title: Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization.
abstract: Adrenomedullin (AM) is a multifunctional 52-amino acid peptide. AM has several effects and acts as a growth factor in several types of cancer cells. Our previous study revealed that an AM antagonist (AMA) suppressed the growth of pancreatic tumors in mice, although its mechanism was not elucidated. In this study, we constructed an AMA expression vector and used it to treat renal cell carcinoma (RCC) in mice. This AMA expression vector significantly reduced tumor growth in mice. In addition, microvessel density was decreased in AMA-treated tumors. To analyze the effect of AMA on tumor angiogenesis in this model, tumor endothelial cells (TECs) were isolated from RCC xenografts. TEC proliferation was stimulated by AM and it was inhibited by AMA significantly. AM induced migration of TECs and it was also blocked by AMA. However, normal ECs (NECs) were not affected by either AM or AMA. These results demonstrate that AMA has inhibitory effects on TECs specifically, not on NEC, thereby inhibiting tumor angiogenesis. Furthermore, we showed that vascular endothelial growth factor-induced mobilization of endothelial progenitor cell (EPC) into circulation was inhibited by AMA. These results suggest that AMA can be considered a good anti-angiogenic reagent that selectively targets TECs and EPC in renal cancer.
authors.affiliation: Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-8586, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hida
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Hida
authors.forename: Chikara
authors.initials: C
authors.lastname: Muraki
authors.forename: Noritaka
authors.initials: N
authors.lastname: Ohga
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Akino
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kondo
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Miseki
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Masanobu
authors.initials: M
authors.lastname: Shindoh
authors.forename: Toru
authors.initials: T
authors.lastname: Harabayashi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Shinohara
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nonomura
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D053607:Adrenomedullin / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000627:therapeutic use*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000098:blood supply / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000628:therapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D053607:Adrenomedullin; D004247:DNA