Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells
Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells
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DOI：
10.1158/1078-0432.ccr-06-0749
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发表时间：
2006-10-15
影响因子：
11.5
通讯作者：
Kihara, Kazunori
中科院分区：
文献类型：
--
作者：
Yano, Akihiro;Fujii, Yasuhisa;Kihara, Kazunori
目的：已知糖皮质激素如泼尼松、氢化可的松和地塞米松可为激素难治性前列腺癌患者提供一些临床益处。然而，糖皮质激素影响激素难治性前列腺癌进展的潜在机制尚未明确。我们之前的研究表明，糖皮质激素可能通过下调血管内皮生长因子（VEGF）和白细胞介素8来抑制肿瘤血管生成。在这里，我们假设地塞米松对激素难治性前列腺癌的治疗作用部分归因于糖皮质激素受体通过下调主要淋巴管生成因子VEGF-C直接抑制淋巴管生成。使用表达糖皮质激素受体的不依赖雄激素的人前列腺癌细胞系 DU145 检测地塞米松或 VEGF-C 及其受体 VEGF 受体 3 (VEGFR-3) 的表达。通过分析 VEGF-C 基因表达、淋巴管密度和相对淋巴管面积，确定地塞米松对 DU145 异种移植物中肿瘤相关淋巴管生成的影响。结果：常氧条件下，地塞米松显着下调 VEGF-C 基因表达和蛋白产量，分别达 48% (P = 0.003) 和 44% (P = 0.002)。同样，氢化可的松下调 VEGF-C 基因表达。地塞米松的作用被糖皮质激素受体拮抗剂 RU486 完全逆转。即使在类缺氧条件下，地塞米松也会抑制 VEGF-C 基因表达。在 DU145 异种移植物中，地塞米松显着下调 VEGF-C 基因表达并减少淋巴管生成。地塞米松在体外和体内均不影响VEGFR-3基因表达。结论：在体内雄激素非依赖性前列腺癌细胞中，糖皮质激素通过糖皮质激素受体下调VEGF-C来抑制肿瘤相关淋巴管生成。
Purpose: Glucocorticoids such as prednisone, hydrocortisone, and dexamethasone are known to provide some clinical benefit for patients with hormone-refractory prostate cancer. However, the underlying mechanisms by which glucocorticoids affect hormone-refractory prostate cancer progression are not well established as yet. Our previous study has shown that glucocorticoids inhibit tumor angiogenesis possibly by down-regulation of vascular endothelial growth factor (VEGF) and interleukin 8. Here, we hypothesized that the therapeutic effect of dexamethasone on hormone-refractory prostate cancer can be partly attributed to a direct inhibition of lymphangiogenesis through the glucocorticoid receptor by down-regulating a major lymphangiogenic factor, VEGF-C.Experimental Design: The effects of dexamethasone oh the expression of VEGF-C and its receptor, VEGF receptor-3 (VEGFR-3), were examined using an androgen-independent human prostate cancer cell line, DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on tumor-associated lymphangiogenesis in DU145 xenografts were determined by analyzing VEGF-C gene expression, lymphatic vessel density, and relative lymphatic vessel area.Results: Dexamethasone significantly down-regulated VEGF-C gene expression and protein production by 48% (P = 0.003) and 44% (P = 0.002), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF-C gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF-C gene expression. In DU145 xenografts, dexamethasone significantly down-regulated VEGF-C gene expression and decreased lymphangiogenesis. Dexamethasone did not affect VEGFR-3 gene expression in vitro and in vivo.Conclusion: Glucocorticoids suppressed tumor-associated lymphangiogenesis by downregulating VEGF-C through glucocorticoid receptor in androgen-independent prostate cancer cells in vivo.