mPGES-1-expressing bone marrow-derived cells enhance tumor growth and angiogenesis in mice
mPGES-1-expressing bone marrow-derived cells enhance tumor growth and angiogenesis in mice
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表达 mPGES-1 的骨髓来源细胞增强小鼠肿瘤生长和血管生成
DOI：
10.1016/j.biopha.2010.01.017
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发表时间：
2010
影响因子：
7.5
通讯作者：
Majima M
中科院分区：
文献类型：
--
作者：
Kamata H;Hosono K;Suzuki T;Ogawa Y;Kubo H;Katoh H;Ito Y;Uematsu S;Akira S;Watanabe M;Majima M
微粒体前列腺素E合酶1（mPGES）-1是一种主要的前列腺素E合酶，最近有报道在几种癌症类型中以高水平表达。我们先前报道了PGE受体EP 3在骨髓（BM）来源的细胞中表达，在基质组织中富集，并增强肿瘤血管生成的潜力。在本研究中，我们使用BM嵌合小鼠研究了表达mPGES-1的BM细胞对肿瘤血管生成的作用。在致死辐射后，切除野生型（WT）BM并用从mPGES-1敲除小鼠（mPGES-1−/−）分离的BM细胞替换。皮下植入刘易斯肺癌细胞，测量新血管生成水平。与野生型BM嵌合小鼠相比，mPGES-1−/−BM嵌合小鼠中的肿瘤生长显著降低。通过组织学分析测量的肿瘤相关血管生成定位于肿瘤间质，并且与野生型BM嵌合小鼠相比，mPGES-1−/−BM嵌合小鼠中的肿瘤相关血管生成显著较低。通过免疫组织化学探测的肿瘤切片显示，与野生型BM嵌合体相比，mPGES-1−/−BM嵌合体小鼠中基质组织中存在的血管内皮生长因子（VEGF）显著减少。这些结果表明，募集mPGES-1表达的BM细胞肿瘤相关的基质组织是至关重要的肿瘤生长和血管生成，并与宿主VEGF在基质中的基因表达。总之，这些数据表明，调节表达mPGES-1的BM细胞募集到原发性肿瘤部位可能是治疗实体瘤的新策略。
Microsomal prostaglandin (PG) E synthase 1 (mPGES)-1 is a major PGE synthase and has recently been reported to be expressed at high levels in several cancer types. We previously reported that the PGE receptor EP3 is expressed in bone marrow (BM) derived cells, enriched in stromal tissue, and enhances the potential for tumor angiogenesis. In the present study, we examined the role of mPGES-1-expressing BM cells on tumor angiogenesis using BM chimeric mice. After lethal radiation, wild-type (WT) BMs were excised and replaced with BM cells isolated from mPGES-1 knockout mice (mPGES-1−/−). Lewis lung carcinoma cell were implanted subcutaneously and the levels of neoangiogenesis were measured tumor growth in mPGES-1−/−BM chimeric mice was significantly reduced compared to that observed in wild-type BM chimeric mice. Tumor-associated angiogenesis as measured by histological analysis was localized to tumor stroma, and was significantly lower in mPGES-1−/−BM chimeric mice compared to that in wild-type BM chimeric mice. Tumor sections probed by immunohistochemistry revealed that vascular endothelial growth factor (VEGF) that was present in the stromal tissue was markedly reduced in mPGES-1−/−BM chimeric mice compared to wild-type BM chimeras. These results suggest that the recruitment of mPGES-1-expressing BM cells to tumor-associated stromal tissue is crucial for tumor growth and angiogenesis, and correlates with gene expression of host VEGF in stroma. Taken together, these data suggest that regulation of mPGES-1-expressing BM cell recruitment to the site of primary tumors may be a novel strategy for the treatment of solid tumors.