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Carcinogenesis Advance Access originally published online on November 11, 2004
Carcinogenesis 2005 26(2):429-440; doi:10.1093/carcin/bgh332
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Carcinogenesis vol.26 no.2 © Oxford University Press 2005; all rights reserved.

ARTICLE

1{alpha},25-Dihydroxyvitamin D3 is a preventive factor in the metastasis of lung cancer

Kimie Nakagawa, Akihiko Kawaura, Shigeaki Kato1, Eiji Takeda2 and Toshio Okano*

Department of Hygienic Sciences, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan, 1 Institute of Molecular and Cellular Bioscience, University of Tokyo, Japan and 2 Department of Clinical Nutrition, School of Medicine, University of Tokushima, Japan

* To whom correspondence should be addressed. Tel: +81 78 441 7563; Fax: +81 78 441 7565; Email: t-okano{at}kobepharma-u.ac.jp

1{alpha},25-Dihydroxyvitamin D3 [1{alpha},25(OH)2D3], the major regulator of calcium homeostasis, has potent antiproliferative and anti-invasive properties in vitro in cancer cells. Studies in vivo demonstrated that 1{alpha},25(OH)2D3 slows the progression of breast, prostate and other carcinomas. A key question is whether 1{alpha},25(OH)2D3 exerts its anticarcinogenic effects in vivo by a mechanism that is dependent on its capacity to limit the proliferation and invasiveness of cancer cells in vitro. It has not been clear whether the calcemic activity and regulation of the host defenses by 1{alpha},25(OH)2D3 contribute to the effect on cancer cells. In this study we have focused on the influence of 1{alpha},25(OH)2D3 on the metastasis of lung cancer, without involvement of the calcemic activity and other effects of 1{alpha},25(OH)2D3 in the host. We used metastatic Lewis lung carcinoma cells expressing green fluorescent protein (LLC-GFP cells) and examined metastatic activity in vitamin D receptor (VDR) null mutant (VDR–/–) mice and their wild-type counterparts (VDR+/+ mice). VDR–/– mice exhibit hypocalcemia and extremely high serum levels of 1{alpha},25(OH)2D3. We expected that serum 1{alpha},25(OH)2D3 would act in vivo to directly inhibit the metastatic growth of VDR-positive LLC-GFP cells in VDR–/– mice. The metastatic activities of LLC-GFP cells were remarkably reduced in VDR–/– mice compared with VDR+/+ mice. To test the hypothesis that serum 1{alpha},25(OH)2D3 is an intrinsic factor that inhibits metastatic growth of lung cancer cells, we corrected hypocalcemia and/or hypervitaminosis D in VDR–/– mice by dietary manipulation. The metastatic growth of LLC-GFP cells was remarkably reduced in response to serum levels of 1{alpha},25(OH)2D3, but not to serum calcium levels. Furthermore, we found that VDR+/+ mice fed the manipulated diets displayed an apparent inverse relationship between the physiological levels of serum 1{alpha},25(OH)2D3 (8–15 pg/ml) and tumorigenesis. Here we show that 1{alpha},25(OH)2D3 inhibits the metastatic growth of lung cancer cells in a defined animal model.


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