The ADAMs family of proteases: new biomarkers and therapeutic targets for cancer?

Abstract

The ADAMs are transmembrane proteins implicated in proteolysis and cell adhesion. Forty gene members of the family have been identified, of which 21 are believed to be functional in humans. As proteases, their main substrates are the ectodomains of other transmembrane proteins. These substrates include precursor forms of growth factors, cytokines, growth factor receptors, cytokine receptors and several different types of adhesion molecules. Although altered expression of specific ADAMs has been implicated in different diseases, their best-documented role is in cancer formation and progression. ADAMs shown to play a role in cancer include ADAM9, ADAM10, ADAM12, ADAM15 and ADAM17. Two of the ADAMs, i.e., ADAM10 and 17 appear to promote cancer progression by releasing HER/EGFR ligands. The released ligands activate HER/EGFR signalling that culminates in increased cell proliferation, migration and survival. Consistent with a causative role in cancer, several ADAMs are emerging as potential cancer biomarkers for aiding cancer diagnosis and predicting patient outcome. Furthermore, a number of selective ADAM inhibitors, especially against ADAM10 and ADAM17, have been shown to have anti-cancer effects. At least one of these inhibitors is now undergoing clinical trials in patients with breast cancer.

NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17)

“…This would suggest that once an NK cell sheds CD16 from the surface, high threshold functions are reduced highlighting a potential benefit for the use of ADAM17 inhibitors clinically. Increased ADAM17 expression is associated with poor prognosis in breast cancer, 49 perhaps because it can cleave EGFR ligands to promote metastasis. The monoclonal antibody trastuzumab, currently used to treat breast cancer, works at least in part through NK cell mediated ADCC.…”

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

“…Similarly, the combination of valproate, which is known to upregulate cell surface MICA/B (25,55), and metalloproteinase inhibitors substantially stabilized cell surface MICA/B on ovarian carcinoma cells and enhanced the efficacy of immune cell therapy in vivo (56). In addition, the use of ADAM10 and ADAM17 inhibitors was shown to ameliorate the response to chemotherapy treatments in different in vivo models of cancer (57,58), and ADAM inhibitors were used in clinical trials in breast cancer patients (59). Of interest, combined treatment using chemotherapy and metalloproteinase inhibitors recently was proposed as a therapeutic regimen in MM, because drug-induced ADAM-mediated CD138 release was shown to promote tumor growth (60).…”

Insights into Ectodomain Shedding and Processing of Protein-tyrosine Pseudokinase 7 (PTK7)

“…MMPs and ADAMs are synthesized as inactive zymogens (39,41). Once activated, MMPs/ADAMs can be inhibited by tissue inhibitors of metalloproteinases (TIMPs).…”