DOI QR코드

DOI QR Code

Overexpression of Platelet-derived Growth Factor-D as a Poor Prognosticator in Endometrial Cancer

  • Ding, Jie (Department of Obstetrics and Gynecology, Third Affiliated Hospital, Sun Yat-sen University) ;
  • Li, Xiao-Mao (Department of Obstetrics and Gynecology, Third Affiliated Hospital, Sun Yat-sen University) ;
  • Liu, Sui-Ling (Department of Obstetrics and Gynecology, Third Affiliated Hospital, Sun Yat-sen University) ;
  • Zhang, Yu (Department of Obstetrics and Gynecology, Third Affiliated Hospital, Sun Yat-sen University) ;
  • Li, Tian (Department of Obstetrics and Gynecology, Third Affiliated Hospital, Sun Yat-sen University)
  • Published : 2014.04.30

Abstract

Background: Emerging evidence implicates the platelet-derived growth factor-D (PDGF-D) in many types of human solid tumors. We investigated whether PDGF-D plays an important role in endometrial cancer (EC) in relation to clinicopathologic phenotype, angiogenesis, and patient prognosis. Materials and Methods: We analyzed PDGF-D protein expression by Western blotting in twenty-seven human endometrial cancer tissues, and matched normal endometrial controls collected at the third Affiliated hospital of Sun Yat-sen University during 2012-2013 (n=27). Immunohistochemical staining was performed using a human PDGF-D antibody on the endometrial cancer patients collected in the same facility during January 2001 and October 2013 (n=152). Patients were followed from the time of primary surgery in 2001-2013 until death or last follow-up. We correlated the PDGF-D expression levels with clinicopathologic parameters and prognosis in human endometrial cancer patients. Results: Compared with matched normal endometrial cases, PDGF-D was up-regulated in endometrial cancer. Expression of PDGF-D protein, found in 78% of the cases, was associated with nonendometrioid histologic type (p=0.028), FIGO stage III/IV (p=0.039), >50% solid tumor growth (p=0.048), pelvic LN metastasis (p=0.035) and ER and PR negativity (p=0.04 and 0.002). PDGF-D expression was also significantly associated with expression of VEGF-A (p=0.021). In multivariate analysis, PDGF-D expression proved to be an independent prognostic factor in addition to histologic grade and FIGO stage. Patients with high expression levels of PDGF-D had a significantly poorer overall survival rate compared with patients with no expression. Conclusions: PDGF-D expression is frequently up-regulated in endometrial cancer, and is associated with aggressive features and poor prognosis.

References

  1. Aas T, Borresen AL, Geisler S, et al (1996). Specific P53 mutations are associated with denovo resistance to doxorubicin in breast cancer patients. Nat Med, 2, 811-4. https://doi.org/10.1038/nm0796-811
  2. Creasman WT, Morrow CP, Bundy BN, et al (1987). Surgical pathologic spread patterns of endometrial cancer. Cancer, 60, 2035-41. https://doi.org/10.1002/1097-0142(19901015)60:8+<2035::AID-CNCR2820601515>3.0.CO;2-8
  3. Deuel TF (1987). Polypeptide growth factors: roles in normal and abnormal cell growth. Annu Rev Cell Biol, 3, 443-92. https://doi.org/10.1146/annurev.cb.03.110187.002303
  4. Engelsen IB, Stefansson IM, Akslen LA, et al (2008). GATA3 expression in estrogen receptor alpha-negative endometrial carcinomas identifies aggressive tumors with high proliferation and poor patient survival. Am J Obstet Gynecol, 199, 541-7.
  5. Hwang RF, Yokoi K, Bucana CD, et al (2003). Inhibition of platelet-derived growth factor receptor phosphorylation by STI571 (Gleevec) reduces growth and metastasis of human pancreatic carcinoma in an orthotopic nude mouse model. Clin Cancer Res, 9, 6534-44.
  6. Jemal A, Siegel R, Xu J, et al (2010). Cancer statistics, 2010. CA Cancer J Clin, 60, 277-300. https://doi.org/10.3322/caac.20073
  7. Kong D, Banerjee S, Huang W, et al (2008). Mammalian target of rapamycin repression by3,3’-diindolylmethane inhibits invasion and angiogenesis in platelet-derived growth factor-D over-expressing PC3 cells. Cancer Res, 68, 1927-34. https://doi.org/10.1158/0008-5472.CAN-07-3241
  8. LaRochelle WJ, Jeffers M, Corvalan JR, et al (2002). Platelet derived growth factor D: tumorigenicity in mice and dysregulated expression in human cancer. Cancer Res, 62, 2468-73.
  9. Lokker NA, Sullivan CM, Hollenbach SJ, et al (2002). Plateletderived growth factor autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res, 62, 3729-35.
  10. Mannelqvist M, Stefansson IM, Bredholt G, et al (2010). Gene expression patterns related to vascular invasion and aggressive features in endometrial cancer. Am J Pathol, 178, 861-71.
  11. Mannelqvist M, Stefansson IM, Salvesen HB, et al (2009). Importance of tumour cell invasion in blood and lymphatic vasculature among patients with endometrial carcinoma. Histopathology, 54, 174-83. https://doi.org/10.1111/j.1365-2559.2008.03201.x
  12. Rosenkranz S, Kazlauskas A (1999). Evidence for distinct signaling properties and biological responses induced by the PDGF receptor alpha and beta subtypes. Growth Factors, 16, 201-16. https://doi.org/10.3109/08977199909002130
  13. Stefansson IM, Salvesen HB, Akslen LA (2006). Vascular proliferation is important for clinical progress of endometrial cancer. Cancer Res, 66, 3303-9. https://doi.org/10.1158/0008-5472.CAN-05-1163
  14. Stefansson IM, Salvesen HB, Immervoll H, et al (2004). Prognostic impact of histological grade and vascular invasion compared with tumour cell proliferation in endometrial carcinoma of endometrioid type. Histopathology, 44, 472-9. https://doi.org/10.1111/j.1365-2559.2004.01882.x
  15. Ustach CV, Kim HR (2005). Platelet-derived growth factor D is activated by urokinase plasminogen activator in prostate carcinoma cells. Mol Cell Biol, 25, 6279-88. https://doi.org/10.1128/MCB.25.14.6279-6288.2005
  16. Ustach CV, Taube ME, Hurst NJ, et al (2004). A potential oncogenic activity of platelet-derived growth factor d in prostate cancer progression. Cancer Res, 64, 1722-9. https://doi.org/10.1158/0008-5472.CAN-03-3047
  17. Wan J, Li X (2012). PELP1/MNAR suppression inhibits proliferation and metastasis of endometrial carcinoma cells. Oncology Reports, 12, 2035-42.
  18. Wang HL, Ren YF, Yang J, et al (2013).Total laparoscopic hysterectomy versus total abdominal hysterectomy for endometrial cancer: a meta-analysis. Asian Pac J Cancer Prev, 14, 2515-9. https://doi.org/10.7314/APJCP.2013.14.4.2515
  19. Wang XW, Zhong TY, Xiong YH, et al (2012). Lack of association between the ,CYP1A1 Ile462Val polymorphism and endometrial cancer risk: a meta-analysis. Asian Pac J Cancer Prev, 13, 3717-21. https://doi.org/10.7314/APJCP.2012.13.8.3717
  20. Wang ZW, Ahmad A, Li YW, et al (2010). Emerging roles of PDGF-D signaling pathway in tumor development and progression. Biochim Biophys Acta, 1806, 122-30.
  21. Wang ZW, Kong DJ, Banerjee S, et al (2007). Down-regulation of platelet derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and Nuclear Factor-$\kappa$B Signaling. Cancer Res, 67, 11377-85. https://doi.org/10.1158/0008-5472.CAN-07-2803
  22. Wang ZW, Kong DJ, Li YW, et al (2009). PDGF-D signaling: a novel target in cancer therapy. Curr Drug Targets, 10, 38-41. https://doi.org/10.2174/138945009787122914
  23. Xiao L, Yang YB, Li XM, et al (2010). Differential sensitivity of human endometrial carcinoma cells with different PTEN expression to mitogen-activated protein kinase signaling inhibits and implications for therapy. J Cancer Res Clin Oncol, 136, 1089-99. https://doi.org/10.1007/s00432-009-0756-4
  24. Xu C, Li X, Li T, et al (2011). Combination effects of paclitaxel with signaling inhibitors in endometrial cancer cells. Asian Pac J Cancer Prev, 12, 2951-7.
  25. Xu L, Tong R, Cochran DM, et al (2005). Blocking platelet derived growth factor-D/platelet-derived growth factor receptor signaling inhibits human renal cell carcinoma progression in an orthotopic mouse model. Cancer Res, 65, 5711-9. https://doi.org/10.1158/0008-5472.CAN-04-4313
  26. Yu J, Ustach C, Kim HR (2003). Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol, 36, 49-59. https://doi.org/10.5483/BMBRep.2003.36.1.049

Cited by

  1. Relationships Between C-Kit Expression and Mean Platelet Volume in Benign, Preneoplastic and Neoplastic Endometrium vol.16, pp.4, 2015, https://doi.org/10.7314/APJCP.2015.16.4.1495