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

DIEGO CROCCI; MARIANA SALATINO; NATALIA RUBINSTEIN; L CAVALLIN; H LEUNG; J OUYANG; J ILARREGUI; M TOSCANO; J CERLIANI; C DOMAICA; C CROCI; M SHIPP; E MESRI; A ALBINI ; G RABINOVICH.

JOURNAL OF EXPERIMENTAL MEDICINE

ROCKEFELLER UNIV PRESS

Lugar: New York; Año: 2012

0022-1007

SUMMARY Kaposi?s sarcoma (KS), a multifocal vascular neoplasm linked to human herpesvirus-8 (HHV-8/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. Here we show that interactions between the regulatory lectin, galectin-1 (Gal1) and specific target N-glycans link tumor hypoxia to neovascularization as part of the pathogenesis of KS. Expression of Gal1 was found to be a hallmark of human KS but not other vascular pathologies and was directly induced by KSHV and hypoxia. Interestingly, hypoxia induced Gal1 through mechanisms that were independent of hypoxia-inducible factor (HIF)-1 and HIF-2, but involved reactive oxygen species (ROS)-dependent activation of the transcription factor nuclear factor (NF)-B. Targeted disruption of Gal1-N-glycan interactions eliminated hypoxia-driven angiogenesis and suppressed tumorigenesis in vivo. Therapeutic administration of a Gal1-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.