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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2010-08, Vol.120 (8), p.2684-2698
Main Authors: Casazza, Andrea, Finisguerra, Veronica, Capparuccia, Lorena, Camperi, Andrea, Swiercz, Jakub M, Rizzolio, Sabrina, Rolny, Charlotte, Christensen, Claus, Bertotti, Andrea, Sarotto, Ivana, Risio, Mauro, Trusolino, Livio, Weitz, Jurgen, Schneider, Martin, Mazzone, Massimiliano, Mazzone, Massimilano, Comoglio, Paolo M, Tamagnone, Luca
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Biomedical research
Cancer
Cancer cells
Cancer invasiveness
Cell adhesion & migration
Cell Adhesion Molecules, Neuronal - physiology
Cell Line, Tumor
Cell Movement
Cellular signal transduction
Cercopithecus aethiops
Colon
COS Cells
Development and progression
Female
Gene expression
Genetic aspects
Humans
Kinases
Melanoma
Metastasis
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplasm Transplantation
Properties
ras Proteins - genetics
Receptor, ErbB-2 - physiology
rho GTP-Binding Proteins - analysis
Semaphorins
Semaphorins - analysis
Semaphorins - physiology
Signal Transduction - physiology
Tumors
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI42118