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Clinical & Experimental Metastasis

, Volume 30, Issue 6, pp 731–740 | Cite as

The expression and characterization of endoglin in uterine leiomyosarcoma

  • Hiroko Mitsui
  • Kiyosumi ShibataEmail author
  • Yukio Mano
  • Shiro Suzuki
  • Tomokazu Umezu
  • Mika Mizuno
  • Eiko Yamamoto
  • Hiroaki Kajiyama
  • Tomomi Kotani
  • Takeshi Senga
  • Fumitaka Kikkawa
Research Paper

Abstract

Endoglin (CD105), an accessory receptor of transforming growth factor-β, is expressed in vascular endothelial cells. Recently, it was reported that endoglin expression was significantly associated with poorer survival in several cancers. In this study, we evaluated the role of endoglin in uterine leiomyosarcoma. We examined the expression of endoglin in 22 uterine leiomyosarcomas and the association between their expression and the outcome. Additionally, to evaluate the function of endoglin, we used SKN cells, a human uterine leiomyosarcoma cell line. We generated SKN cells stably transfected with plasmids encompassing shRNA targeting endoglin (shEng cells), and compared the ability of proliferation, migration, and invasion to control shRNA-transfected cells (shCon cells). We compared the level of VEGF and matrix metalloproteinases (MMP) in culture supernatants of shEndoglin and shControl cells. Nine patients were endoglin-positive and 13 patients were -negative. The endoglin-positive group had a significantly poorer overall survival and progression-free survival than the endoglin-negative group. In an in vitro study, there was no difference in cell proliferation between shEng and shCon cells. On the other hand, shEng cells showed a lower ability for migration and invasion than shControl cells. The activity of MMP-9 and VEGF level in the supernatant from shEng cells were lower than in shCon cells. In uterine leiomyosarcoma, endoglin expression was associated with a poor prognosis. It was suggested that endoglin up-regulated invasion and VEGF secretion. The investigation of endoglin may lead to a new strategy in uterine leiomyosarcoma therapy.

Keywords

Endoglin Leiomyosarcoma Prognosis MMP-9 VEGF 

References

  1. 1.
    Brooks SE, Zhan M, Cote T, Baquet CR (2004) Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989–1999. Gynecol Oncol 93:204–208. doi: 10.1016/j.ygyno.2003.12.029 PubMedCrossRefGoogle Scholar
  2. 2.
    Leitao MM, Sonoda Y, Brennan MF, Barakat RR, Chi DS (2003) Incidence of lymph node and ovarian metastases in leiomyosarcoma of the uterus. Gynecol Oncol 91:209–212. doi: 10.1016/S0090-8258(03)00478-5 PubMedCrossRefGoogle Scholar
  3. 3.
    Zaloudek C, Norris HJ (1994) Mesenchymal tumors of the uterus. In: Kurman RJ (ed) Blausteins pathology of the female genital tract, 4th edn. Springer, New York, pp 487–528CrossRefGoogle Scholar
  4. 4.
    Sagae S, Yamashita K, Ishioka S et al (2004) Preoperative diagnosis and treatment results in 106 patients with uterine sarcoma in Hokkaido, Japan. Oncology 67:33–39. doi: 10.1159/000080283 PubMedCrossRefGoogle Scholar
  5. 5.
    Benoit L, Arnould L, Cheynel N et al (2005) The role of surgery and treatment trends in uterine sarcoma. Eur J Surg Oncol 31:434–442. doi: 10.1016/j.ejso.2005.01.010 PubMedCrossRefGoogle Scholar
  6. 6.
    Park JY, Kim DY, Suh DS et al (2008) Prognostic factors and treatment outcomes of patients with uterine sarcoma: analysis of 127 patients at a single institution, 1989–2007. J Cancer Res Clin Oncol 134:1277–1287. doi: 10.1007/s00432-008-0422-2 PubMedCrossRefGoogle Scholar
  7. 7.
    Nam JH, Park JY (2010) Update on treatment of uterine sarcoma. Curr Opin Obstet Gynecol 22:36–42. doi: 10.1097/GCO.0b013e328334d90f PubMedCrossRefGoogle Scholar
  8. 8.
    Fonsatti E, Altomonte M, Nicotra MR, Natali PG, Maio M (2003) Endoglin (CD105): a powerful therapeutic target on tumorassociated angiogenetic blood vessels. Oncogene 22:6557–6563. doi: 10.1038/sj.onc.1206813 PubMedCrossRefGoogle Scholar
  9. 9.
    Barbara NP, Wrana JL, Letarte M (1999) Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-β superfamily. J Biol Chem 274:584–594. doi: 10.1074/jbc.274.2.584 PubMedCrossRefGoogle Scholar
  10. 10.
    Lebrin F, Goumans MJ, Jonker L et al (2004) Endoglin promotes endothelial cell proliferation and TGF-beta/ALK1 signal transduction. EMBO 23(20):4018–4028. doi: 10.1038/sj.emboj.7600386 CrossRefGoogle Scholar
  11. 11.
    ten Dijke P, Goumans MJ, Pardali E (2008) Endoglin in angiogenesis and vascular diseases. Angiogenesis 11:79–89. doi: 10.1007/s10456-008-9101-9 PubMedCrossRefGoogle Scholar
  12. 12.
    Hawinkels L, Kuiper P, Wiercinska E, Verspaget HW, Liu Z, Pardali E, Sier CFM, ten Dijke P (2010) Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis. Cancer Res 70:4141–4150. doi: 10.1158/0008-5472.CAN-09-4466 PubMedCrossRefGoogle Scholar
  13. 13.
    Jeyabalan A, McGonigal S, Gilmour C, Hubel CA, Rajakumar A (2008) Circulating and placental endoglin concentrations in pregnancies complicated by intrauterine growth restriction and preeclampsia. Placenta 29(6):555–563. doi: 10.1016/j.placenta.2008.03.006 PubMedCrossRefGoogle Scholar
  14. 14.
    Fonsatti E, Maio M (2004) Highlights on endoglin (CD105): frombasic findings towards clinical applications in human cancer. J Transl Med 2:18. doi: 10.1186/1479-5876-2-18 PubMedCrossRefGoogle Scholar
  15. 15.
    Duff SE, Li C, GarlandJM Kumar S (2003) CD105 is important for angiogenesis: evidence and potential applications. FASEB J 17:984–992. doi: 10.1096/fj.02-0634rev PubMedCrossRefGoogle Scholar
  16. 16.
    Saad RS, LiuYL Nathan G, CelebrezzeJ Medich D, Silverman JF (2004) Endoglin (CD105) and vascular endothelial growth factor as prognosticmarkers in colorectal cancer. Mod Pathol 17:197–203. doi: 1038/modpathol.3800034 PubMedCrossRefGoogle Scholar
  17. 17.
    El-Gohary YM, Silverman JF, Olson PR et al (2007) Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in prostatic adenocarcinoma. Am J Clin Pathol 127:572–579. doi: 10.1309/X6NXYE57DLUE2NQ8 PubMedCrossRefGoogle Scholar
  18. 18.
    Li C, Guo B, Wilson PB, Stewart A et al (2000) Plasma levels of soluble CD105 correlate with metastasis in patients with breast cancer. Int J Cancer 89:122–126. doi: 10.1002/(SICI)1097-0215(20000320 PubMedCrossRefGoogle Scholar
  19. 19.
    Takahashi N, Kawanishi-Tabata R, Haba A, et al (2001) Association of serum endoglin with metastasis in patients with colorectal, breast, and other solid tumors, and suppressive effect of chemotherapy on the serum endoglin. Clin Cancer Res 7:524–32. http://clincancerres.aacrjournals.org/content/7/3/524
  20. 20.
    Suzuki S, Terauchi M, Umezu T, Kajiyama H, Shibata K, Nawa A, Kikkawa F (2010) Identification and characterization of cancer stem cells in ovarian yolk sac tumors. Cancer Sci 101(10):2179–2185. doi: 10.1111/j.1349-7006.2010.01672.x PubMedCrossRefGoogle Scholar
  21. 21.
    Ishiwata I, Nozawa S, Nagai S, Kurihara S, Mikata A (1977) Establishment of a human leiomyosarcoma cell line. Cancer Res 37:658–664. http://cancerres.aacrjournals.org/content/37/3/658 Google Scholar
  22. 22.
    D’Angelo E, Spagnoli LG, Prat J (2009) Comparative clinicopathologic and immunohistochemical analysis of uterine sarcomas diagnosed using the World Health Organization classification system. Human Pathol 40:1571–1585. doi: 10.1016/j.humpath.2009.03.018
  23. 23.
    Zhai YL, Nikaido T, Toki T, Shiozawa A, Orii A, Fujii S (1999) Prognostic significance of bcl-2 expression in leiomyosarcoma of the uterus. Br J Cancer 80:1658–1664. doi: 10.1038/sj.bjc.6690578 Google Scholar
  24. 24.
    Dubinski W, Gabril M, Iakovlev VV et al (2011) Assessment of the prognostic significance of endoglin (CD105) in clear cell renal cell carcinoma using automated image analysis. Hum Pathol 43(7):1037–1043. doi: 10.1016/j.humpath.2011.08.012
  25. 25.
    Steg AD, Bevis KS, Katre AA, Ziebarth A, Alvarez RD, Zhang K, Conner MB, Landen CN Jr (2011) Stem cell pathways contribute to clinical chemoresistance in ovarian cancer. Clin Cancer Res 18(3):869–881. doi: 10.1158/1078-0432.CCR-11-2188 Google Scholar
  26. 26.
    Oxmann D, Held-Feindt J, Stark AM, Hattermann K, Yoneda T, Mentlein R (2008) Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype. Oncogene 27:3567–3575. doi: 10.1038/sj.onc.1211025 Google Scholar
  27. 27.
    Henry LA, Johnson DA, Sarrió D, Lee S, Quinlan PR, Crook T, Thompson AM, Reis-Filho JS, Isacke CM (2011) Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome. Oncogene 30(9):1046–1058. doi: 10.1038/onc.2010.488 Google Scholar
  28. 28.
    Lakshman M, Huang X, Ananthanarayanan V, Jovanovic B, Liu Y, Craft CS, Romero D, Vary CP, Bergan RC (2011) Endoglin suppresses human prostate cancer metastasis. Clin Exp Metastasis 28(1):39–53. doi: 10.1007/s10585-010-9356-6 Google Scholar
  29. 29.
    Finnson KW, Parker WL, Chi Y, Hoemann CD, Goldring MB, Antoniou J, Philip A (2010) Endoglin differentially regulates TGF-β-induced Smad2/3 and Smad1/5 signalling and its expression correlates with extracellular matrix production and cellular differentiation state in human chondrocytes. Osteoarthr Cartil 18(11):1518–1527. doi: 10.1016/j.joca.2010.09.002 Google Scholar
  30. 30.
    Arita S, Kikkawa F, Kajiyama H, Shibata K, Kawai M, Mizuno K, Nagasaka T, Ino K, Nomura S (2005) Prognostic importance of vascular endothelial growth factor and its receptors in the uterine sarcoma. Int J Gynecol Cancer 15(2):329–336Google Scholar
  31. 31.
    Nikiteas NI, Tzanakis N, Theodoropoulos G et al (2007) Vascular endothelial growth factor and endoglin (CD-105) in gastric cancer. Gastric Cancer 10(1):12–17. doi: 10.1007/s10120-006-0401-8 Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Hiroko Mitsui
    • 1
  • Kiyosumi Shibata
    • 1
    Email author
  • Yukio Mano
    • 1
  • Shiro Suzuki
    • 1
  • Tomokazu Umezu
    • 1
  • Mika Mizuno
    • 1
  • Eiko Yamamoto
    • 1
  • Hiroaki Kajiyama
    • 1
  • Tomomi Kotani
    • 1
  • Takeshi Senga
    • 2
  • Fumitaka Kikkawa
    • 1
  1. 1.Department of Obstetrics and GynecologyNagoya University Graduate School of MedicineShowa-kuJapan
  2. 2.Division of Cancer BiologyNagoya University Graduate School of MedicineNagoyaJapan

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