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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

阐明膜结合PGES-1在前列腺癌骨转移模型中的转移抑制机制

基本信息

批准号：
25870709
负责人：
高橋亮
金额：
$ 2.66万
依托单位：
Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2013
资助国家：
日本
起止时间：
2013-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-25870709/
关键词：
prostate cancer metastasis angiogenesis

项目摘要

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.

前列腺癌是日本老年男性中最常见的恶性肿瘤。我们以前曾报道，宿主间质微粒体前列腺素E合酶-1（mPGES-1）信号传导对肿瘤相关血管生成和肿瘤生长至关重要。为了探讨mPGES-1在前列腺癌肺转移形成中的作用，将小鼠前列腺癌细胞（RM 9）静脉注射给野生型小鼠（WT）和mPGES-1基因敲除小鼠（mPGES-1 KO）。通过计数肺中的集落和肺重量来估计肺转移。通过测量血管生成刺激因子VEGF-A和SDF-1的血浆水平和mRNA表达来评估血管生成，与野生型小鼠相比，mPGES-1基因敲除小鼠肺转移灶的形成受到明显抑制，集落形成数和肺重量明显减少。mPGES-1 KO小鼠血浆中SDF-1水平较WT小鼠明显降低，肺组织中VEGF-A和SDF-1表达明显降低。我们认为mPGES-1在RM 9血行肺转移和外渗后的肿瘤定植中起重要作用，目前正在开发的mPGES-1选择性抑制剂将成为抑制肿瘤血行转移的一种有希望的治疗工具。