Prostanoid induces premetastatic niche in regional lymph nodes
Prostanoid induces premetastatic niche in regional lymph nodes
复制标题
DOI：
10.1172/jci73530
复制
发表时间：
2014-11-01
影响因子：
15.9
通讯作者：
Majima, Masataka
中科院分区：
文献类型：
--
作者：
Ogawa, Fumihiro;Amano, Hideki;Majima, Masataka
淋巴系统是癌症扩散的重要途径，淋巴结转移（LNM）是癌症患者预后的关键决定因素。我们研究了考克斯-2衍生的前列腺素E-2（PGE（2））在转移前小生境和LNM形成中的作用。小鼠刘易斯肺癌（LLC）细胞转移模型显示，考克斯-2在淋巴结包膜下区域的早期阶段在DC中表达，并且考克斯-2抑制显著抑制纵隔LNM。在LLC细胞浸润至淋巴结之前，DC中基质细胞衍生因子-1（SDF-1）升高，考克斯-2抑制剂、SDF-1拮抗剂和CXCR 4中和抗体均降低LNM。此外，在缺乏PGE（2）受体EP 3的小鼠中，LNM减少，并且用EP 3激动剂刺激培养的DC增加SDF-1的产生。与WT CD 11 c（+）DCs相比，注射EP 3缺陷型CD 11 c（+）DCs显著减少了注射LLC小鼠局部LN和LNM中SDF-1（+）CD 11 c（+）DCs的积聚。甲状腺素的积累和淋巴结淋巴管生成也是考克斯-2/EP 3依赖性的，这可能影响转移的肿瘤细胞的命运。这些结果表明，DC诱导转移前的小生境在LNM通过考克斯-2/EP 3依赖性诱导SDF-1，并表明，抑制这一信号传导轴可能是一种有效的策略，以抑制转移前的小生境的形成和LNM。
The lymphatic system is an important route for cancer dissemination, and lymph node metastasis (LNM) serves as a critical prognostic determinant in cancer patients. We investigated the contribution of COX-2-derived prostaglandin E-2 (PGE(2)) in the formation of a premetastatic niche and LNM. A murine model of Lewis lung carcinoma (LLC) cell metastasis revealed that COX-2 is expressed in DCs from the early stage in the lymph node subcapsular regions, and COX-2 inhibition markedly suppressed mediastinal LNM. Stromal cell-derived factor-1 (SDF-1) was elevated in DCs before LLC cell infiltration to the lymph nodes, and a COX-2 inhibitor, an SDF-1 antagonist, and a CXCR4 neutralizing antibody all reduced LNM. Moreover, LNM was reduced in mice lacking the PGE(2) receptor EP3, and stimulation of cultured DCs with an EP3 agonist increased SDF-1 production. Compared with WT CD11c(+) DCs, injection of EP3-deficient CD11c(+) DCs dramatically reduced accumulation of SDF-1(+)CD11c(+) DCs in regional LNs and LNM in LLC-injected mice. Accumulation of Tregs and lymph node lymphangiogenesis, which may influence the fate of metastasized tumor cells, was also COX-2/EP3-dependent. These results indicate that DCs induce a premetastatic niche during LNM via COX-2/EP3-dependent induction of SDF-1 and suggest that inhibition of this signaling axis may be an effective strategy to suppress premetastatic niche formation and LNM.