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

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Abstract
1α,25-Dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ], the major regulator of calcium homeostasis, has potent antiproliferative and anti-invasive properties in vitro in cancer cells. Studies in vivo demonstrated that 1α,25(OH) 2 D 3 slows the progression of breast, prostate and other carcinomas. A key question is whether 1α,25(OH) 2 D 3 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 1α,25(OH) 2 D 3 contribute to the effect on cancer cells. In this study we have focused on the influence of 1α,25(OH) 2 D 3 on the metastasis of lung cancer, without involvement of the calcemic activity and other effects of 1α,25(OH) 2 D 3 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 1α,25(OH) 2 D 3 . We expected that serum 1α,25(OH) 2 D 3 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 1α,25(OH) 2 D 3 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 1α,25(OH) 2 D 3 , 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 1α,25(OH) 2 D 3 (8–15 pg/ml) and tumorigenesis. Here we show that 1α,25(OH) 2 D 3 inhibits the metastatic growth of lung cancer cells in a defined animal model.

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