Targeting MAdCAM-1 can prevent colitic cancer progression by suppressing immune cell infiltration and inflammatory signals

Abstract

Chronic inflammation by infiltrating immune cells promotes colitis-associated dysplasia/colitic cancer in ulcerative colitis (UC) via activating inflammatory cytokine signalling (IL-6/p-STAT3 and TNFα/NF-κB). Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is a cell adhesion molecule expressed on high endothelial venules that promote immune cell migration from the bloodstream to the gut. MAdCAM-1 targeting strategy is attracting attention as a novel therapeutic option for UC. However, the significance of MAdCAM-1-positive vessels in dysplasia/colitic cancers remains unclear. We conducted immunohistochemistry against MAdCAM-1, and immune cell markers in surgically resected samples from 11 UC patients with dysplasia/colitic cancer and 17 patients with sporadic colorectal cancer (SCRC). Moreover, we used a colitic cancer model, azoxymethane (AOM)/dextran sodium sulphate (DSS) mouse, to evaluate whether anti-MAdCAM-1 blocking antibody can suppress colitic cancer progression. MAdCAM-1-positive vessel number and infiltrating CD8-, CD68-, and CD163-positive immune cell numbers were significantly higher in dysplasia/colitic cancer than in normal mucosa, SCRC, and UC mucosa. In the AOM/DSS mouse model, MAdCAM-1 antibody reduced the tumour number, tumour diameter, number of CD8-, CD68-, and CD163-positive immune cells, and IL-6/p-STAT3 and TNFα/NF-κB expression levels. Targeting MAdCAM-1 could be promising for inflammatory carcinogenesis, and tumour progression by regulating inflammation/immune cell infiltration in patients with UC. Keywords: colitic cancer, colitis-associated cancer, MAdCAM-1, AOM/DSS mouse, immune cells.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was supported by the Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research (KAKENNHI; 22K16528).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study conformed to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board for Clinical Research at Gunma University Hospital, Maebashi, Gunma, Japan (approval number: HS2018-092)

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Yes

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Data Availability

All data produced in the present study are available upon reasonable request to the authors

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