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

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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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
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Acceso en línea:http://hdl.handle.net/20.500.12110/paper_00221007_v209_n11_p1985_Croci
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spelling paperaa:paper_00221007_v209_n11_p1985_Croci2023-06-12T16:43:49Z Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma J. Exp. Med. 2012;209(11):1985-2000 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. 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 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. 2012 info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion application/pdf eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00221007_v209_n11_p1985_Croci
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-134
collection Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
language Inglés
orig_language_str_mv eng
topic 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
spellingShingle 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
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.
Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma
topic_facet 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
description 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.
format Artículo
Artículo
publishedVersion
author 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.
author_facet 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.
author_sort Croci, D.O.
title Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma
title_short Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma
title_full Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma
title_fullStr Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma
title_full_unstemmed Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma
title_sort disrupting galectin-1 interactions with n-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in kaposi's sarcoma
publishDate 2012
url http://hdl.handle.net/20.500.12110/paper_00221007_v209_n11_p1985_Croci
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