Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform

Andrea Casazza, Boaz Kigel, Federica Maione, Lorena Capparuccia, Ofra Kessler, Enrico Giraudo, Massimiliano Mazzone, Gera Neufeld, Luca Tamagnone

Research output: Contribution to journalArticlepeer-review

Abstract

Secreted Semaphorin 3E (Sema3E) promotes cancer cell invasiveness and metastatic spreading. The pro-metastatic activity of Sema3E is due to its proteolytic fragment p61, capable of transactivating the oncogenic tyrosine kinase ErbB2 that associates with the Sema3E receptor PlexinD1 in cancer cells. Here, we show that a mutated, uncleavable variant of Sema3E (Uncl-Sema3E) binds to PlexinD1 like p61-Sema3E, but does not promote the association of PlexinD1 with ErbB2 nor activates the ensuing signalling cascade leading to metastatic spreading. Furthermore, Uncl-Sema3E competes with endogenous p61-Sema3E produced by tumour cells, thereby hampering their metastatic ability. Uncl-Sema3E also acts independently as a potent anti-angiogenic factor. It activates a PlexinD1-mediated signalling cascade in endothelial cells that leads to the inhibition of adhesion to extracellular matrix, directional migration and cell survival. The putative therapeutic potential of Uncl-Sema3E was validated in multiple orthotopic or spontaneous tumour models in vivo, where either local or systemic delivery of Uncl-Sema3E-reduced angiogenesis, growth and metastasis, even in the case of tumours refractory to treatment with a soluble vascular endothelial growth factor trap. In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading.

Original languageEnglish
Pages (from-to)234-250
Number of pages17
JournalEMBO Molecular Medicine
Volume4
Issue number3
DOIs
Publication statusPublished - Mar 2012

Keywords

  • Angiogenesis
  • Metastasis
  • Plexin
  • Semaphorin
  • Tumour growth

ASJC Scopus subject areas

  • Molecular Medicine

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