“Galectin-1 regulates neovascularization through ERK1/2 and PI3K/AKT-dependent pathways”

D. O CROCI,; M. SALATINO,; N. RUBINSTEIN,; M. TOSCANO,; J.M. ILARREGUI,; G. BIANCO,; G.A. RABINOVICH

Valle Hermoso, Córdoba

Workshop; Meeting Tango Lessons for Brain Cancer Research: Understanding Cellular Intrincacy, Improvising New Therapies”.; 2007

James S. McDonnel Foundation Workshop”

Accumulating evidence, Based on resistance to VEGF-targeted antiangiogenic strategies suggest the contribution of alternative ‘non-canonical’ pathways to hypoxia-driven neovascularization. Here we identified a regulatory circuit, mediated by lectin-glycan lattices, which links tumor hypoxia to HIF-1a-independent VEGFR2-mediated neovascularization. Instauration of a tumor hypoxic microenvironment resulted in HIF-1a-independent, ROS- and NF-kB-dependent up-regulation of galectin-1 and , which promoted endothelial cell proliferation, migration and morphogenesis through specific cross-linking of N-glycans on VEGFR2 (KDR) and activation of PI3K/Akt and ERK1/2 signaling pathways. These pro-angiogenic effects were independent of VEGF; yet they involved VEGFR2 phosphorylation and its segregation into membrane microdomains. In a highly vascularized model of Kaposi’s Sarcoma (KS), disruption of galectin-glycan lattices either by shRNA-mediated silencing of galectin-1 or hindrance of N-glycan elongation, prevented hypoxia-driven angiogenesis. Moreover, therapeutic intervention using galectin-1-specific blocking antibodies suppressed tumor growth and promoted vascular normalization, as shown by decreased microvessel density, increased pericyte coverage and improved tumor oxygenation. In human biopsies, galectin-1 expression correlated with pathological angiogenesis and delineated the transition from benign to malignant vascular lesions, including KS. Thus, in addition to stimulating antitumor immunity, disruption of galectin-1-glycan lattices may contribute to normalize vascular networks in tumors resistant to current anti-angiogenic therapies.