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RESEARCH ARTICLEAn HGFMSP chimera disassociates the
trophic properties of scatter factors from their
pro-invasive activity.com2002 Nature Publishing Group http://biotech.naturePaolo Michieli1*, Silvia Cavassa1, Cristina Basilico1, Annarita De Luca1, Massimiliano Mazzone1, Cinzia Asti2,
Riccardo Chiusaroli2, Mario Guglielmi2, Paola Boss2, Francesco Colotta2, Gianfranco Caselli2,
and Paolo M. Comoglio1Hepatocyte 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 -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.Hepatocyte growth factor (HGF) is a pleiotropic factor that promotes mitogenesis, scattering, motogenesis, survival, and morphogenetic remodeling of a wide spectrum of tissues, including
epithelial, endothelial, hematopoietic, and neuronal cells18. The
coordinated orchestration of these processes by HGF plays a major
role in organ formation during embryogenesis and in tissue homeostasis in adults913. HGF is secreted as a single-chain precursor
(pro-HGF) that needs proteolytic activation by specific proteases to
acquire biological activity14,15. Pro-HGF is found in serum and in
the extracellular matrix of several tissues, where it accumulates as a
result of its high affinity for proteoglycans16,17. Upon tissue injury,
upregulation of specific pro-HGF convertases, including urokinase
and HGF activator, is responsible for a local burst in active HGF that
limits cell damage and induces tissue regeneration1820.Unfortunately, the very same HGF-controlled processes that promote organ development and maintain tissue complexity are
responsible for tumor invasiveness. Inappropriate activation of the
HGF pathway induces invasive growth, a malignant process by which
cancer cells weaken tissue constraints and invade foreign areas,
where they migrate and give rise to metastases2124. The HGF receptorthe Met tyrosine kinaseis activated in human cancer by...