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

  • Chen, Ying (Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital) ;
  • Zhang, Lei (Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital) ;
  • Lv, Rui (Reproductive Medical Center, Tianjin Medical University General Hospital) ;
  • Zhang, Wen-Qi (Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital)
  • Published : 2013.10.30


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 ($CD163^{high}$) 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.


Semaphorin4D;ascites;macrophage;ovarian cancer;prognosis


  1. Carmeliet P, Tessier-Lavigne M (2005). Common mechanisms of nerve and blood vessel wiring. Nature, 436, 193-200.
  2. Abdollahi T, Robertson NM, Abdollahi A, et al (2003). Identification of interleukin 8 as an inhibitor of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in the ovarian carcinoma cell line OVCAR3. Cancer Res, 63, 4521-6.
  3. Auersperg N, Ota T, Mitchell GW (2002). Early events in ovarian epithelial carcinogenesis: progress and problems in experimental approaches. Int J Gynecol Cancer, 12, 691-703.
  4. Basile JR, Castilho RM, Williams VP, et al (2006). Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci U S A, 103, 9017-22.
  5. Basile JR, Holmbeck K, Bugge TH, et al (2007). MT1-MMP controls tumor-induced angiogenesis through the release of semaphorin 4D. J Biol Chem, 282, 6899-905.
  6. Bast RJ, Hennessy B, Mills GB (2009). The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer, 9, 415-28.
  7. Chen Y, Zhang L, Pan Y, et al (2012). Over-expression of semaphorin4D, hypoxia-inducible factor-$1{\alpha}$ and vascular endothelial growth factor is related to poor prognosis in ovarian epithelial cancer. Int J Mol Sci, 13, 13264-74.
  8. Ch'Ng E, Tomita Y, Zhang B, et al (2007). Prognostic significance of CD100 expression in soft tissue sarcoma. Cancer, 110, 164-72.
  9. Delaire S, Billard C, Tordjman R, et al (2001). Biological activity of soluble CD100. II. Soluble CD100, similarly to H-SemaIII, inhibits immune cell migration. J Immunol, 166, 4348-54.
  10. Denholm EM, Wolber FM, Phan SH (1989). Secretion of monocyte chemotactic activity by alveolar macrophages. Am J Pathol, 135, 571-80.
  11. Eisenhauer EA, Therasse P, Bogaerts J, et al (2009). New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 45, 228-47.
  12. Jensen TO, Schmidt H, Moller HJ, et al (2009). Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. J Clin Oncol, 27, 3330-7.
  13. Eisenhauer EL, Abu-Rustum NR, Sonoda Y, et al (2008). The effect of maximal surgical cytoreduction on sensitivity to platinum-taxane chemotherapy and subsequent survival in patients with advanced ovarian cancer. Gynecol Oncol, 108, 276-81.
  14. Giuntoli RN, Webb TJ, Zoso A, et al (2009). Ovarian cancer-associated ascites demonstrates altered immune environment: implications for antitumor immunity. Anticancer Res, 29, 2875-84.
  15. Ishida I, Kumanogoh A, Suzuki K, et al (2003). Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses. Int Immunol, 15, 1027-34.
  16. Kumanogoh A, Kikutani H (2004). Biological functions and signaling of a transmembrane semaphorin, CD100/Sema4D. Cell Mol Life Sci, 61, 292-300.
  17. Lan C, Huang X, Lin S, et al (2013). Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technol Cancer Res Treat, 12, 259-67.
  18. Lane D, Matte I, Rancourt C, et al (2011). Prognostic significance of IL-6 and IL-8 ascites levels in ovarian cancer patients. BMC Cancer, 11, 210.
  19. Lee CH, Espinosa I, Vrijaldenhoven S, et al (2008). Prognostic significance of macrophage infiltration in leiomyosarcomas. Clin Cancer Res, 14, 1423-30.
  20. Martinez FO, Sica A, Mantovani A, et al (2008). Locati M. Macrophage activation and polarization. Front Biosci, 13, 453-61.
  21. Sanchez-Espiridion B, Martin-Moreno AM, Montalban C, et al (2012) F. Immunohistochemical markers for tumor associated macrophages and survival in advanced classical Hodgkin's lymphoma. Haematologica, 97, 1080-4.
  22. Nakanishi Y, Nakatsuji M, Seno H, et al (2011). COX-2 inhibition alters the phenotype of tumor-associated macrophages from M2 to M1 in ApcMin/+ mouse polyps. Carcinogenesis, 32, 1333-9.
  23. Qian BZ, Pollard JW (2010). Macrophage diversity enhances tumor progression and metastasis. Cell, 141, 39-51.
  24. Sakurai A, Doci CL, Gutkind JS (2012). Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer. Cell Res, 22, 23-32.
  25. Shabo I, Olsson H, Sun XF, et al (2009). Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time. Int J Cancer, 125, 1826-31.
  26. Shabo I, Stal O, Olsson H, et al (2008). Breast cancer expression of CD163, a macrophage scavenger receptor, is related to early distant recurrence and reduced patient survival. Int J Cancer, 123, 780-6.
  27. Sica A, Larghi P, Mancino A, et al (2008). Macrophage polarization in tumour progression. Semin Cancer Biol, 18, 349-55.
  28. Siegel R, Naishadham D, Jemal A (2012). Cancer statistics. CA Cancer J Clin, 62, 10-29.
  29. Sierra JR, Corso S, Caione L, et al (2008). Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med, 205, 1673-85.
  30. van Dongen M, Savage ND, Jordanova ES, et al (2010). Anti-inflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor-treated gastrointestinal stromal tumors. Int J Cancer, 127, 899-909.
  31. Zhou H, Binmadi NO, Yang YH, et al (2012). Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression. Angiogenesis, 15, 391-407.
  32. Wang R, Zhang T, Ma Z, et al (2010). The interaction of coagulation factor XII and monocyte/macrophages mediating peritoneal metastasis of epithelial ovarian cancer. Gynecol Oncol, 117, 460-6.
  33. Zhang B, Yao G, Zhang Y, et al (2011). M2-polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma. Clinics (Sao Paulo), 66, 1879-86.
  34. Zhang T, Ma Z, Wang R, et al (2010). Thrombin facilitates invasion of ovarian cancer along peritoneum by inducing monocyte differentiation toward tumor-associated macrophage-like cells. Cancer Immunol Immunother, 59, 1097-108.

Cited by

  1. Expression and clinical significance of Semaphorin4D in non-small cell lung cancer and its impact on malignant behaviors of A549 lung cancer cells vol.34, pp.4, 2014,
  2. Semaphorin 4D and hypoxia-inducible factor-1α overexpression is related to prognosis in colorectal carcinoma vol.21, pp.7, 2015,
  3. The role of Sema4D/CD100 as a therapeutic target for tumor microenvironments and for autoimmune, neuroimmune and bone diseases vol.20, pp.7, 2016,
  4. Semaphorin 4D correlates with increased bone resorption, hypercalcemia, and disease stage in newly diagnosed patients with multiple myeloma vol.8, pp.5, 2018,
  5. Association between prognosis and SEMA4D/Plexin-B1 expression in various malignancies vol.98, pp.7, 2019,