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

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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 an...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Artículo publishedVersion
Lenguaje:Inglés
Publicado: 2012
Materias:
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
Acceso en línea:http://hdl.handle.net/20.500.12110/paper_00221007_v209_n11_p1985_Croci
Aporte de:
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires
Descripción
Sumario: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.

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