ABSTRACT
ADAMs are zinc-dependent transmembrane metalloproteinases that cleave the extracellular domains of membrane bound growth factors, cytokines and receptors among them, the EGFR ligands which are currently the targets for anti-tumor therapies. Since ADAMs are also responsible for shedding of other factors involved in angiogenesis and metastasis, targeting ADAMs may provide a therapeutic strategy on their own or a complement to existing anti-EGFR therapies. ADAMs have been shown to be upregulated in several types of cancer and based on the fact that ADAMs are themselves cleaved, or that they can encode soluble forms by alternative splicing, it is conceivable that circulating metalloproteinases may themselves be a marker for disease. In addition to their role as potential therapeutics and markers, metalloproteinases are responsible for the generation of soluble circulating ectodomains from diff erent transmembrane proteins that can potentially function as prognostic/diagnostic biomarkers, ectomarkers. Emerging soluble biomarkers detectable in body fl uids-serum, urine, saliva-have earned considerable interest as potential contributors to improving detection and response to cancer therapies. Soluble biomarkers represent a great advantage over tissue biomarkers since they are not invasive a biopsy is not necessary, and they allow determining variations in real time. However, to date only a few randomized trials have included circulating biomarkers, and unfortunately, none have yet identifi ed a strong one. Th e discovery of soluble cancer prognostic and predictive biomarkers generated by shedding remains complicated, with lack of sensitivity and specifi city being some of the most diffi cult challenges. In fact, as shown in Table 2, changes in the levels of an ectomarker can be observed in diff erent cancer types indicating lack of specifi city (this is not a comprehensive list and only a few examples were included). Th erefore, in addition to reliable methods to allow sensitive detection of circulating proteins, there is a need to identify ectomarkers that off er specifi city. In that sense, proteins with a restricted expression, like TMEFF2, could show promise.
