Role of Lymphatic Deficiency in the Pathogenesis and Progression of Inflammatory Bowel Disease to Colorectal Cancer in an Experimental Mouse Model

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.

Clostridium butyricum alleviates dextran sulfate sodium-induced experimental colitis and promotes intestinal lymphatic vessel regeneration in mice

“…It has been demonstrated that intestinal colonization by C butyricum suppresses intestinal inflammation in DSSinduced colitis (25). However, the IBD-model mice in most studies were treated with DSS for 6 to 8 days, with histological changes during the acute inflammation stage under observation (6,23). Few studies have focused on the pathological changes during the recovery phase after DSS stimulation ceases.…”

“…Intestinal LVs are essential for chylomicron production, cholesterol and lymphatic absorption, the transport of protein molecules and antigens, and immune cell trafficking (5). Functional LVs have recently been found to have a vital role in preventing and alleviating inflammation in the intestine (6). The LV is critical for in vivo immune response monitoring because it is both the major transport conduit for cells and inflammatory mediators into lymph nodes and the location of immune response and inflammation (7).…”

<p>Prognosis Value of Platelet Counts, Albumin and Neutrophil-Lymphocyte Ratio of Locoregional Recurrence in Patients with Operable Head and Neck Squamous Cell Carcinoma</p>

“…In order to meet "standard multimodality protocols", cases receiving surgery and adjuvant therapy (chemoradiation and radiation) were included. To avoid the impact of tumor pathological heterogeneity on inflammatory measures, 36,37 this model is specific for head and neck cancer patients pathologically diagnosed with squamous cell carcinoma. Reasonably, patients using thrombolytic agents (like aspirin), NSAIDs could not be included.…”

YAP Activates STAT3 Signalling to Promote Colonic Epithelial Cell Proliferation in DSS-Induced Colitis and Colitis Associated Cancer

“…For DSS-induced colitis, the degree of diarrhea, and occult blood or bleeding in the stool of the mice were monitored to evaluate the disease activity index. 20 Mice were examined for occult blood by using a hemoccult test kit (Fisher HealthCare). Occult blood was scored as follows: 0: negative; 2: guiac; 4: gross blood.…”