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Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice

Itidal Kaafarani^*,, Samantha Fernandez-Sauze^*,, Caroline Berenguer^*,, Olivier Chinot^*,, Christine Delfino^*,, Christophe Dussert^*,, Philippe Metellus^*,, Françoise Boudouresque^*,, Kamel Mabrouk, François Grisoli^||, Dominique Figarella-Branger^*, Pierre-Marie Martin^*,, and L'Houcine Ouafik^*,,,1

^* INSERM, Unité Mixte de Recherche (UMR) 911-CRO2, Marseille, France;

Aix Marseille Université, Faculté de Médecine Secteur Nord, Laboratoire de Cancérologie Expérimentale, Marseille, France;

Laboratoire de Transfert d'Oncologie Biologique [Assistance Publique—Hôpitaux de Marseille (AP-HM)], Marseille, France;

Centre National de la Recherche Scientifique, UMR 6264, Aix Marseille Université, Faculté de Saint Jérôme, Equipe Chimie Radicalaire Organique et Polymère de Specialité (CROPS) Laboratoire de Chimie Provence, Marseille, France; and

^|| Service de Neurochirurgie (AP-HM), Hôpital Timone, Marseille, France

¹ Correspondence: INSERM, UMR 911-CRO2, Faculté de Médecine Nord, Bd Pierre Dramard, 13916 Marseille Cedex 20, France. E-mail: lhoucine.ouafik{at}univmed.fr

Adrenomedullin (AM) is a multifunctional peptide vasodilator that transduces its effects through calcitonin receptor-like receptor/receptor activity modifying protein-2 and -3 (CLR/RAMP2 and CLR/RAMP3). Previously, we reported on the development of an anti-AM antibody that potently inhibits tumor cell proliferation in vitro and tumor growth in vivo. Here, we report the effect of anti-AM receptor antibodies (AMRs) on angiogenesis and tumor growth. We demonstrate that AMRs decrease in a dose-dependent manner the growth of U87 glioblastoma cells and HT-29 colorectal cancer cells, but not A549 lung cancer cells, in vitro. In vivo, AM in Matrigel plugs induces angiogenesis by promoting recruitment of endothelial cells, pericytes, myeloid precursor cells, and macrophages and by promoting channel formation. Remarkably, systemic administration of AMRs every 3 d markedly reduced neovascularization of Matrigel plugs in a dose-dependent fashion, as demonstrated by reduced numbers of the recruited cells and vessel structures. Several human tumor xenografts in athymic mice were used to examine the effect of AMR treatment on tumor angiogenesis and growth. AMR treatment significantly suppressed the growth of glioblastoma, lung, and colon tumors. Histological examination of AMR-treated tumors showed evidence of disruption of tumor vascularity with decreased microvessel density, depletion of endothelial and pericyte cells, and increased tumor cell apoptosis. These findings support the conclusion that AMR treatment inhibits tumor growth by suppression of angiogenesis and tumor growth and suggest that AMRs may be useful therapeutic targets.—Kaafarani, I., Fernandez-Sauze, S., Berenguer, C., Chinot, O., Delfino, C., Dussert, C., Metellus, P., Boudouresque, F., Mabrouk, K., Grisoli, F., Figarella-Branger, D., Martin, P.-M., Ouafik, L. H. Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice

Key Words: CLR/RAMP2 • CLR/RAMP3 • endothelial cells • pericytes • proangiogenic cells