Over-Expression of Semaphorin4D, Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Is Related to Poor Prognosis in Ovarian Epithelial Cancer
Semaphorin4D (SEMA4D) has been regarded as an important protein in tumor angiogenesis, though originally identified in neurodevelopment. SEMA4D is extensively expressed in several malignant solid tumors. Nevertheless, the function and expression of SEMA4D in epithelial ovarian cancer (EOC) is as yet not well understood. The aim of this study was to investigate SEMA4D expression in EOC and evaluate its clinical–pathological and prognostic significance. Immunohistochemistry was used to analyze SEMA4D expression and tumor angiogenesis-related proteins (HIF-1α and VEGF) in tissues from 40 patients with normal ovarian epithelia and 124 EOC patients. SEMA4D was found to be expressed in 61.3% of the 124 EOC tissues, which was significantly higher than in the normal ovarian epithelia ( p < 0.001). SEMA4D expression correlated with HIF-1α and VEGF closely ( ρ = 0.349 and 0.263, p < 0.001). Positive SEMA4D staining was significantly higher in tissues from patients with low histological grade, FIGO stage III-IV, lymph node metastasis and residual disease ≥1 cm ( p < 0.05). In the Cox proportional hazard mode, SEMA4D expression and histologic grade were independent indicators of overall survival (OS) and progress-free survival (PFS) for EOC patients. These findings suggest that the cooperation of SEMA4D, HIF-1α, and VEGF may indicate poor prognosis for patients with EOC, thereby demonstrating that SEMA4D and its role in angiogenesis in EOC warrants further study.
References
[1]
Sakurai, A.; Do？i, C.L.; Gutkind, J.S. Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer. Cell Res 2012, 22, 23–32.
[2]
Carmeliet, P.; Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 2005, 436, 193–200.
[3]
Basile, J.R.; Castilho, R.M.; Williams, V.P.; Gutkind, J.S. Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc. Natl. Acad. Sci. USA 2006, 103, 9017–9022.
[4]
Conrotto, P.; Valdembri, D.; Corso, S.; Serini, G.; Tamagnone, L.; Comoglio, P.M.; Bussolino, F.; Giordano, S. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 2005, 105, 4321–4329.
[5]
Folkman, J. What is the evidence that tumors are angiogenesis dependent? J. Natl. Cancer Inst 1990, 82, 4–6.
[6]
Lu, X.; Kang, Y. Hypoxia and hypoxia-inducible factors: Master regulators of metastasis. Clin. Cancer Res 2010, 16, 5928–5935.
[7]
Wang, G.L.; Jiang, B.H.; Rue, E.A.; Semenza, G.L. Hypoxia-inducible factor 1 is a basic-helix-loophelix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl. Acad. Sci. USA 1995, 92, 5510–5514.
[8]
Vajkoczy, P.; Farhadi, M.; Gaumann, A.; Heidenreich, R.; Erber, R.; Wunder, A.; Tonn, J.C.; Menger, M.D.; Breier, G. Microtumor growth initiates angiogenic sprouting with simultaneous expression of VEGF, VEGF receptor-2, and angiopoietin-2. J. Clin. Invest 2002, 109, 777–785.
[9]
Siebold, C.; Berrow, N.; Walter, T.S.; Harlos, K.; Owens, R.J.; Stuart, D.I.; Terman, J.R.; Kolodkin, A.L.; Pasterkamp, R.J.; Jones, E.Y. High-resolution structure of the catalytic region of MICAL (molecule interacting with CasL), a multidomain flavoenzyme-signaling molecule. Proc. Natl. Acad. Sci. USA 2005, 102, 16836–16841.
[10]
Sun, Q.; Zhou, H.; Binmadi, N.O.; Basile, J.R. Hypoxia-inducible factor-1-mediated regulation of semaphorin 4D affects tumor growth and vascularity. J. Biol. Chem 2009, 284, 32066–32074.
[11]
Zhou, H.; Binmadi, N.O.; Yang, Y.H.; Proia, P.; Basile, J.R. Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression. Angiogenesis 2012, 15, 391–407.
[12]
Zhou, H.; Yang, Y.H.; Binmadi, N.O.; Proia, P.; Basile, J.R. The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma. Exp. Cell Res 2012, 318, 1685–1698.
Sopo, M.; Anttila, M.; Sallinen, H.; Tuppurainen, L.; Laurema, A.; Laidinen, S.; Hamalainen, K.; Tuunanen, P.; Koponen, J.K.; Kosma, V.M.; et al. Antiangiogenic gene therapy with soluble VEGF-receptors -1, -2 and -3 together with paclitaxel prolongs survival of mice with human ovarian carcinoma. Int. J. Cancer 2012, 131, 2394–2401.
Neufeld, G.; Cohen, T.; Gengrinovitch, S.; Poltorak, Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999, 13, 9–22.
[17]
Basile, J.R.; Barac, A.; Zhu, T.; Guan, K.L.; Gutkind, J.S. Class IV Semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 2004, 64, 5212–5224.
[18]
Mizukami, Y.; Kohgo, Y.; Chung, D.C. Hypoxia inducible factor-1 independent pathways in tumor angiogenesis. Clin. Cancer Res 2007, 13, 5670–5674.
[19]
Shimogai, R.; Kigawa, J.; Itamochi, H.; Iba, T.; Kanamori, Y.; Oishi, T.; Shimada, M.; Sato, S.; Kawaguchi, W.; Sato, S.; et al. Expression of hypoxia-inducible factor 1alpha gene affects the outcome in patients with ovarian cancer. Int. J. Gynecol. Cancer 2008, 18, 499–505.
[20]
Ch’ng, E.; Tomita, Y.; Zhang, B.; He, J.; Hoshida, Y.; Qiu, Y.; Morii, E.; Nakamichi, I.; Hamada, K.; Ueda, T.; et al. Prognostic significance of CD100 expression in soft tissue sarcoma. Cancer 2007, 110, 164–172.
[21]
Bachtiary, B.; Schindl, M.; P？tter, R.; Dreier, B.; Knocke, T.H.; Hainfellner, J.A.; Horvat, R.; Birner, P. Cervical cancer prognosis in patients receiving radical radiotherapy for diminished response to radiotherapy and unfavorable over expression. Clin. Cancer Res 2003, 9, 2234–2240.
