HMGB1 combining with tumor-associated macrophages enhanced lymphangiogenesis in human epithelial ovarian cancer

Within tumor microenvironment, high-mobility group box protein 1 (HMGB1) and tumor-associated macrophages (TAMs) are able to influence ovarian cancer development and progression via facilitating tumor lymphatic metastasis. However, little is known about the association between HMGB1 and TAMs on lymphangiogenesis in epithelial ovarian cancer (EOC). To investigate the effect of HMGB1 and TAMs on lymphangiogenesis in EOC, immunohistochemistry was performed to determine the expressions of HMGB1, TAMs, and lymphatic vessel density (LVD) in a total of 108 ovarian tissue specimens. Then, the relationships between HMGB1 or TAMs and LVD were assessed by correlation test. In our in vitro study, TAMs were isolated from ascites of EOC patients. Effects of HMGB1, TAMs, and HMGB1 combining with TAMs on lymphatic endothelial cell (LEC) proliferation, migration, and the capillary-like tube formation were measured. Results showed that the expression of HMGB1 and the number of TAMs infiltration were overexpressed in malignant ovarian tumors compared with that in normal ovarian and were closely associated with lymph node metastasis. Positive correlations existed between HMGB1 expression or TAMs count and LVD determination. In an in vitro study, data demonstrated that either HMGB1 or TAMs could facilitate lymphangiogenesis by inducing LEC proliferation, migration, and capillary-like tube formation. Meanwhile, HMGB1 combining with TAMs may augment the pro-lymphangiogenic property. Our data suggest that either HMGB1 or TAMs could facilitate lymphangiogenesis, while HMGB1 coculture with TAMs may strengthen the pro-lymphangiogenic potential, which may serve as a therapeutic target for ovarian cancer.