Abstract
Previously, we demonstrated overexpression of semaphorin4D (SEMA4D, CD100) to be closely related to tumor angiogenesis in epithelial ovarian cancers (EOCs). However, the function and expression of SEMA4D in the EOC microenvironment has yet to be clarified in detail. In this study, we confirmed that overexpression of SEMA4D in primary tumors and ascites was related to low differentiation, platinum resistance and a refractory status (P<0.05), while high M2 macrophage count and percentage were evident in EOC patients with advanced FIGO stage and platinum resistance (P<0.05), using immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and fluorescence-activated cell sorting (FACS), respectively. The data showed correlations of SEMA4D 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 independent indicator of overall survival (OS) and progression-free survival (PFS) for EOC patients. Furthermore, higher expression of SEMA4D in ovarian cancer cell lines (SKOV3, A2780, and SW626) and their supernatants were found 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) tended towards the M2-polarized macrophage phenotype (CD163high) in vitro after human recombined soluble SEMA4D protein stimulation. These findings suggest that SEMA4D might possibly serve as a reliable tool for early and accurate prediction of EOC poor prognosis and could playan important role in promoting tumor dissemination and metastasis in the EOC microenvironment. Thus SEMA4D and its role in macrophage polarization in EOC warrants further study.
Highlights
Epithelial ovarian cancer (EOC) is the leading killer among all gynecological malignancies (Siegel et al, 2012)
We confirmed that overexpression of SEMA4D in primary tumors and ascites was related to low differentiation, platinum resistance and a refractory status (P
Semaphorins were originally identified as molecules regulating a functional activity of axons in the nervous system, SEMA4D recently have been implicated in a host of responses including regulation of cell migration, angiogenesis, immune and inflammation responses, and tumor progression
Summary
Epithelial ovarian cancer (EOC) is the leading killer among all gynecological malignancies (Siegel et al, 2012). Recent evidences suggested that ascites of EOC play a positive role on cancer peritoneal dissection and metastasis owing to containing plenty of growth factors, cytokines, extracellular matrix constituents, and cancer-promoting immunocytes, especially tumor-associated macrophages (TAMs), which induced tumorigenesis closely (Abdollahi et al, 2003; Martinez et al, 2008; Giuntoli et al, 2009). Former data demonstrated soluble SEMA4D protein released from the breast cancer cell surface acted on local as well as distant tumor microenvironments, inducing tumor angiogenesis and metastasis (Basile et al, 2007). We focus on detecting the expressions of SEMA4D and M2 macrophage in primary tumor tissues and ascites of EOC patients and assess their association with the established clinicopathologic factors of the disease as well as patient prognosis. Phenotypes of MOs (from healthy donors) stimulated with/ without human recombined soluble SEMA4D protein and macrophages (from EOC ascites) were investigated by Fluorescence-activated cell sorting (FACS)
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