Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo.
Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor-derived endothelial cells and tumor angiogenesis in vivo.
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DOI：
10.1158/0008-5472.can-08-2307
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Johnson CS
中科院分区：
文献类型：
--
作者：
Chung I;Han G;Seshadri M;Gillard BM;Yu WD;Foster BA;Trump DL;Johnson CS
骨化三醇（1，25-二羟基胆钙化醇）是维生素D的主要活性形式，在肿瘤细胞和肿瘤衍生的内皮细胞（TDEC）中具有抗增殖作用。骨化三醇的这些作用至少部分由维生素D受体（VDR）介导，所述维生素D受体在包括内皮细胞的许多组织中表达。为了研究VDR在骨化三醇对肿瘤脉管系统的作用中的作用，我们在VDR野生型（WT）或敲除（KO）小鼠中皮下建立了TRAMP-2肿瘤。在接种后30天内，KO小鼠的肿瘤比WT小鼠的肿瘤大（P<0.001）。来自WT的TDEC表达VDR并且能够反式激活报告基因，而来自KO小鼠的TDEC则不能。用骨化三醇处理导致表达VDR的TDEC的生长抑制。然而，来自KO小鼠的TDEC相对耐药，表明骨化三醇介导的对TDEC的生长抑制是VDR依赖性的。TRAMP-C2肿瘤切片的进一步分析显示，与WT相比，KO小鼠中的血管扩大并且具有较少的周细胞覆盖（P<0.001）。对比增强MRI显示，与WT小鼠相比，在VDR KO小鼠中生长的TRAMP肿瘤的血管体积增加（P<0.001），并且FITC-葡聚糖渗透性测定表明来自KO小鼠的肿瘤中血管渗漏程度更高。使用ELISA和Western印迹分析，在KO小鼠的肿瘤中观察到HIF-1 α、VEGF、Ang 1和PDGF-BB水平增加。这些结果表明，骨化三醇介导的对TDEC的抗增殖作用是VDR依赖性的，并且VDR的丧失可导致异常的肿瘤血管生成。
Calcitriol (1, 25-dihydroxycholecalciferol), the major active form of vitamin D, is anti-proliferative in tumor cells and tumor-derived endothelial cells (TDEC). These actions of calcitriol are mediated at least in part by vitamin D receptor (VDR), which is expressed in many tissues including endothelial cells. To investigate the role of VDR in calcitriol effects on tumor vasculature, we established TRAMP-2 tumors subcutaneously into either VDR wild type (WT) or knockout (KO) mice. Within 30 days post inoculation, tumors in KO mice were larger than those in WT (P<0.001). TDEC from WT expressed VDR and were able to transactivate a reporter gene whereas TDEC from KO mice were not. Treatment with calcitriol resulted in growth inhibition in TDEC expressing VDR. However, TDEC from KO mice were relatively resistant, suggesting that calcitriol-mediated growth inhibition on TDEC is VDR-dependent. Further analysis of the TRAMP-C2 tumor sections revealed that the vessels in KO mice were enlarged and had less pericyte coverage compared to WT (P<0.001). Contrast-enhanced MRI demonstrated an increase in vascular volume of TRAMP tumors grown in VDR KO mice compared to WT mice (P<0.001) and FITC-dextran permeability assay suggested a higher extent of vascular leakage in tumors from KO mice. Using ELISA and Western blot analysis, there was an increase of HIF-1 alpha, VEGF, Ang1 and PDGF-BB levels observed in tumors from KO mice. These results indicate that calcitriol-mediated anti-proliferative effects on TDEC are VDR dependent and loss of VDR can lead to abnormal tumor angiogenesis.