8th Euro Global Summit on Cancer Therapy
University of Rouen, UK
Title: Vasoactive peptide urotensin II as a new chemokine exhibiting migration/adhesion mesenchymal properties during glioma development: New therapeutic target
Biography: Helene Castel
One of the most potent vasoactive peptides, urotensin II (UII), is involved in endothelial cell proliferation and migration, by activating a G protein-coupled receptor, the UT receptor. We showed a high expression of UII/UT in human glioblastomas (GBM), gliosarcoma and a number of carcinoma compared to oligodendrogliomas or health brain tissue. In GBM, a strong staining in vascular and peri-necrotic area and a systematic co-expression of UII/UT with SDF1α/CXCR4 were observed. In glioma and endothelial cells, gradient concentrations of UII induced chemoattracting migratory eff ects and tube formation. Th is eff ect was blocked by UT antagonists and mainly involved the G13/Rho/ROCK pathway while partially requiring Gi/o/PI3K components. In contrast, we observed that homogeneous concentrations of UII blocked cell motility and stimulated cell-matrix adhesions through a UT/Gi/o signaling cascade, partially involving PI3K. Finally, homogeneous concentration of UII allowed translocation of Gα13 to the UT receptor at the plasma membrane and increased actin stress fi bers, lamellipodia formation and vinculin-stained focal adhesions. UII also induced relocalization of UT pre-coupled to Gαi in fi lipodia and initiated integrin-stained focal points. In C57/Bl6 mice, UT agonists stimulated matrigel sponge invasion by macrophages, endothelial and smooth muscle cells, stressing the chemokine and pro-neoangiogenic properties of UII in vivo. In heterotopic GBM xenograft ed in Nude mice, intratumoral injection of UII accelerated tumor growth and necrosis, and stimulated neo-angiogenesis through metalloprotease activation. UT Antagonists/biased ligands inhibited tumor growth, neo-angiogenesis and prolonged mice survival. Micro-SPECT imaging showed increased integrin expression, correlated with large necrotic area in tumors treated with UII. Th us, UII promotes the recruitment of pro-angiogenic cells, induces cell adhesions and stimulates necrosis and neo-angiogenesis involved in glioblastoma growth. Th e specifi c blockage of UT signalings by using antagonists or biased ligands would constitute a new route for the treatment of GBM.