Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma

• Autores: Croci, D.O.; Salatino, M.; Rubinstein, N.; Cerliani, J.P.; Cavallin, L.E.; Leung, H.J.; Ouyang, J.; Ilarregui, J.M.; Toscano, M.A.; Domaica, C.I.; Croci, M.C.; Shipp, M.A.; Mesri, E.A.; Albini, A.; Rabinovich, G.A.
• Año de publicación: 2012
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: J. Exp. Med. 2012;209(11):1985-2000
• Materia: galectin 1; glycan; hypoxia inducible factor 1alpha; hypoxia inducible factor 2alpha; immunoglobulin enhancer binding protein; messenger RNA; monoclonal antibody; reactive oxygen metabolite; angiogenesis; animal cell; animal experiment; animal model; animal tissue; apoptosis; article; carcinogenesis; cell growth; cell invasion; cell migration; cell proliferation; controlled study; human; human cell; human tissue; hypoxia; in vivo study; Kaposi sarcoma; male; mouse; nonhuman; priority journal; protein expression; protein function; protein protein interaction; protein targeting; spindle cell; tumor regression; Animals; Anoxia; Antibodies, Monoclonal; Antibodies, Neutralizing; Cell Hypoxia; Cell Line, Tumor; Cells, Cultured; Galectin 1; Gene Expression Regulation, Neoplastic; HEK293 Cells; Herpesvirus 8, Human; Host-Pathogen Interactions; Humans; Immunoblotting; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Neovascularization, Pathologic; Polysaccharides; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sarcoma, Kaposi; Xenograft Model Antitumor Assays
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

Kaposi's sarcoma (KS), a multifocal vascular neoplasm linked to human herpesvirus-8 (HHV-8/KS-associated herpesvirus [KSHV]) infection, is the most common AIDS-associated malignancy. Clinical management of KS has proven to be challenging because of its prevalence in immunosuppressed patients and its unique vascular and inflammatory nature that is sustained by viral and host-derived paracrine-acting factors primarily released under hypoxic conditions. We show that interactions between the regulatory lectin galectin-1 (Gal-1) and specific target N-glycans link tumor hypoxia to neovascularization as part of the pathogenesis of KS. Expression of Gal-1 is found to be a hallmark of human KS but not other vascular pathologies and is directly induced by both KSHV and hypoxia. Interestingly, hypoxia induced Gal-1 through mechanisms that are independent of hypoxia-inducible factor (HIF) 1α and HIF-2α but involved reactive oxygen species-dependent activation of the transcription factor nuclear factor κB. Targeted disruption of Gal-1-N-glycan interactions eliminated hypoxia-driven angiogenesis and suppressed tumorigenesis in vivo. Therapeutic administration of a Gal-1-specific neutralizing mAb attenuated abnormal angiogenesis and promoted tumor regression in mice bearing established KS tumors. Given the active search for HIF-independent mechanisms that serve to couple tumor hypoxia to pathological angiogenesis, our findings provide novel opportunities not only for treating KS patients but also for understanding and managing a variety of solid tumors. © 2012 Croci et al.
Fil:Croci, D.O. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Salatino, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Rubinstein, N. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Ilarregui, J.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Toscano, M.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Domaica, C.I. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.
Fil:Mesri, E.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.