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-mesenchymal 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.

中文翻译：

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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。

尽管手术和铂类联合化疗后反应率很高，但由于肿瘤的复发和转移，卵巢癌的治疗仍然具有挑战性。肿瘤相关的巨噬细胞（TAMs）已与癌症的进展和转移有关。但是，化学疗法和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活化巨噬细胞（CAM）通过增加CCL20的产生来促进卵巢癌细胞的迁移，从而激活其在卵巢癌细胞上的受体CCR6，触发上皮向间充质的转变。在临床卵巢癌样本中，卵巢癌细胞上较高的CCR6表达与癌症转移呈正相关，从而导致不良预后。CCL20在顺铂刺激的CAMs上的药理阻断和siRNA介导的癌细胞CCC6失活有效地消除了顺铂刺激的CAMs诱导的卵巢癌细胞迁移。总的来说，我们的研究结果揭示了由顺铂和CAM之间的串扰驱动的新型促迁移机制，并暗示CCL20-CCR6轴可能是减少晚期卵巢癌化疗引起的转移的潜在治疗靶标。