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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

2009; Wiley; Volume: 23; Issue: 10 Linguagem: Inglês

10.1096/fj.08-127852

1530-6860

Itidal Kaafarani, Samantha Fernandez-Sauze, Caroline Bérenguer, Olivier Chinot, Christine Delfino, Christophe Dussert, Philippe Métellus, Françoise Boudouresque, Kamel Mabrouk, F. Grisoli, Dominique Figarella‐Branger, Pierre‐Marie Martin, L’Houcine Ouafik,

Receptor Mechanisms and Signaling

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 (αAMRs) on angiogenesis and tumor growth. We demonstrate that αAMRs 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 αAMRs every 3 d markedly reduced neovascularization of Matrigel plugs in a dosedependent 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 αAMR treatment on tumor angiogenesis and growth. αAMR treatment significantly suppressed the growth of glioblastoma, lung, and colon tumors. Histological examination of αAMR-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 αAMR 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. FASEB J. 23, 3424–3435 (2009). www.fasebj.org