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Carcinogenesis Advance Access published online on November 11, 2004
Carcinogenesis, doi:10.1093/carcin/bgh332
© 2004 by Oxford University Press
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Received July 31, 2004
Revised October 27, 2004
Accepted November 1, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

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

Kimie Nakagawa 1, Akihiko Kawaura 1, Shigeaki Kato 2, Eiji Takeda 3, and Toshio Okano 1*

1 Department of Hygienic Sciences, Kobe Pharmaceutical University, Japan
2 Institute of Molecular and Cellular Bioscience, University of Tokyo, Japan
3 Department of Clinical Nutrition, School of Medicine, University of Tokushima, Japan

* To whom correspondence should be addressed.
Toshio Okano, E-mail: t-okano{at}kobepharma-u.ac.jp


  Abstract

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 the host's defenses regulated by 1{alpha},25(OH)2D3 contribute to the effect on cancer cells. In this study, we focused on the influence of 1{alpha},25(OH)2D3 on the metastasis of lung cancer, without 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 the 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 the serum 1{alpha},25(OH)2D3 in VDR-/- mice to act in vivo to directly inhibit the metastatic growth of VDR-positive LLC-GFP cells. The metastatic activities of LLC-GFP cells were remarkably reduced in VDR-/- mice compared to VDR+/+ mice. To test the hypothesis that serum 1{alpha},25(OH)2D3 is an intrinsic factor that inhibits the 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 the serum levels of 1{alpha},25(OH)2D3 but not to serum calcium levels. Furthermore, we found that the 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.

Keywords: 1{alpha},25-dihydroxyvitamin D3; vitamin D receptor; lung cancer; metastasis.
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