Targeting the tumor and its microenvironment by a dual-function decoy Met receptor.
Met, the receptor for hepatocyte growth factor (HGF), is activated in human cancer by both ligand-dependent and -independent mechanisms. We engineered a soluble Met receptor (decoy Met) that interferes with both HGF binding to Met and Met homodimerization. By lentiviral vector technology, we achieved local or systemic delivery of decoy Met in mice. We provide evidence that in vivo expression of decoy Met (1) inhibits tumor cell proliferation and survival in a variety of human xenografts, (2) impairs tumor angiogenesis by preventing host vessel arborization, (3) suppresses or prevents the formation of spontaneous metastases, and (4) synergizes with radiotherapy in inducing tumor regression, without (5) affecting housekeeping physiological functions in the adult animal.
Michieli
Paolo
P
Division of Molecular Oncology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, I-10060 Candiolo (Torino), Italy. paolo.michieli@ircc.it
Mazzone
Massimiliano
M
Basilico
Cristina
C
Cavassa
Silvia
S
Sottile
Antonino
A
Naldini
Luigi
L
Comoglio
Paolo M
PM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D019281:Dimerization; D018572:Disease-Free Survival; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met