Review Ectopeptidases in Tumour Biology

Histol Histopathol (2006) 21: 1339-1353 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review Ectopeptidases in tumour biology: A review S. Carl-McGrath1, U. Lendeckel2, M. Ebert3 and C. Röcken1 1Institute of Pathology, Charité University Hospital, Berlin, Germany, 2Institute of Experimental Internal Medicine, Otto-von-Guericke-University, Magdeburg, Germany and 3Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Germany Summary. Cell membrane-bound proteolytic enzymes Introduction (ectopeptidases) are integral membrane proteins, orientated asymmetrically with the catalytic site exposed It has long been recognized that the expression to the extracellular surface, which enables a versatile pattern of proteases may be changed in malignant range of physiological and pathological functions. tumours, indicating a putative involvement in tumour Ectopeptidases may regulate the release of many growth development and tumour growth. Their roles in cancer factors and their receptors into the circulation, as well as progression and invasion are evidenced by the ability to activating or inactivating circulating signalling influence proliferation, angiogenesis, tumour cell molecules, thereby regulating the availability of ligands migration, and metastatic behaviour. Neutral for the corresponding receptors. Additionally, many of endopeptidase 24.11 (NEP, CD10), aminopeptidase N these ectopeptidases have functions not limited to (APN, CD13), dipeptidyl peptidase IV (DPIV, CD26) proteolysis, but are able in themselves to function as and angiotensin-I converting enzyme (ACE, CD143), receptors, transducing intracellular signals. A versatile and the disintegrin-metalloproteinases, ADAM9, range of functions, such as the modulation of cell- ADAM12 and ADAM15, belong to a large group of signalling, matrix degradation, cell adhesion and multifunctional, extracellularly orientated, membrane- migration, which are particularly important for tumour bound proteolytic enzymes classified as ectopeptidases, cell growth and dissemination, are attributed largely to which have all been shown to participate in the post- the ectopeptidases. Even a minor disruption in the secretory processing of neuropeptides, peptide hormones normal proteolytic equilibrium can influence tumor and growth factors. They are all widely distributed and progression, and a range of ectopeptidases, including have been found in various different cell types of neutral endopeptidase 24.11, aminopeptidase N, different organs and tissues, including benign and dipeptidyl peptidase IV, angiotensin-converting enzyme, malignant tumours (Nanus et al., 1997; Antczak et al., and the disintegrin-metalloproteinases, have been shown 2001). Each ectopeptidase has the potential to possess to be involved in tumour development and metastasis. proteolytic, adhesion, and signalling abilities, enabling a The ability to degrade and inactivate peptide hormones versatile range of physiological and pathological and growth factors, with the resultant modulation of the functions. Tumour cell growth, invasion, and metastasis tumour-host interface, may play an important role in the depend on timely balanced changes of proteolytic pathogenesis, development or progression of a range of activity and cell-cell and cell-matrix interactions, which cancers, and the extracellular orientation of the could be influenced by the activity of these ectopeptidases makes them particularly accessible, and ectopeptidases. therefore interesting, with regard to therapeutical applications. The ectopeptidases in tumour biology Key words: NEP, APN, DPIV, ACE, GPCR, EGFR The accumulation of mutations during transactivation carcinogenesis results in six essential alterations in cell physiology that collectively dictate malignant growth: self sufficiency in cell growth, insensitivity to growth- inhibitory signals, evasion of cell death, limitless replicative potential, sustained angiogenesis, and tissue Offprint requests to: Dr. Stacy Carl-McGrath, Charité University Hospital, invasion and metastasis (Hanahan and Weinberg, 2000). Institute of Pathology, Schumannstraße 20/21 D-101117 Berlin, Most of these alterations affect cell signalling pathways, Germany. e-mail: [email protected] and the majority of oncogenes and tumour suppressor 1340 Ectopeptidases in tumour biology genes are integral components of cellular signalling environment, such as the availability of the extracellular circuits, which are up-regulated or constitutively signalling molecules. Many of these signalling pathways activated in malignant cells. However, the true initiators involve the extracellular regulation of ligand availability of these circuits are the extracellularly-derived signalling through proteolysis, which may be mediated by cell molecules, which may be secreted by the host cells or membrane-bound proteolytic enzymes (ectopeptidases) the tumour cell itself. expressed on the surface of tumour or host cells. Autocrine, paracrine and juxtacrine modulation of Cell membrane-bound proteolytic enzymes cell signalling by growth factors, cytokines, hormones (ectopeptidases) are multifunctional membrane proteins, and signalling peptides plays a key role in the promotion which are widely distributed among various cell of proliferation, inhibition of apoptosis, and facilitation systems. Ectopeptidases are integral membrane proteins, of invasion and migration through tissues, as well as the orientated asymmetrically with the catalytic site exposed induction of angiogenesis. Synthesis and/or amplified to the extracellular surface, which enables a versatile secretion of growth factors and regulatory peptides is range of physiological and pathological functions, often a feature obtained during carcinogenesis, even of ranging from proteolytic 'shedding' of signalling non-endocrine tumours, and a single tumour may molecules, degradation of the extracellular matrix and express a number of different autocrine or paracrine tissue remodelling, to adhesion and cell migration, and loops to maintain malignant growth. Both autocrine and the transduction of specific intracellular signals and paracrine loops have been observed in most cancers, and involvement in inflammation. these cell signalling pathways are frequently composed Proteases may regulate the release of many growth of three main aspects. Extracellular signalling molecules factors and their receptors into the circulation, as well as bind to cell-surface receptors, which activate activating or inactivating circulating signalling intracellular circuits to initiate the cellular effect (Fig. 1). molecules. Additionally, many proteases have functions Alterations in any of these pathway components may not limited to proteolysis, but are able in themselves to give rise to tumour biology-relevant modifications in function as receptors, transducing intracellular signals. cell signalling and affect the sensitivity of the tumour The individual ectopeptidases are each able to perform cell to external stimuli: changes to the availability of several, often overlapping functions, and, as a result, the extracellular signalling molecules by increased or expression of each ectopeptidase must be precisely decreased synthesis, to the transcellular transducers of regulated, in a tissue- and cell-specific manner. Even a those signals, such as the receptor molecules, or to the minor disruption in the normal proteolytic equilibrium functioning of the intracellular circuits by structural can influence the development of inflammatory and changes to molecular components. autoimmune diseases (Bank et al., 2000). Functions, While the majority of molecular analyses in cancer such as cell-signalling, matrix degradation, cell adhesion searched for changes in the intracellular circuits, little is and migration, which are particularly important for known about the biological function of cell surface tumour cell growth and dissemination have been molecules that modulate the immediate cellular reported for a number of ectopeptidases. Fig. 1. Ectopeptidase modulation of signal transduction pathways. Inactivation or activation of extracellular signalling molecules by ectopeptidases may modulate intracellular signalling pathways by regulating the availability of ligands for their receptors, of which there may be a varied range, often with more than one subtype (modified from Ino et al., 2004). 1341 Ectopeptidases in tumour biology Neutral endopeptidase 24.11 (NEP) inactivating growth-promoting peptides (Papandreou et al., 1998), promoting apoptosis (Sumitomo et al., 2000a) Neutral endopeptidase 24.11 (NEP, neprilysin, and inhibiting migration (Sumitomo et al., 2000b). enkephalinase, CD10, EC 3.4.24.11) is a 90-110 kDa Indeed, in the liver, the overall expression pattern of zinc-dependent metallopeptidase belonging to the NEP corresponds to proliferation and/or differentiation gluzincin family of metallopeptidases. The type II of hepatocytes. NEP is generally expressed by bile integral membrane protein is identical to the common canaliculi in normal liver and many HCCs (Chu and acute lymphoblastic leukaemia antigen (CALLA). The Arber 2000; Borscheri et al., 2001; Chu et al., 2002). 80kb NEP gene is located on chromosome 3q21-27 However, NEP is only occasionally expressed by foetal (Barker et al., 1989), and the transcribed mRNAs range hepatocytes (Röcken et al., 2004). The association from 2.7 to 5.7 kb and exhibit tissue-specific and between proliferation and NEP expression in

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