Cisplatin-stimulated macrophages promote ovarian cancer migration via the CCL20-CCR6 axis
Cisplatin-stimulated macrophages promote ovarian cancer migration via the CCL20-CCR6 axis
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顺铂刺激的巨噬细胞通过 CCL20-CCR6 轴促进卵巢癌迁移
DOI：
10.1016/j.canlet.2019.12.024
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发表时间：
2020-01-01
期刊：
影响因子：
9.7
通讯作者：
Di, Wen
中科院分区：
文献类型：
--
作者：
Liu, Wan;Wang, Wenjing;Di, Wen
尽管手术和铂类联合化疗后的反应率很高，但由于肿瘤复发和转移，卵巢癌的治疗仍然具有挑战性。肿瘤相关巨噬细胞（TAM）与癌症进展和转移有关。然而，化疗和TAM之间的串扰对卵巢癌进展的影响仍不清楚。在这里，我们证明了顺铂刺激的经典激活的巨噬细胞（CAM）通过增加CCL 20的产生来促进卵巢癌细胞迁移，CCL 20激活卵巢癌细胞上的受体CCR 6，触发上皮细胞向间充质细胞的转变。在临床卵巢癌样本中，卵巢癌细胞上CCR 6的高表达与癌症转移正相关，导致预后不良。药物阻断CCL 20对顺铂刺激的CAM和siRNA介导的CCR 6对癌细胞的失活有效地消除了卵巢癌细胞迁移诱导的顺铂刺激的CAM。总的来说，我们的研究结果揭示了一种新的促迁移机制，由顺铂和CAM之间的串扰驱动，并暗示CCL 20-CCR 6轴作为一个潜在的治疗靶点，以减少化疗诱导的晚期卵巢癌转移。
Despite the high response rate after surgery and platinum-combination chemotherapy, treatment of ovarian cancer remains challenging due to tumor recurrence and metastasis. Tumor-associated macrophages (TAMs) have been linked to cancer progression and metastasis. However, the impact of the crosstalk between chemotherapy and TAMs on ovarian cancer progression remains unclear. Here, we demonstrated that cisplatin-stimulated classically activated macrophages (CAMs) promote ovarian cancer cell migration by increasing CCL20 production, which activates its receptor CCR6 on ovarian cancer cells, triggering epithelial-to-me-senchymal transition. In clinical ovarian cancer samples, high CCR6 expression on ovarian cancer cells positively correlates with cancer metastasis, leading to poor prognosis. Pharmacological blockage of CCL20 on cisplatin-stimulated CAMs and siRNA-mediated inactivation of CCR6 on cancer cells effectively abrogated ovarian cancer cell migration induced by cisplatin-stimulated CAMs. Collectively, our results reveal a novel pro-migration mechanism driven by the crosstalk between cisplatin and CAMs, and implicate the CCL20-CCR6 axis as a potential therapeutic target to reduce chemotherapy-induced metastasis in advanced stage ovarian cancer.