An HGF-MSP chimera disassociates the trophic properties of scatter factors from their pro-invasive activity.
Hepatocyte growth factor (HGF) and macrophage-stimulating protein (MSP) have an intrinsic dual nature: they are trophic cytokines preventing apoptosis on one side and scatter factors promoting invasion on the other. For therapeutic use, their anti-apoptotic activity must be separated from their pro-invasive activity. To this end, we engineered chimeric factors containing selected functional domains of HGF and/or MSP in different combinations, and tested their biological activity. Here we present a chimeric cytokine derived from the alpha-chains of HGF and MSP, named Metron factor 1 for its ability to concomitantly activate the HGF receptor (Met) and the MSP receptor (Ron). We provide evidence that Metron factor 1 prevents apoptosis and stimulates cell proliferation at nanomolar concentrations, but is devoid of any pro-invasive activity. In an in vivo murine model of drug-induced nephrotoxicity, intravenous injection of recombinant Metron factor 1 prevented renal damage and preserved tubular integrity.
Michieli
Paolo
P
Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, I-10060 Candiolo, Torino, Italy. pmichieli@ircc.unito.it
Cavassa
Silvia
S
Basilico
Cristina
C
De Luca
Annarita
A
Mazzone
Massimiliano
M
Asti
Cinzia
C
Chiusaroli
Riccardo
R
Guglielmi
Mario
M
Bossù
Paola
P
Colotta
Francesco
F
Caselli
Gianfranco
G
Comoglio
Paolo M
PM
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism*; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000473:pathology; D006133:Growth Substances / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D051437:Renal Insufficiency / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D003432:Cross-Linking Reagents; D016207:Cytokines; D006133:Growth Substances; D008024:Ligands; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; C082332:macrophage stimulating protein; C529731:metron factor-1; D017228:Hepatocyte Growth Factor