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 language | English |
|---|---|
| Pages (from-to) | 234-250 |
| Number of pages | 17 |
| Journal | EMBO Molecular Medicine |
| Volume | 4 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2012 |
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Keywords
- Angiogenesis
- Metastasis
- Plexin
- Semaphorin
- Tumour growth
ASJC Scopus subject areas
- Molecular Medicine
Cite this
Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. / Casazza, Andrea; Kigel, Boaz; Maione, Federica; Capparuccia, Lorena; Kessler, Ofra; Giraudo, Enrico; Mazzone, Massimiliano; Neufeld, Gera; Tamagnone, Luca.
In: EMBO Molecular Medicine, Vol. 4, No. 3, 03.2012, p. 234-250.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform
AU - Casazza, Andrea
AU - Kigel, Boaz
AU - Maione, Federica
AU - Capparuccia, Lorena
AU - Kessler, Ofra
AU - Giraudo, Enrico
AU - Mazzone, Massimiliano
AU - Neufeld, Gera
AU - Tamagnone, Luca
PY - 2012/3
Y1 - 2012/3
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Metastasis
KW - Plexin
KW - Semaphorin
KW - Tumour growth
UR - http://www.scopus.com/inward/record.url?scp=84858114637&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84858114637&partnerID=8YFLogxK
U2 - 10.1002/emmm.201100205
DO - 10.1002/emmm.201100205
M3 - Article
C2 - 22247010
AN - SCOPUS:84858114637
VL - 4
SP - 234
EP - 250
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 3
ER -