前立腺癌骨転移モデルにおける膜結合型PGES-1の転移抑制機序の解明

前列腺癌是日本老年男性最常见的恶性肿瘤。我们之前已经报道过宿主基质微粒体前列腺素E合成酶-1(mPGES-1)信号在肿瘤相关血管生成和肿瘤生长中起关键作用。我们研究了mPGES-1在前列腺癌肺转移形成中是否起关键作用。将小鼠前列腺癌细胞(RM9)静脉注射到野生型小鼠(WT)和mPGES-1基因敲除小鼠(mPGES-1 KO)中。通过计算肺内菌落数和肺重量来评估肺转移。通过检测血管生成刺激因子VEGF-A和SDF-1的水平和mRNA的表达来评估血管生成。与WT小鼠相比，mPGES-1 KO小鼠的肺转移明显受到抑制，肺组织中的集落数和重量明显减少，血浆和肺组织中血管内皮生长因子(VEGF)和基质衍生因子-1(SDF-1)的表达水平明显受到抑制，与WT小鼠相比，mPGES-1KO小鼠血浆中SDF-1的水平明显降低。我们认为mPGES-1在RM9肺血行转移和肿瘤渗出后的定植中起重要作用，目前正在开发的选择性mPGES-1抑制剂有望成为抑制肿瘤血行转移的一种有前景的治疗工具。

Prostate cancer is the most commonly malignancy in elderly men in Japan. We have previously reported that host stromal microsomal prostaglandin E synthase-1 (mPGES-1) signaling appeared critical for tumor-associated angiogenesis and tumor growth. We estimated whether mPGES-1 has a critical role in prostate cancer in lung metastasis formation or not.Murine prostate cancer cells (RM9) were intravenously injected to Wild type mice (WT) and mPGES-1 knockout mice (mPGES-1 KO). Lung metastasis was estimated by counting colonies in the lung and the lung weight. Angiogenesis was estimated by measuring plasma level and mRNA expression of angiogenesis stimulates factors, VEGF-A and SDF-1, and microvessel density and microvessel area in the lung.The lung metastasis formation was significantly suppressed in mPGES-1 KO mice compared with WT mice.The number of colonies and the weight of lung is significantly reduced in mPGES-1 KO mice.The plasma and mRNA level of vascular endothelial growth factor (VEGF) and stromal derived factor-1 (SDF-1) were significantly suppressed in mPGES-1 KO mice.The plasma levels of SDF-1 in mPGES-1KO mice were decreased compared with WT.The expressions of VEGF-A and SDF-1 in the lung tissue were significantly suppressed in mPGES-1KO mice. We thought that mPGES-1was important in RM9 hematogenous metastasis to the lungs and in the colonization of tumors after extravasation.The present results indicated that the selective mPGES-1 inhibitors under development will be a promising therapeutic tool for the inhibition of tumor hematogenous metastasis.