Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice

Luca Tamagnone, Andrea Casazza, Veronica Finisguerra, Lorena Capparuccia, Andrea Camperi, Jakub M. Swiercz, Sabrina Rizzolio, Charlotte Rolny, Claus Christensen, Andrea Bertotti, Ivana Sarotto, Mauro Risio, Livio Trusolino, Jurgen Weitz, Martin Schneider, Massimilano Mazzone, Paolo M. Comoglio

Risultato della ricerca: Contributo in rivistaArticolo in rivista

118 Citazioni (Scopus)

Abstract

Semaphorin 3E (Sema3E) is a secreted molecule implicated in axonal path finding and inhibition of developmental and postischemic angiogenesis. Sema3E is also highly expressed in metastatic cancer cells, but its mechanistic role in tumor progression was not understood. Here we show that expression of Sema3E and its receptor Plexin D1 correlates with the metastatic progression of human tumors. Consistent with the clinical data, knocking down endogenous expression of either Sema3E or Plexin D1 in human metastatic carcinoma cells hampered their metastatic potential when injected into mice, while tumor growth was not markedly affected. Conversely, overexpression of exogenous Sema3E in cancer cells increased their invasiveness, transendothelial migration, and metastatic spreading, although it inhibited tumor vessel formation, resulting in reduced tumor growth in mice. The proinvasive and metastatic activity of Sema3E in tumor cells was dependent on transactivation of the Plexin D1-associated ErbB2/Neu oncogenic kinase. In sum, Sema3E-Plexin D1 signaling in cancer cells is crucially implicated in their metastatic behavior and may therefore be a promising target for strategies aimed at blocking tumor metastasis.
Lingua originaleEnglish
pagine (da-a)2684-2698
Numero di pagine15
RivistaTHE JOURNAL OF CLINICAL INVESTIGATION
Volume120
DOI
Stato di pubblicazionePubblicato - 2010

Keywords

  • Animals
  • COS Cells
  • Cell Adhesion Molecules, Neuronal
  • Cell Line, Tumor
  • Cell Movement
  • Cercopithecus aethiops
  • Female
  • Humans
  • Medicine (all)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Receptor, ErbB-2
  • Semaphorins
  • Signal Transduction
  • ras Proteins
  • rho GTP-Binding Proteins

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