Role of lymphatic deficiency in the pathogenesis and progression of inflammatory bowel disease to colorectal cancer in an experimental mouse model

Sarah K. Daley, Marlys H. Witte, Jalicia Washington, Michael Bernas, Pawel Kiela, Jennifer Thorn, Nathan Tanoue, J. Steven Alexander

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1919-1926
Number of pages8
JournalInflammatory bowel diseases
Volume25
Issue number12
DOIs
StatePublished - Dec 1 2019

Keywords

  • Angiopoietin-2 mice
  • Azoxymethane
  • Colorectal carcinoma
  • Dextran sodium sulfate
  • Inflammatory bowel disease
  • Lymphangiogenesis
  • Lymphatic deficiency

ASJC Scopus subject areas

  • Immunology and Allergy
  • Gastroenterology

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