title: Melanoma cell therapy: Endothelial progenitor cells as shuttle of the MMP12 uPAR-degrading enzyme.
abstract: The receptor for the urokinase-type plasminogen activator (uPAR) accounts for many features of cancer progression, and is therefore considered a target for anti-tumoral therapy. Only full length uPAR mediates tumor progression. Matrix-metallo-proteinase-12 (MMP12)-dependent uPAR cleavage results into the loss of invasion properties and angiogenesis. MMP12 can be employed in the field of "targeted therapies" as a biological drug to be delivered directly in patient's tumor mass. Endothelial Progenitor Cells (EPCs) are selectively recruited within the tumor and could be used as cellular vehicles for delivering anti-cancer molecules. The aim of our study is to inhibit cancer progression by engeneering ECFCs, a subset of EPC, with a lentivirus encoding the anti-tumor uPAR-degrading enzyme MMP12. Ex vivo manipulated ECFCs lost the capacity to perform capillary morphogenesis and acquired the anti-tumor and anti-angiogenetic activity. In vivo MMP12-engineered ECFCs cleaved uPAR within the tumor mass and strongly inhibited tumor growth, tumor angiogenesis and development of lung metastasis. The possibility to exploit tumor homing and activity of autologous MMP12-engineered ECFCs represents a novel way to combat melanoma by a "personalized therapy", without rejection risk. The i.v. injection of radiolabelled MMP12-ECFCs can thus provide a new theranostic approach to control melanoma progression and metastasis.
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Laurenzana
authors.forename: Alessio
authors.initials: A
authors.lastname: Biagioni
authors.forename: Silvia
authors.initials: S
authors.lastname: D'Alessio
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.forename: Anastasia
authors.initials: A
authors.lastname: Chillà
authors.forename: Francesca
authors.initials: F
authors.lastname: Margheri
authors.forename: Cristina
authors.initials: C
authors.lastname: Luciani
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzanti
authors.forename: Nicola
authors.initials: N
authors.lastname: Pimpinelli
authors.forename: Eugenio
authors.initials: E
authors.lastname: Torre
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.forename: Lido
authors.initials: L
authors.lastname: Calorini
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Italy; ITT, Istituto Toscano Tumori.
authors.forename: Mario
authors.initials: M
authors.lastname: Del Rosso
authors.affiliation: Department of Experimental and Clinical Biomedical Science, University of Florence, Italy; ITT, Istituto Toscano Tumori.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Fibbi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D066026:Endothelial Progenitor Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D055293:Receptors, Urokinase Plasminogen Activator / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator; D053508:Matrix Metalloproteinase 12