Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform.
Bottom Line: 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.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.In summary, we conclude that Uncl-Sema3E is a novel inhibitor of tumour angiogenesis and growth that concomitantly hampers metastatic spreading.
Affiliation: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy.Show MeSH
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Mentions: The disruption of vessel networks usually correlates with deficient tissue oxygenation. In fact, we found that Uncl-Sema3E-expressing tumours were diffusely hypoxic as revealed by pimonidazole (PIMO) staining (Fig 6A) and heavily apoptotic compared to controls (Fig 6B); this likely accounted for the observed shrinkage of the tumours, as the mitotic index was not significantly affected by the treatment (Fig 6C). Notably, tumours expressing Uncl-Sema3E did not give rise to increased secondary metastatic foci with respect to controls (Fig 6D), whereas we have previously shown that either wild-type cleavable Sema3E or the mature fragment p61 are actively pro-metastatic in vivo (Casazza et al, 2010).
Affiliation: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy.