MAdCAM-1 targeting strategy can prevent colitic cancer carcinogenesis and progression via suppression of immune cell infiltration and inflammatory signals
Chronic inflammation caused by infiltrating immune cells can promote colitis-associated dysplasia/colitic cancer in ulcerative colitis (UC) by activating inflammatory cytokine signaling through the IL-6/p-STAT3 and TNFa/NF-?B pathways. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on high endothelial venules promotes the migration of immune cells from the bloodstream to the gut via interaction with a4ß7 integrin expressed on the immune cells. MAdCAM-1, has therefore drawn interest as a novel therapeutic target for treating active UC. However, the role of MAdCAM-1-positive endothelial cells in immune cell infiltration in dysplasia/colitic cancers remains unclear. We evaluated the expression of MAdCAM-1, CD31, and immune cell markers (CD8, CD68, CD163, and FOXP3) in samples surgically resected from 11 UC patients with dysplasia/colitic cancer and 17 patients with sporadic colorectal cancer (SCRC), using immunohistochemical staining. We used an azoxymethane/dextran sodium sulfate mouse model (AOM/DSS mouse) to evaluate whether dysplasia/colitic cancer could be suppressed with an anti-MAdCAM-1 blocking antibody by preventing immune cell infiltration. The number of MAdCAM-1-positive vessels and infiltrating CD8+, CD68+, and CD163+ immune cells was significantly higher in dysplasia/colitic cancer than in normal, SCRC, and UC mucosa. In AOM/DSS mice, the anti-MAdCAM-1 antibody reduced the number, mean diameter, depth of tumors, Ki67 positivity, number of CD8+, CD68+, and CD163+ immune cells, and the IL-6/p-STAT3 and TNF-a/NF-?B signaling. Our results indicate that targeting MAdCAM-1 is a promising strategy for controlling not only UC severity, but also carcinogenesis and tumor progression by regulating inflammation/immune cell infiltration in patients with UC. Overall design: Examination of 3 different method in  2 mouse RNA extracted from tumors arising in a mouse model of inflammatory colorectal cancer (AOM/DSS mice) treated with an anti-inflammatory MAdCAM-1 antibody and a control group treated with an IgG antibody. two mice from each group were selected.