Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice.
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 (alphaAMRs) on angiogenesis and tumor growth. We demonstrate that alphaAMRs 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 alphaAMRs 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 alphaAMR treatment on tumor angiogenesis and growth. AlphaAMR treatment significantly suppressed the growth of glioblastoma, lung, and colon tumors. Histological examination of alphaAMR-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 alphaAMR treatment inhibits tumor growth by suppression of angiogenesis and tumor growth and suggest that AMRs may be useful therapeutic targets.
Kaafarani
Itidal
I
INSERM, UMR 911-CRO2, Faculté de Médecine Nord, Bd Pierre Dramard, 13916 Marseille Cedex 20, France.
Fernandez-Sauze
Samantha
S
Berenguer
Caroline
C
Chinot
Olivier
O
Delfino
Christine
C
Dussert
Christophe
C
Metellus
Philippe
P
Boudouresque
Françoise
F
Mabrouk
Kamel
K
Grisoli
François
F
Figarella-Branger
Dominique
D
Martin
Pierre-Marie
PM
Ouafik
L'Houcine
L
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D006801:Humans; D007797:Laminin; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000628:therapy*; D011509:Proteoglycans; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000906:Antibodies; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D058265:Receptors, Adrenomedullin; D018000:Receptors, Peptide; C059485:matrigel; D003094:Collagen