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.

Figure 1

Mode of action of ADAMs in the activation of EGFR/HER receptor signalling. ADAMs (primarily ADAM10 and ADAM17) are involved in proteolytic ectodomain shedding of membrane bound ligands. The released ligands (for example, EGF, HB-EGF, TGFα, heregulins) are free to bind to and activate EGFR, HER3 and HER4. Following receptor dimerisation (though HER3 has weak tyrosine kinase activity, its preferred dimerization partner is HER2), downstream signalling through many pathways is activated, including MAPK, PI3K and JAK/STAT.