An uncleavable form of pro-scatter factor suppresses tumor growth and dissemination in mice

Massimiliano Mazzone, Cristina Basilico, Silvia Cavassa, Selma Pennacchietti, Mauro Risio, Luigi Naldini, Paolo M. Comoglio, Paolo Michieli

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1418-1432
Number of pages15
JournalJournal of Clinical Investigation
Volume114
Issue number10
DOIs
Publication statusPublished - Nov 2004

ASJC Scopus subject areas

  • Medicine(all)

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