Role of Lymphatic Deficiency in the Pathogenesis and Progression of Inflammatory Bowel Disease to Colorectal Cancer in an Experimental Mouse Model
| Autor: | Jennifer Thorn, Nathan Tanoue, M. Bernas, Pawel R. Kiela, J. Steven Alexander, Marlys H. Witte, Sarah Daley, Jalicia Washington |
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| Rok vydání: | 2019 |
| Předmět: |
Male
medicine.medical_specialty Colon Colorectal cancer Original Basic Science Articles Azoxymethane Inflammation Gastroenterology Inflammatory bowel disease Angiopoietin-2 Mice 03 medical and health sciences 0302 clinical medicine Internal medicine Animals Immunology and Allergy Medicine Lymphangiogenesis Mice Knockout Tumor Necrosis Factor-alpha business.industry Dextran Sulfate Cancer Inflammatory Bowel Diseases medicine.disease Mice Inbred C57BL Disease Models Animal Lymphatic system 030220 oncology & carcinogenesis Knockout mouse Disease Progression Female 030211 gastroenterology & hepatology Tumor necrosis factor alpha medicine.symptom Colorectal Neoplasms business Biomarkers |
| Zdroj: | Inflamm Bowel Dis |
| ISSN: | 1536-4844 1078-0998 |
| DOI: | 10.1093/ibd/izz112 |
| Popis: | BackgroundInflammatory 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.MethodsAngiopoietin-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.ResultsAng2 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).ConclusionsLymphatic deficiency, defective lymphangiogenesis, and impaired lymphatic-generated inflammation did not protect against clinical IBD or progression to colorectal cancer in this experimental model. |
| Databáze: | OpenAIRE |
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