Progression of Inflammatory Bowel Disease to Cancer: Is the Patient Better Off without Lymphatic Vessels or Nodes (or Angiopoietin 2)

摘要

This proposal addresses inflammatory bowel disease (IBD). Multiple factors have been implicated in the progression of ulcerative/granulomatous (Crohn s) colitis to colorectal carcinoma (CRC) in IBD patients and experimental models. Nonetheless, the pathogenic link, interrelationship, and practical clinical application of these various theories of progression have remained elusive. We proposed that a reduced number of functioning lymphatic vessels and impaired lymph drainage (lymphatic vascular insufficiency) in the colon actually protects against progression of inflammatory colitis to CRC. Our primary objective is to determine whether there is a reduced incidence of CRC in mice with lymphatic insufficiency from genetic knockout of angiopoietin2 (Ang2) compared to controls. We have: 1) completed and secured approval of ACURO Appendix; 2) revised dextran sodium sulfate (DSS) dosing in our model; 3) completed mouse cohorts chronically exposed to DSS; 4) added pre-carcinogen azoxymethane (AOM) before chronic DSS; and 5) completed additional experimental groups, and are continuing final data analysis and latest imaging studies. This project has potentially high impact because of the substantial incidence of IBD- CRC progression with associated morbidity and mortality and importance of clarifying positive and negative interactions of lymphatic functional status and Ang2, identifying potential biomarkers, and developing new imaging, preventive, and treatment approaches to IBD-induced CRC.