Disrupting galectin-1 interactions with Nglycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi?s sarcoma

DIEGO O. CROCI; MARIANA SALATINO ; NATALIA RUBINSTEIN; JUAN P. CERLIANI ; LUCAS E. CAVALLIN ; HOWARD J. LEUNG ; JING OUYANG; JUAN M. ILARREGUI; MARTA A. TOSCANO ; CAROLINA I. DOMAICA; MARÍA C. CROCI ; MARGARET A. SHIPP ; ENRIQUE A. MESRI ; ADRIANA ALBINI; GABRIEL 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-associatedmalignancy. Clinical management of KS has proven to be challenging because of its prevalencein immunosuppressed patients and its unique vascular and infl ammatory nature thatis sustained by viral and host-derived paracrine-acting factors primarily released underhypoxic conditions. We show that interactions between the regulatory lectin galectin-1(Gal-1) and specifi c target N-glycans link tumor hypoxia to neovascularization as part ofthe pathogenesis of KS. Expression of Gal-1 is found to be a hallmark of human KS but notother vascular pathologies and is directly induced by both KSHV and hypoxia. Interestingly,hypoxia induced Gal-1 through mechanisms that are independent of hypoxia-induciblefactor (HIF) 1  and HIF-2  but involved reactive oxygen species?dependent activation ofthe transcription factor nuclear factor  B. Targeted disruption of Gal-1?N-glycan interactionseliminated hypoxia-driven angiogenesis and suppressed tumorigenesis in vivo. Therapeuticadministration of a Gal-1?specifi c neutralizing mAb attenuated abnormalangiogenesis and promoted tumor regression in mice bearing established KS tumors. Giventhe active search for HIF-independent mechanisms that serve to couple tumor hypoxia topathological angiogenesis, our fi ndings provide novel opportunities not only for treating KSpatients but also for understanding and managing a variety of solid tumors.