DISRUPTING GALECTIN-1 INTERACTIONS WITH N-GLYCANS SUPPRESSES HYPOXIA-DRIVEN ANGIOGENESIS AND TUMORIGENESIS IN KAPOSI'S SARCOMA

CROCI DO; M. SALATINO; N. RUBINSTEIN; CERLIANI JP; CAVALLIN LE; LEUNG HJ; J. OUYANG; ILARREGUI JM; M. A. TOSCANO; CAROLINA I. DOMAICA; CROCI MC; MA. SHIPP; MESRI EA; A. ALBINI; G. A. RABINOVICH

JOURNAL OF EXPERIMENTAL MEDICINE

ROCKEFELLER UNIV PRESS

Lugar: New York; Año: 2012 vol. 209 p. 1985 - 2000

0022-1007

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 preva- lence 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- (Gal-) and specific target N-glycans link tumor hypoxia to neovascularization as part of the pathogenesis of KS. Expression of Gal- 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- through mechanisms that are independent of hypoxia-inducible factor (HIF)  and HIF-2 but involved reactive oxygen species?dependent activation of the transcription factor nuclear factor B. Targeted disruption of Gal-?N-glycan interactions eliminated hypoxia-driven angiogenesis and suppressed tumorigenesis in vivo. Therapeutic administration of a Gal-?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.