An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice.
Scatter factor (SF), also known as hepatocyte growth factor, is ubiquitously present in the extracellular matrix of tissues in the form of an inactive precursor (pro-SF). In order to acquire biological activity, pro-SF must be cleaved by specific proteases present on the cell surface. The mature form of SF controls invasive cues in both physiological and pathological processes through activation of its receptor, the Met tyrosine kinase. By substituting a single amino acid in the proteolytic site, we engineered an unprocessable form of pro-SF (uncleavable SF). Using lentivirus vector technology, we achieved local or systemic delivery of uncleavable SF in mice. We provide evidence that (a) uncleavable SF inhibits both protease-mediated pro-SF conversion and active SF-induced Met activation; (b) local expression of uncleavable SF in tumors suppresses tumor growth, impairs tumor angiogenesis, and prevents metastatic dissemination; and (c) systemic expression of uncleavable SF dramatically inhibits the growth of transplanted tumors and abolishes the formation of spontaneous metastases without perturbing vital physiological functions. These data show that proteolytic activation of pro-SF is a limiting step in tumor progression, thus suggesting a new strategy for the treatment or prevention of the malignant conversion of neoplastic lesions.
Mazzone
Massimiliano
M
Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy.
Basilico
Cristina
C
Cavassa
Silvia
S
Pennacchietti
Selma
S
Risio
Mauro
M
Naldini
Luigi
L
Comoglio
Paolo M
PM
Michieli
Paolo
P
D019943:Amino Acid Substitution; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology; D002277:Carcinoma / Q000473:pathology; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D005973:Glutamine / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009362:Neoplasm Metastasis / Q000628:therapy*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D015202:Protein Engineering; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D047368:Tumor Burden
D011994:Recombinant Proteins; D005973:Glutamine; D017228:Hepatocyte Growth Factor; D003094:Collagen; D008715:Methionine; D011505:Protein-Tyrosine Kinases