title: Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice.
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.
authors.affiliation: Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Casazza
authors.forename: Veronica
authors.initials: V
authors.lastname: Finisguerra
authors.forename: Lorena
authors.initials: L
authors.lastname: Capparuccia
authors.forename: Andrea
authors.initials: A
authors.lastname: Camperi
authors.forename: Jakub M
authors.initials: JM
authors.lastname: Swiercz
authors.forename: Sabrina
authors.initials: S
authors.lastname: Rizzolio
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rolny
authors.forename: Claus
authors.initials: C
authors.lastname: Christensen
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.forename: Ivana
authors.initials: I
authors.lastname: Sarotto
authors.forename: Mauro
authors.initials: M
authors.lastname: Risio
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.forename: Jurgen
authors.initials: J
authors.lastname: Weitz
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Massimilano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Luca
authors.initials: L
authors.lastname: Tamagnone
mesh_terms: D000818:Animals; D019556:COS Cells; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D039961:Semaphorins / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics; D020741:rho GTP-Binding Proteins / Q000032:analysis
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D039961:Semaphorins; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; C493082:PLXND1 protein, human; C494123:SEMA3E protein, human; C508053:ERBB2 protein, human; C085929:RRAS protein, human; C508704:RND2 protein, human