Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's “Seed and Soil” hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor β (TGFβ), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.

Advanced ovarian cancers with peritoneal metastases are usually accompanied with metastatic recurrence and high mortality. Macrophages, as a primary cell population in the tumor microenvironment, can be active and polarized into heterogeneous tumor-associated macrophages (TAMs). Clinical evidence indicates that a high M2/M1 ratio of TAMs are commonly found in malignant ascites microenvironment (MAM), and is attributed to a poor prognosis in advanced ovarian cancers. However, the molecular mechanisms of macrophage polarization in MAM remain elusive. Here, we report that MAM could modulate Hippo and/or Wnt signaling cascades in facilitating M2 macrophage polarization. In this study, we firstly evidenced the heterogeneity macrophage populations in cancerous omental tissues and ascites cancer cell spheroids of ovarian cancers by multiplex immunohistochemical, flow cytometry and immunofluorescent analyses. Consistently, in vitro polarization model demonstrated that co-cultured monocyte (THP-1 and U937) with omentum conditioned medium (OCM) or ascites significantly led to more CD206+ M2 macrophage than CD86+ M1 macrophage or M2/M1 ratio. Quantitative RT-PCR (qPCR) analysis showed that TAM-related genes: CCL2, IL6, and IL10 genes were significantly upregulated in OCM treated macrophage. Intriguingly, OCM treated macrophage could significantly promotes ovarian cancer cell migratory capacities. Importantly, RNA-seq analysis identified Hippo and Wnt signaling cascades may play important roles in macrophage polarization in malignant OCM and ascites. Further investigations of these pathways in M2/M1 macrophage polarization in MAM are warranted. Citation Format: Huogang Wang, Mingo MH Yung, Arvin FS Chen, Hextan YS Ngan, David W. Chan. Maligant ascites microenvironment skews M2/M1 macrophage polarization in ovarian cancer during peritoneal metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 980.