Virchows Archiv

, Volume 450, Issue 2, pp 187–194 | Cite as

Taxol-resistance-associated gene-3 (TRAG-3/CSAG2) expression is predictive for clinical outcome in ovarian carcinoma patients

  • Verena Materna
  • Paweł Surowiak
  • Irina Kaplenko
  • Marek Spaczyński
  • Zhenfeng Duan
  • Maciej Zabel
  • Manfred Dietel
  • Hermann LageEmail author
Original Article


An obstacle in chemotherapy of ovarian cancer is the development of drug resistance. Taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2) was found to be overexpressed in a paclitaxel-resistant ovarian carcinoma cell line. However, clinical impact of TRAG-3 in ovarian carcinoma has not been demonstrated previously. For demonstration of potential clinical impact of TRAG-3, immunohistochemistry was applied to determine TRAG-3 protein expression in specimens obtained from ovarian carcinoma patients (n = 37) who received a paclitaxel-based chemotherapy at two different time points, initial laparotomy before chemotherapy, and secondary cytoreduction after chemotherapy. The TRAG-3-specific immunohistochemical staining was correlated with clinical outcome. In ovarian carcinoma specimens obtained at the initial laparotomy, an advantage in overall (P < 0.001) and progression-free (P = 0.003) survival for patients with weak TRAG-3 expression could be demonstrated. Tumor specimens excised at secondary cytoreduction procedure were not predictive for clinical outcome. In summary, TRAG-3 was found to be a prognostic factor for the prediction of clinical outcome after the application of paclitaxel-based chemotherapy.


Ovarian carcinoma Paclitaxel TRAG-3 CSAG2 Chemotherapy 



This study was supported in part by the “Berliner Krebsgesellschaft e.V.” and by grant LA 1039/2-3 of the “Deutsche Forschungsgemeinschaft”.


  1. 1.
    Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22:7468–7485PubMedCrossRefGoogle Scholar
  2. 2.
    Chen Z, Zhu B, Wu Y (2002) Expression of TRAG-3 antigen in non-small-cell lung carcinomas. Lung Cancer 38:101–102PubMedCrossRefGoogle Scholar
  3. 3.
    Duan Z, Duan Y, Lamendola DE, Yusuf RZ, Naeem R, Penson RT, Seiden MV (2003) Overexpression of MAGE/GAGE genes in paclitaxel/doxorubicin-resistant human cancer cell lines. Clin Cancer Res 9:2778–2785PubMedGoogle Scholar
  4. 4.
    Duan Z, Feller AJ, Toh HC, Makastorsis T, Seiden MV (1999) TRAG-3, a novel gene, isolated from taxol-resistant ovarian carcinoma cell line. Gene 229:75–81PubMedCrossRefGoogle Scholar
  5. 5.
    Feller AJ, Duan Z, Penson R, Toh HC, Seiden MV (2000) TRAG-3, a novel cancer/testis antigen, is overexpressed in the majority of melanoma cell lines and malignant melanoma. Anticancer Res 20:4147–4151PubMedGoogle Scholar
  6. 6.
    Giannakakou O, Sackett DL, Kang YK, Zhan Z, Buters JT, Fojo T, Poruchynsky MS (1997) Paclitaxel-resistant human ovarian cancer cells have mutant beta-tubulins that exhibit impaired paclitaxel-driven polymerization. J Biol Chem 272:17118–17125PubMedCrossRefGoogle Scholar
  7. 7.
    Haber M, Burkhart CA, Regl DL, Madafiglio J, Norris MD, Horwitz SB (1995) Altered expression of Mbeta2, the class II beta-tubulin isotype, in a murine J774.2 cell line with a high level of taxol resistance. J Biol Chem 270:31269–31275PubMedCrossRefGoogle Scholar
  8. 8.
    Lage H, Dietel M (1997) Cloning and characterization of human cDNAs encoding a protein with high homology to rat intestinal development protein OCI-5. Gene 188:151–156PubMedCrossRefGoogle Scholar
  9. 9.
    Lin C, Mak S, Meitner PA, Wolf JM, Bluman EM, Block JA, Terek RM (2002) Cancer/testis antigen CSAGE is concurrently expressed with MAGE in chondrosarcoma. Gene 285:269–278PubMedCrossRefGoogle Scholar
  10. 10.
    Materna V, Pleger J, Hoffmann U, Lage H (2004) RNA expression of MDR1/P-glycoprotein, DNA-topoisomerase I, and MRP2 in ovarian carcinoma patients: correlation with chemotherapeutic response. Gynecol Oncol 94:152–160PubMedCrossRefGoogle Scholar
  11. 11.
    McGuire WP 3rd, Markman M (2003) Primary ovarian cancer chemotherapy: current standards of care. Br J Cancer 89:53–58CrossRefGoogle Scholar
  12. 12.
    Nimmrich I, Erdmann S, Melchers U, Finke U, Hentsch S, Moyer MP, Hoffmann I, Muller O (2000) Seven genes that are differentially transcribed in colorectal tumor cell lines. Cancer Lett 160:37–43PubMedCrossRefGoogle Scholar
  13. 13.
    Ohta M, Tanaka F, Sadanaga N, Yamaguchi H, Inoue H, Mori M (2006) Expression of the TRAG-3 gene in human esophageal cancer: The frequent synchronous expression of MAGE-3 gene. Oncol Rep 15:1529–1532PubMedGoogle Scholar
  14. 14.
    Ozols RF, Schwartz PE, Eifel PJ (2001) Ovarian cancer, fallopian tube carcinoma and peritoneal carcinoma. In: De Vita Jr. VT, Hellman S, Rosenberg SA (eds) Cancer: principles & practice of oncology, 6th edn. Lippincott-Raven, Philadelphia, pp 1597–1632Google Scholar
  15. 15.
    Remmele W, Stegner HE (1987) Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue [Article in German]. Pathologe 8:138–140PubMedGoogle Scholar
  16. 16.
    Rowinsky EK, Donehower RC (1995) Paclitaxel (taxol). N Engl J Med 332:1004–1014PubMedCrossRefGoogle Scholar
  17. 17.
    Scheffer GL, Wijngaard PL, Flens MJ, Izquierdo MA, Slovak ML, Pinedo HM, Meijer CJ, Clevers HC, Scheper RJ (1995) The drug resistance-related protein LRP is the human major vault protein. Nat Med 1:578–582PubMedCrossRefGoogle Scholar
  18. 18.
    Shimizu Y, Kamoi S, Amada S, Akiyama F, Silverberg SG (1998) Toward the development of a universal grading system for ovarian epithelial carcinoma. Cancer 82:893–901PubMedCrossRefGoogle Scholar
  19. 19.
    Sobin LH, Wittekind C (eds) (2002) TNM classification of malignant tumors (UICC). Wiley-Liss, New YorkGoogle Scholar
  20. 20.
    Stewart BW, Kleihues P (eds) (2003) World cancer report. IARC, Lyon, pp 220–222Google Scholar
  21. 21.
    Surowiak P, Materna M, Denkert C, Kaplenko I, Spaczynski M, Dietel M, Zabel M, Lage H (2006) Significance of cyclooxygenase 2 and MDR1/P-glycoprotein coexpression in ovarian cancers. Cancer Lett 235:272–280PubMedCrossRefGoogle Scholar
  22. 22.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92: 205–216PubMedCrossRefGoogle Scholar
  23. 23.
    Wichert A, Stege A, Midorikawa Y, Holm PS, Lage H (2004) Glypican-3 is involved in cellular protection against mitoxantrone in gastric carcinoma cells. Oncogene 23:945–955PubMedCrossRefGoogle Scholar
  24. 24.
    Wu Y, Zhao T, Ni B, Zou L, Liu H, Zhu B (2003) Expression of TRAG-3 in breast cancer. Int J Cancer 107:167–168PubMedCrossRefGoogle Scholar
  25. 25.
    Yao X, Hu J, Li T, Yang Y, Sun Z, Ulaner GA, Vu TH, Hoffman AR (2004) Epigenetic regulation of the taxol resistance-associated gene TRAG-3 in human tumors. Cancer Genet Cytogenet 151:1–13PubMedCrossRefGoogle Scholar
  26. 26.
    Zhu B, Chen Z, Cheng X, Wu Y (2002) Induction of TRAG-3 expression in A549 lung adenocarcinoma cell line by 5-aza-2′ deoxyazacytidine. Lung Cancer 38:321–322PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Verena Materna
    • 1
  • Paweł Surowiak
    • 1
    • 2
    • 3
  • Irina Kaplenko
    • 4
  • Marek Spaczyński
    • 4
  • Zhenfeng Duan
    • 5
  • Maciej Zabel
    • 2
    • 6
  • Manfred Dietel
    • 1
  • Hermann Lage
    • 1
    Email author
  1. 1.Institute of PathologyCharité Campus MitteBerlinGermany
  2. 2.Department of Histology and EmbryologyWrocław Medical UniversityWrocławPoland
  3. 3.Lower Silesian Center of OncologyWrocławPoland
  4. 4.Department of Obstetrics and GynecologyPoznań University of Medical SciencesPoznańPoland
  5. 5.Division of Hematology/OncologyMassachusetts General HospitalBostonUSA
  6. 6.Department of Histology and EmbryologyPoznań University of Medical SciencesPoznańPoland

Personalised recommendations