Cisplatin-stimulated macrophages promote ovarian cancer migration via the CCL20-CCR6 axis

Abstract

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.

Keywords: CCL20; CCR6; Chemotherapy; Metastasis; Tumor associated macrophages.