Adrenomedullin antagonist suppresses tumor formation in renal cell carcinoma through inhibitory effects on tumor endothelial cells and endothelial progenitor mobilization.
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.
Tsuchiya
Kunihiko
K
Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-8586, Japan.
Hida
Kyoko
K
Hida
Yasuhiro
Y
Muraki
Chikara
C
Ohga
Noritaka
N
Akino
Tomoshige
T
Kondo
Takeshi
T
Miseki
Tetsuya
T
Nakagawa
Koji
K
Shindoh
Masanobu
M
Harabayashi
Toru
T
Shinohara
Nobuo
N
Nonomura
Katsuya
K
Kobayashi
Masanobu
M
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
D000970:Antineoplastic Agents; D053607:Adrenomedullin; D004247:DNA