Ectopeptidases in tumour biology: a review

Cell membrane-bound proteolytic enzymes (ectopeptidases) are integral membrane proteins, orientated asymmetrically with the catalytic site exposed to the extracellular surface, which enables a versatile range of physiological and pathological functions. Ectopeptidases may regulate the release of many growth factors and their receptors into the circulation, as well as activating or inactivating circulating signalling molecules, thereby regulating the availability of ligands for the corresponding receptors. Additionally, many of these ectopeptidases have functions not limited to proteolysis, but are able in themselves to function as receptors, transducing intracellular signals. A versatile range of functions, such as the modulation of cell-signalling, matrix degradation, cell adhesion and migration, which are particularly important for tumour cell growth and dissemination, are attributed largely to the ectopeptidases. Even a minor disruption in the normal proteolytic equilibrium can influence tumor progression, and a range of ectopeptidases, including neutral endopeptidase 24.11, aminopeptidase N, dipeptidyl peptidase IV, angiotensin-converting enzyme, and the disintegrin-metalloproteinases, have been shown to be involved in tumour development and metastasis. The ability to degrade and inactivate peptide hormones and growth factors, with the resultant modulation of the tumour-host interface, may play an important role in the pathogenesis, development or progression of a range of cancers, and the extracellular orientation of the ectopeptidases makes them particularly accessible, and therefore interesting, with regard to therapeutical applications.