TY - JOUR
T1 - Role of lymphatic deficiency in the pathogenesis and progression of inflammatory bowel disease to colorectal cancer in an experimental mouse model
AU - Daley, Sarah K.
AU - Witte, Marlys H.
AU - Washington, Jalicia
AU - Bernas, Michael
AU - Kiela, Pawel
AU - Thorn, Jennifer
AU - Tanoue, Nathan
AU - Alexander, J. Steven
N1 - Funding Information:
Received for publications March 14, 2019; Editorial Decision May 15, 2019. From the *Department of Pathology, University of Arizona, Tucson, Arizona; †Department of Surgery, University of Arizona, Tucson, Arizona; ‡Texas Christian University and University of North Texas Health Science Center School of Medicine, Fort Worth, Texas; §Department of Pediatrics, University of Arizona, Tucson, Arizona; ¶Department of Molecular and Cellular Physiology, Louisiana Health Sciences Center-Shreveport, Louisiana Conflicts of interest: The authors declare no conflicts of interest. Supported by: NIH HL T35 07049, R25 HL108837; from NIH and DOD PR100654, PR100451. We thank Dr. Edward Meister for valuable discussions and statistical advice. We also thank Dr. Anil Prasad and Dr. John Davis for review of slides and Dr. David Raichlen for helpful suggestions on this manuscript. Address correspondence to: Sarah Daley, MD, Department of Pathology, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724 (skdaley@email. arizona.edu). © 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. doi: 10.1093/ibd/izz112 Published online 7 June 2019
Publisher Copyright:
© 2019 Crohn's & Colitis Foundation.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Angiopoietin-2 mice
KW - Azoxymethane
KW - Colorectal carcinoma
KW - Dextran sodium sulfate
KW - Inflammatory bowel disease
KW - Lymphangiogenesis
KW - Lymphatic deficiency
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U2 - 10.1093/ibd/izz112
DO - 10.1093/ibd/izz112
M3 - Article
C2 - 31173626
AN - SCOPUS:85075090538
VL - 25
SP - 1919
EP - 1926
JO - Inflammatory Bowel Diseases
JF - Inflammatory Bowel Diseases
SN - 1078-0998
IS - 12
ER -