EP3/EP4 signaling regulates tumor microenvironment formation by bone marrow-derived fibroblasts
EP3/EP4 signaling regulates tumor microenvironment formation by bone marrow-derived fibroblasts
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DOI：
10.2492/inflammregen.31.316
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发表时间：
2011
影响因子：
8.1
通讯作者：
H. Katoh;K. Hosono;Tatsunori Suzuki;M. Watanabe;M. Majima
中科院分区：
文献类型：
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作者：
H. Katoh;K. Hosono;Tatsunori Suzuki;M. Watanabe;M. Majima
最近，研究表明，骨髓（BM）来源的造血细胞作为肿瘤基质的主要成分在肿瘤微环境中具有关键作用，并调节肿瘤的进展。此外，造血细胞需要趋化因子信号传导来进行招募。另一方面，考克斯-2和内源性的胰高血糖素是肿瘤生长和肿瘤相关血管生成的重要决定因素。然而，它们在基质形成和血管生成中的确切机制仍然难以捉摸。我们最近的数据表明，考克斯-2抑制减少CXCL 12/CXCR 4表达以及肿瘤间质形成、肿瘤相关血管生成和肿瘤生长。PGE 2促进基质形成、血管生成和CXCL 12/CXCR 4表达。此外，考克斯-2抑制剂抑制肿瘤间质中成纤维细胞标志物（S100 A4）的表达。通过敲除4种PGE 2受体中的EP 3或EP 4，发现这些抑制活性。使用GFP-骨髓嵌合小鼠的实验显示，CXCL 12 + CXCR 4 + S100 A4+成纤维细胞主要组成基质细胞，并且其中大部分从BM募集。此外，在体外通过EP 3或EP 4特异性激动剂刺激成纤维细胞产生CXCL 12。因此，考克斯-2/PGE 2-EP 3/EP 4信号通路可能通过CXCL 12/CXCR 4趋化因子系统在肿瘤间质形成和血管生成中发挥重要作用。这些结果可能会导致进一步研究和癌症治疗的新方法。
Recently, it has been shown that bone marrow (BM)-derived hematopoietic cells have critical roles in the tumor microenvironment as a major components of tumor stroma and regulate tumor progression. In addition, hematopoietic cells need chemokine signaling for their recruitment. On the other hand, COX-2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis. However, their precise mechanisms in stromal formation and angiogenesis remain elusive. Our recent data suggest that COX-2 inhibition reduced CXCL12/CXCR4 expression as well as tumor stromal formation, tumor-associated angiogenesis and tumor growth. Consistently, PGE2 enhanced stromal formation, angiogenesis and CXCL12/CXCR4 expression. Moreover, a COX-2 inhibitor suppressed expression of a fibroblast marker (S100A4) in tumor stroma. These suppressive activities were found by either EP3 or EP4 knockout among 4 PGE2 receptors. Experiments using GFP-bone marrow chimeric mice revealed that CXCL12+CXCR4+S100A4+ fibroblasts dominantly composed stromal cells and most of which were recruited from BM. Additionally, fibroblasts were stimulated to produce CXCL12 by either EP3 or EP4 specific agonist in vitro. Therefore, COX-2/PGE2-EP3/EP4 signaling may play a crucial role in tumor stromal formation and angiogenesis via CXCL12/CXCR4 chemokine system. These results may lead to new approaches in further studies and cancer treatment.