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 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.
Casazza
Andrea
A
Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy.
Finisguerra
Veronica
V
Capparuccia
Lorena
L
Camperi
Andrea
A
Swiercz
Jakub M
JM
Rizzolio
Sabrina
S
Rolny
Charlotte
C
Christensen
Claus
C
Bertotti
Andrea
A
Sarotto
Ivana
I
Risio
Mauro
M
Trusolino
Livio
L
Weitz
Jurgen
J
Schneider
Martin
M
Mazzone
Massimiliano
M
Mazzone
Massimilano
M
Comoglio
Paolo M
PM
Tamagnone
Luca
L
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
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