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

 

Autores
Croci Russo, Diego Omar; Salatino, Mariana; Rubinstein, Natalia; Cerliani, Juan Pablo; Cavallin, Lucas E.; Leung, Howard J.; Ouyang, Jing; Ilarregui, Juan Martin; Toscano, Marta Alicia; Domaica, Carolina Ines; Croci, María C.; Shipp, Margaret A.; Mesri, Enrique A.; Albini, Adriana; Rabinovich, Gabriel Adrian
Tipo de recurso
artículo
Estado
Versión publicada
Año de publicación
2012
País
Argentina
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
Repositorio
CONICET Digital (CONICET)
Descripción
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.
Idioma
inglés
OAI Identifier
oai:ri.conicet.gov.ar:11336/12352
Enlace del recurso
http://hdl.handle.net/11336/12352
Nivel de acceso
Acceso abierto
Materia
GAlectin -1
angiogenesis
hypoxia
Kaposi's Sarcoma
Otras Medicina Básica
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD