COX-2 and Prostaglandin EP3/EP4 Signaling Regulate the Tumor Stromal Proangiogenic Microenvironment via CXCL12-CXCR4 Chemokine Systems
COX-2 and Prostaglandin EP3/EP4 Signaling Regulate the Tumor Stromal Proangiogenic Microenvironment via CXCL12-CXCR4 Chemokine Systems
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DOI：
10.2353/ajpath.2010.090607
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发表时间：
2010-03-01
影响因子：
6
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
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作者：
Katoh, Hiroshi;Hosono, Kanako;Majima, Masataka
骨髓来源的造血细胞是肿瘤间质的主要成分，决定肿瘤微环境，调节肿瘤表型。环氧合酶(COX)-2和内源性前列腺素是肿瘤生长和肿瘤相关血管生成的重要决定因素，但它们在间质形成和血管生成中的作用尚不清楚。在这项研究中，我们观察到Lewis肺癌细胞移植到野生型小鼠体内形成了一个具有广泛间质形成的肿瘤块，COX-2抑制显著抑制了该肿瘤的形成，从而减少了BM细胞的募集。值得注意的是，COX-2抑制CXCL12/CXCR4的表达以及其他几种趋化因子的表达。事实上，在Matrigel模型中，前列腺素E-2促进间质形成和CXCL12/CXCR4的表达。此外，在微孔室模型中，COX-2抑制剂抑制间质形成，减少CXCL12/CXCR4和成纤维细胞标志物(S100A4)的表达。此外，EP3(-/-)和EP4(-/-)小鼠移植瘤后的间质形成受到抑制，CXCL12/CXCR4和S100A4的间质表达减少。EP3或EN基因敲除可抑制S100A4(+)成纤维细胞、CXCL12(+)和/或CXCR4(+)基质细胞。免疫荧光分析显示，CXCL12(+)、CXCR4(+)、S100A4(+)成纤维细胞主要由基质细胞组成，其中大部分来源于骨髓。此外，EP3或EP4特异性激动剂在体外可刺激成纤维细胞表达CXCL12。这些结果揭示了调控肿瘤生物学的COX-2/PGE(2)-EP3/EP4信号通路的新活性，表明CXCL12/CXCR4轴可能在前列腺素调控下的肿瘤间质形成和血管生成中发挥重要作用。(Am J Pathol2010,176：1469-148.3，-doi：10.2353/ajpath.2010.090607)
Bone marrow (BM)-derived hematopoietic cells, which are major components of tumor stroma, determine the tumor microenvironment and regulate tumor phenotypes. Cyclooxygenase (COX)-2 and endogenous prostaglandins are important determinants for tumor growth and tumor-associated angiogenesis; however, their contributions to stromal formation and angiogenesis remain unclear. in this study, we observed that Lewis lung carcinoma cells implanted in wild-type mice formed a tumor mass with extensive stromal formation that was markedly suppressed by COX-2 inhibition, which reduced the recruitment of BM cells. Notably, COX-2 inhibition attenuated CXCL12/CXCR4 expression as well as expression of several other chemokines. Indeed, in a Matrigel model, prostaglandin (PG) E-2 enhanced stromal formation and CXCL12/CXCR4 expression. in addition, a COX-2 inhibitor suppressed stromal formation and reduced expression of CXCL12/CXCR4 and a fibroblast marker (S100A4) in a micropore chamber model. Moreover, stromal formation after tumor implantation was suppressed in EP3(-/-) mice and EP4(-/-) mice, in which stromal expression of CXCL12/CXCR4 and S100A4 was reduced. The EP3 or EN knockout suppressed S100A4(+) fibroblasts, CXCL12(+), and/or CXCR4(+) stromal cells as well. Immunofluorescent analyses revealed that CXCL12(+)CXCR4(+)S100A4(+) fibroblasts mainly comprised stromal cells and most of these were recruited from the BM. Additionally, either EP3- or EP4-specific agonists stimulated CXCL12 expression by fibroblasts in vitro. The present results address the novel activities of COX-2/PGE(2)-EP3/EP4 signaling that modulate tumor biology and show that CXCL12/CXCR4 axis may play a crucial role in tumor stromal formation and angiogenesis under die control of prostaglandins. (Am J Pathol 2010, 176:1469-148.3,- DOI: 10.2353/ajpath.2010.090607)