Dissecting the role of extracellular galectin-1 in the regulation of neovascularization

D. O. CROCI1, M. SALATINO1, N. RUBINSTEIN1, L. PELARI2, A. ALBINI2, G. A. RABINOVICH1;

Rio de Janeiro, Brazil

Congreso; 13th International Congress of Immunology; 2007

Angiogenesis is a critical process for tumor progression. We previously demonstrated that galectin-1, a glycan-binding protein with immunosuppressive activity, controls tumor growth by favoring tumor-immune escape and promoting angiogenesis in a model of Kaposi Sarcoma. The present study was focussed on dissecting the mechanisms underlying the proangiogeneic effects of galectin-1. Recombinant galectin-1 bound human umbilical vascular endothelial cells (HUVEC) in a dose-dependent manner. This effect was carbohydrate-dependent since it was prevented by lactose,a specific disaccharide (p<0.01). Moreover, treatment of HUVEC cells with recombinant galectin-1 promoted tubulogenesis (p<0.01) and proliferation (p<0.05). A mechanistic analysis of the intracellular signals involved in this effect revealed a pronounced increase in phosphorylated-Akt and Erk½ following galectin-1 treatment (F.I>3) To evaluate the relevance of MAPK and PI3K/Akt pathways in galectin-1-induced angiogenesis we analyzed the requirement of these pathways for endothelial tubule-like formation and proliferation. Pretreatment of HUVEC with either PI3K-inhibitor LY294.002 (2ìM) or Erk1/2-inhibitor U0126 (5ìM) abolished the ability of galectin-1 to induce tubulogenesis (p<0.01) and proliferation (p<0.05). Finally, expression of galectin-1 in human Kaposi sarcoma cells was found to be strongly up-regulated under conditions of profound hypoxia, the main proangiogenic stimulus. Our results suggest that hypoxia-regulated galectin-1 is a key modulator of tumor cell angiogenesis by promoting tubulogenesis and proliferation of endothelial cells through ERK1/2 and PI3K/Akt-dependent pathways. Thus galectin-1 present in the tumor microenvironment, not only regulates tumor-immune escape but also controls other critical events in tumor progression including cell migration and angiogenesis. Whether these events are interconnected still remains to be elucidated.