With five transcriptionally spliced OPN isoforms, multiple post-translational modifications (phosphorylation, glycosylation and sulfation) and multiple functionally-active proteolytic forms cleaved by thrombin, MMPs, plasmin and cathepsin D, OPN is a versatile modulator of many physiological and pathological processes, including cancer progression [33, 81–87]. This evidence concerns the gene CTSD and cancer.