Abrogation of the interaction between osteopontin and alphavbeta3 integrin reduces tumor growth of human lung cancer cells in mice.
Osteopontin (OPN) is a multifunctional cytokine involved in cell signaling by interacting with alphavbeta3 integrins. Recent clinical studies have indicated that OPN expression is associated with tumor progression and poor prognosis among patients with lung cancer. However, the biological role of OPN in human lung cancer has not yet been well-defined. The purpose of this study is to investigate and provide evidence for the causal role of OPN regarding tumor growth and angiogenesis in human lung cancer. In this study, we developed a stable OPN transfectant from human lung cancer cell line SBC-3 which does not express the intrinsic OPN mRNA. To reveal the in vivo effect of OPN on tumor growth of human lung cancer, we subcutaneously injected OPN-overexpressing SBC-3 cells (SBC-3/OPN) and control cells (SBC-3/NEO) into the nude mice. Transfection with the OPN gene significantly increased in vivo tumor growth and neovascularization of SBC-3 cells in mice. These in vivo effects of OPN were markedly suppressed with administration of anti-alphavbeta3 integrin monoclonal antibody or anti-angiogenic agent, TNP-470. Furthermore, recombinant OPN protein enhanced human umbilical vein endothelial cell (HUVEC) proliferation in vitro, and this enhancement was significantly inhibited with the addition of anti-alphavbeta3 integrin antibody. Taken together, these results suggest that OPN plays a crucial role for tumor growth and angiogenesis of human lung cancer cells in vivo by interacting with alphavbeta3 integrin. Targeting the interaction between OPN and alphavbeta3 integrin could be effective for future development of anti-angiogenic therapeutic agents for patients with lung cancer.
Cui
Ri
R
Department of Respiratory Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 113-8421, Japan. cri@med.juntendo.ac.jp
Takahashi
Fumiyuki
F
Ohashi
Rina
R
Gu
Tao
T
Yoshioka
Masakata
M
Nishio
Kazuto
K
Ohe
Yuichiro
Y
Tominaga
Shigeru
S
Takagi
Yumiko
Y
Sasaki
Shinichi
S
Fukuchi
Yoshinosuke
Y
Takahashi
Kazuhisa
K
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D049109:Cell Proliferation; D003510:Cyclohexanes / Q000494:pharmacology; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000098:blood supply*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology; D014162:Transfection; D014470:Umbilical Cord / Q000166:cytology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D003510:Cyclohexanes; D039302:Integrin alphaVbeta3; D012717:Sesquiterpenes; D053495:Osteopontin; D000077609:O-(Chloroacetylcarbamoyl)fumagillol