ADAM10 in Cancer Immunology and Autoimmunity: More Than a Simple Biochemical Scissor

The ADAM (A Disintegrin And Metalloproteinase) family includes cell surface transmembrane proteases, that contain a catalytic metalloproteinase domain and an additional unique disintegrin domain responsible for integrin receptor-binding. Thus, ADAMs are involved in multiple biological processes including proteolysis, cell adhesion, proliferation, migration and signalling. An altered expression of these enzymes has been associated with several diseases including asthma, arthritis, neurodegenerative diseases, atherosclerosis and cancer. In addition, ADAM10 enzymatic activity is involved in autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, and in the development of inflammation or allergy. Nevertheless, both intracellular transport and mechanism of enzymatic activity are not yet completely defined for most ADAMs. As proteases, the best characterized function is the proteolytic degradation of different cell transmembrane proteins, a process known as “ectodomain shedding” that targets the extracellular domain of precursor form of growth factors, cytokines, receptors and several types of cell adhesion molecules. Because most of these ligands are involved in cancer progression, the specific ADAMs responsible for their release are expected to contribute to tumor development. ADAM10 is the principal responsible for the shedding of Notch, amyloid precursor protein, betacellulin and EGFR/HER ligands. Moreover, ADAM10 has been reported to shed the “stress related molecules” MIC-A, MIC-B and ULBPs, expressed on cancer cell surface. These molecules are responsible for inducing an immune response against cancer cells upon binding to natural killer group-2 receptors that are expressed on natural killer (NK) cells, γδ T and CD8+ T lymphocytes. Their shedding by ADAMs can impair the recognition of cancer cells by T or NK cells. This mechanism has been evidenced in chronic lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin and Hodgkin's lymphomas. Besides, ADAM10 is overexpressed in many tumors at early stage of disease, therefore it could also be exploited as a potential cancer biomarker.

For all these reasons, in the last decade, an increasing interest has emerged towards the development of selective ADAMs ligands for their potential use for early stage diagnosis and therapy of cancer. In some cases, released soluble substrates of ADAM10 function as immunoregulators, controlling antibody production and improving the prognosis of autoimmune diseases. Thus, ADAM10 is not simply a sheddase and its importance in immunology is not only related to some of its substrates, such as MIC-A, CD30, TNFα. Starting from these considerations, is ADAM10 a reliable biomarker? Is it worth to inhibit ADAM10?

This Research Topic will face some of the different aspects of ADAM10 enzymatic activity and its physiopathologic outcome. We welcome the submission of mini reviews, hypothesis and theories, commentaries or perspectives focusing on, but not limited to, the following subtopics:

1. Biochemical and molecular features of ADAM10

2. The role of ADAM10 in tumor immune response

3. The role of ADAM 10 in immune disregulation and autoimmunity, including multiple sclerosis