
0
Tumor Necrosis Factor-alpha
0
Dextran Sulfate
9042-14-2
Azoxymethane
MO0N1J0SEN
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1919-1926Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK109711
Pays : United States
Organisme : NHLBI NIH HHS
ID : R25 HL108837
Pays : United States
Informations de copyright
© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Références
Lab Invest. 1993 Aug;69(2):238-49
pubmed: 8350599
Gastroenterol Res Pract. 2016;2016:2097274
pubmed: 28070181
Cell Tissue Res. 2007 May;328(2):329-37
pubmed: 17235601
Nat Rev Cancer. 2012 Feb 24;12(3):170-80
pubmed: 22362215
Gut. 2001 Apr;48(4):526-35
pubmed: 11247898
Curr Drug Targets. 2008 May;9(5):375-80
pubmed: 18473765
J Crohns Colitis. 2008 Dec;2(4):279-90
pubmed: 21172225
Gut. 2010 Feb;59(2):197-206
pubmed: 19846409
Dig Dis. 2010;28(4-5):619-24
pubmed: 21088413
Ann Surg. 1936 Oct;104(4):601-16
pubmed: 17856855
Dev Biol. 2008 Jul 15;319(2):309-20
pubmed: 18514180
Inflamm Bowel Dis. 2010 Jun;16(6):1029-39
pubmed: 19902545
World J Gastroenterol. 2011 Jul 14;17(26):3092-100
pubmed: 21912451
Nature. 2002 Dec 19-26;420(6917):860-7
pubmed: 12490959
Digestion. 1980;20(5):307-13
pubmed: 7390055
Dev Cell. 2002 Sep;3(3):411-23
pubmed: 12361603
Oncogene. 2012 Oct 18;31(42):4499-508
pubmed: 22179834
Anticancer Res. 2009 Jul;29(7):2727-37
pubmed: 19596953
Scand J Gastroenterol. 1976;11(4):353-62
pubmed: 935796
Dev Dyn. 2004 Nov;231(3):462-73
pubmed: 15376314