J Mol Med (2005) 83: 856–864 DOI 10.1007/s00109-005-0692-y REVIEW Abdel-Majid Khatib . Daniel Bassi . Geraldine Siegfried . Andres J. P. Klein-Szanto . L ’Houcine Ouafik Endo/exo-proteolysis in neoplastic progression and metastasis Received: 1 December 2004 / Accepted: 22 April 2005 / Published online: 26 August 2005 # Springer-Verlag 2005 Abstract Biological control of individual cells, organs, and organisms is achieved through interplay of a host of specific interactions that involve various peptidic mole- cules as modulators or effectors. In tumor cells, these processes may result in uncontrolled growth as a con- sequence of autocrine and/or paracrine actions. In recent years, growing evidence has accumulated for the important role of proprotein convertases (PCs) and peptide α-ami- dation enzymes in these processes. The widespread belief that these enzymes are involved in the major features of tumor progression, namely, invasiveness and metastasis, has taken place because of their capacity to process and activate many protein precursors involved in the neoplastic progression and metastasis. This includes degrading extra- cellular matrix proteases, growth promoting factors, and adhesion molecules. Usually, when the processing of these precursor proteins is achieved by one or more of the known PC family members within the general motif (K/R)-(X) n - (K/R)↓, where n=0, 2, 4, or 6, and X, any amino acid except Cys, the accomplishment of the maturation of these molecules is attained by various posttranslational mod- ifications, including the carboxy-terminal α-amidation. This review article summarizes recent findings on the role of these enzymatic systems in multiple cellular functions that impact on the invasive/metastatic potential of cancer cells and highlight the potential use of their inhibitors in the treat- ment of multiple cancers. Introduction Cellular proliferation, differentiation, and adhesion are complex biological processes in which different systems MAJID KHATIB obtained his Ph.D. in Cell and Molecular Biology from the University of Paris. As a scien- tist, he first joined the Ottawa Health Research Institute at the University of Ottawa (Ottawa, Canada), and he is currently working at the INSERM, Paris. His research interests are deal- ing with the role of proteins maturation by the convertases in health and disease. L’HOUCINE QUAFIK obtained his Ph.D. in Molecular and Cellular Biology from the University of Meditterannée (Merseilles, France). He is now the head of EMI 0359 research laboratory. His research inter- ests are tumor growth and angiogenesis in glioblastomas and prostate cancer. A.-M. Khatib (*) Laboratoire de Pharmacologie Expérimentale et Clinique, INSERM U 716, Institut de Génétique Moléculaire, Paris, France e-mail: Majid.Khatib@stlouis.inserm.fr Tel.: +33-1-42499260 Fax: +33-1-42494838 A.-M. Khatib Regional Protein Chemistry Centre, Diseases of Ageing Unit, Ottawa Health Research Institute, Loeb Building, 725 Parkdale Ave., Ottawa, Ontario, K1Y 4E9, Canada D. Bassi . A. J. P. Klein-Szanto Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA G. Siegfried INSERM U143, 84 Rue Général Leclerc, 94276 Le Kremlin-Bicêtre, France L. Ouafik Laboratoire de Cancérologie Expérimentale, INSERM E359, IFR Jean-Roche, Faculté de médecine Nord, Marseille, France