Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform.
Bottom Line: 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.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: Consistent with its potent regulatory activity on integrin function and cytoskeletal dynamics, we found that Uncl-Sema3E strongly inhibited endothelial cell migration in a PlexinD1-dependent manner (Fig 4A); notably, this activity paralleled that of the proteolytic fragment p61 (Casazza et al, 2011). Moreover, we found that this inhibitory effect of Sema3E in endothelial cells is dependent on the expression of the intracellular adaptor molecule Rnd2 (Supporting Information Fig 5B). We further assessed the activity of Uncl-Sema3E in HUVEC engaged in vascular tube formation. In fact, HUVEC grown in vitro on a basement membrane matrix (Matrigel) undergo spontaneous alignment into hollow tubes, forming capillary-like networks within 24 h (Grant et al, 1989). However, we found that endothelial tubule formation and stability was significantly impaired in the presence of Uncl-Sema3E compared to untreated cultures (Fig 4B). Moreover, when HUVEC were grown as spheroids in a three-dimensional collagen matrix in the presence of basic fibroblast growth factor (bFGF), they formed elongated sprouts, which were significantly reduced in the presence of either Uncl-Sema3E or the proteolytic fragment p61 (Fig 4C). These data further indicated that full-length uncleaved Sema3E is not an inactive precursor molecule, since it can elicit a potent PlexinD1-mediated inhibitory response in endothelial cells. Moreover, they demonstrated that the endothelial-repelling function of Sema3E pre-exists to, and it is not significantly blocked by, the proteolytic processing of the molecule. Taken together, these findings characterize Uncl-Sema3E as a partial agonist of PlexinD1 as compared to the cleaved mature p61 fragment. In fact, Uncl-Sema3E is able to bind to Plexin-D1 and elicits endothelial cell repulsion and anti-angiogenic activity in vitro, but unlike p61, it is unable to trigger the ErbB2-dependent pathway in cancer cells, and instead, it antagonizes this major signal promoting invasion and metastasis.
Affiliation: Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy.