Overexpression of Semaphorin4D Indicates Poor Prognosis and Prompts Monocyte Differentiation toward M2 Macrophages in Epithelial Ovarian Cancer

Previously, we demonstrated overexpression of semaphorin4D (SEMA4D, CD100) to be closely related totumor angiogenesis in epithelial ovarian cancers (EOCs). However, the function and expression of SEMA4D inthe EOC microenvironment has yet to be clarified in detail. In this study, we confirmed that overexpression ofSEMA4D in primary tumors and ascites was related to low differentiation, platinum resistance and a refractorystatus (P<0.05), while high M2 macrophage count and percentage were evident in EOC patients with advancedFIGO stage and platinum resistance (P<0.05), using immunohistochemistry, enzyme-linked immunosorbentassay (ELISA), and fluorescence-activated cell sorting (FACS), respectively. The data showed correlations ofSEMA4D expression and M2 macrophage counts in primary tumors and M2 macrophage percentage in ascites(r=0.281 and 0.355, each P<0.05). In the Cox proportional hazard mode, SEMA4D expression was an independentindicator of overall survival (OS) and progression-free survival (PFS) for EOC patients. Furthermore, higherexpression of SEMA4D in ovarian cancer cell lines (SKOV3, A2780, and SW626) and their supernatants werefound than that in a human primary cultured ovarian cell and its supernatant by reversed transcript PCR(RT-PCR), Western blotting and ELISA, respectively. Interestingly, peripheral blood monocytes (MOs) tendedtowards the M2-polarized macrophage phenotype (CD163high) in vitro after human recombined soluble SEMA4Dprotein stimulation. These findings suggest that SEMA4D might possibly serve as a reliable tool for early andaccurate prediction of EOC poor prognosis and could playan important role in promoting tumor disseminationand metastasis in the EOC microenvironment. Thus SEMA4D and its role in macrophage polarization in EOCwarrants further study.