Tumor microenvironment remodeling modulates macrophage phenotype in breast cancer lymphangiogenesis

Hyaluronan (HA) is dynamically remodeled in tumor microenvironment (TME) and is reported to be closely related to tumor lymphatic metastasis by inducing lymphangiogenesis. Macrophages are known to be involved in neo-lymphatic vessels formation. However, few studies have investigated the role of HA-mediated TME remodeling on macrophages-dependent lymphangiogenesis. We previously showed that HA could drive macrophages to acquire the M2 phenotype. In this study, we attempt to study the crosstalk between HA in TME and macrophages dependent lymphangiogenesis. First, we found that the abundant assembly of HA in breast cancer tissue was accompanied by increased infiltration of macrophages featured by expressing lymphatic endothelial markers. Then, to further identify the remodeling of HA in regulating macrophage phenotype, we used HA fragments which are usually enriched in TME for this purpose. Our results showed that the reconstructed HA could induce bone marrow-derived macrophages (BMDMs) to express markers of lymphatic endothelium and form tube-like structures, suggesting a novel function of HA from TME on macrophages-dependent lymphangiogenesis. Finally, we found that inhibition of the HA-TLR4 pathway could reduce the ability of BMDMs to exhibit lymphatic endothelial phenotype. Our results provide new insight into tumor microenvironment remodeling and macrophages in breast cancer lymphangiogenesis.