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 Russo, Diego Omar, Salatino, Mariana, Rubinstein, Natalia, Ilarregui, Juan Martín, Toscano, Marta Alicia, Domaica, Carolina Inés, Mesri, Enrique Alfredo
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:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00221007_v209_n11_p1985_Croci 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

id	paper:paper_00221007_v209_n11_p1985_Croci
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spelling	paper:paper_00221007_v209_n11_p1985_Croci2023-06-08T14:45:50Z Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma Croci Russo, Diego Omar Salatino, Mariana Rubinstein, Natalia Ilarregui, Juan Martín Toscano, Marta Alicia Domaica, Carolina Inés Mesri, Enrique Alfredo 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 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00221007_v209_n11_p1985_Croci 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)
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 Russo, Diego Omar Salatino, Mariana Rubinstein, Natalia Ilarregui, Juan Martín Toscano, Marta Alicia Domaica, Carolina Inés Mesri, Enrique Alfredo 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.
author	Croci Russo, Diego Omar Salatino, Mariana Rubinstein, Natalia Ilarregui, Juan Martín Toscano, Marta Alicia Domaica, Carolina Inés Mesri, Enrique Alfredo
author_facet	Croci Russo, Diego Omar Salatino, Mariana Rubinstein, Natalia Ilarregui, Juan Martín Toscano, Marta Alicia Domaica, Carolina Inés Mesri, Enrique Alfredo
author_sort	Croci Russo, Diego Omar
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	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00221007_v209_n11_p1985_Croci http://hdl.handle.net/20.500.12110/paper_00221007_v209_n11_p1985_Croci
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Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi's sarcoma

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