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

Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, 1428 Buenos Aires, Argentina.
Journal of Experimental Medicine (Impact Factor: 13.91). 10/2012; 209(11):1985-2000. DOI: 10.1084/jem.20111665

ABSTRACT 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.

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