The immunological role of ADAMs in the field of gastroenterological chronic inflammatory diseases and cancers: a review

Abstract

Metalloproteinases cleave transmembrane proteins that play critical roles in inflammation and cancers. Metalloproteinases include a disintegrin and metalloprotease (ADAM), which we previously examined using a fluorescence assay system, and described their association with resistance to systemic therapy in cancer patients. There are also many reports on the relation between ADAM expression and the prognosis of patients with gastroenterological chronic inflammatory diseases and cancers. Inhibiting their immunomodulating activity in chronic inflammation restores innate immunity and potentially prevents the development of various cancers. Among the numerous critical immune system-related molecules, we focus on major histocompatibility complex class I polypeptide-related sequence A (MICA), MICB, intracellular adhesion molecule (ICAM)-1, TNF-α, IL-6 receptor (IL-6R), and Notch. This review summarizes our current understanding of the role of ADAMs in gastroenterological diseases with regard to the immune system. Several Food and Drug Administration (FDA)-approved inhibitors of ADAMs have been identified, and potential therapies for targeting ADAMs in the treatment of chronic inflammatory diseases and cancers are discussed. Some ongoing clinical trials for cancers targeting ADAMs are also introduced.

Fig. 1. The mechanism of how ADAMs are associated with tumor progression in CRC.

CRC cells advance as ADAM10 and ADAM17 cleave various membrane-bound molecules during growth, angiogenesis, and metastasis. mIL-6R: membrane-bound IL-6 receptor, mMICA: membrane-bound MICA, mL1-CAM: membrane-bound cell adhesion molecule L1.

Fig. 2. Combination therapy of ADAM9 inhibitors via two pathways could induce stronger NK cell-mediated cytotoxicity against HCC.

In patients with chronic viral hepatitis, mMICA is expressed on the surface of inflammatory hepatocytes, which is an important trigger for NK cells to eliminate them. ADAM9 cleaves mMICA to escape from NK-mediated immunosurveillance, resulting in the development of HCC. The combination of agents targeting ADAM9 activity (leukotriene receptor antagonists and retinoids) and conventional multi-kinase inhibitors (sorafenib and regorafenib) represents a practical future therapeutic strategy to enhance the efficacy of cancer management and treatment. mMICA: membrane-bound MICA, sMICA: soluble MICA.

Fig. 3. The mechanism of how ADAMs are associated with tumor progression in gastric cancer.

H. pylori-induced chronic inflammation upregulates ADAM10 and ADAM17 expression, thereby increasing shedding of mTNFRs or EGFR ligands, and is also associated with tumor proliferation. EGFR epidermal growth factor receptor, mTNFR membrane-bound tumor necrosis factor receptor.