Malignant ascites microenvironment skews M2/M1 macrophage polarization in ovarian cancer during peritoneal metastasis

Abstract

Advanced ovarian cancers with peritoneal metastases are usually accompanied with metastatic recurrence and poor prognosis. Previous studies have confirmed that the malignant ascites provides substantial metabolic and oncogenic impacts in ovarian cancer cells. However, the significance of metabolic reprogramming in immune cells such as tumor-associated macrophages (TAM) in tumor immunity remains unclear. In this study, we report that the ascites microenvironment favors the formation of the heterogeneity of macrophage populations. A higher M2/M1 ratio in TAM could promote the metastatic progression of ovarian cancer cells. By using omentum conditioned medium (OCM) as a model to mimic the ascites microenvironment, we found that the macrophages (THP-1 and U937) co-cultured in OCM led to an increased ratio of CD206+ M2 to CD86+ M1 macrophage population. It was evidenced by the upregulation of the TAM-related genes CD163, CCL2, IL6, and IL10. When ovarian cancer cells co-cultured with OCM-cultured macrophages, the cell migratory capacity, tumor spheroid formation, and colonization capacities of ovarian cancer cells were enhanced. Transcriptome profiling analysis identified Hippo, and Wnt/β-catenin signaling pathways are involved in macrophage polarization. Pharmaceutical inhibition of Mst1/2 could inhibit IL10, IL6, and CCL2 expression, whereas the activation of the Wnt/β-catenin pathway could increase IL10 expression in OCM. Therefore, our findings have manifested that macrophage prefers to differentiate into TAM with a higher ratio of M2/M1 in OCM or ascites microenvironment through activation of Hippo but deactivation of Wnt/β-catenin signaling pathways. This hints targeting Hippo by inhibition of Mst1/2 or activation of Wnt/β-catenin pathways may be a promising immunotherapeutic approach to alter M2/M1 macrophage polarization and ovarian cancer metastatic progression. Further investigation of the functional roles of these two signalings in macrophage polarization in ovarian cancer cells is warranted.