Skip to main content
Log in

Clinical relevance of CD44 surface expression in advanced stage serous epithelial ovarian cancer: a prospective study

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Cluster of differentiation (CD) 44 is a cell surface receptor that correlates with the development of drug resistance in epithelial ovarian cancer (EOC). Here, we prospectively investigated the clinical impact of CD44 expression on the development of chemoresistance, and on disease-free and overall survival in EOC.

Methods

This study included patients with primary serous EOC that was at International Federation of Gynecology and Obstetrics stages IIIB–IVA and tumors that were CD44 positive and negative in a 1:1 ratio. All patients underwent primary surgical cytoreduction, followed by six cycles of combined paclitaxel and carboplatin chemotherapy every 3 weeks. The treatment was considered complete after the chemotherapy had finished. All patients were followed up for 24 months after completing their chemotherapy.

Results

Of the 96 patients with serous EOC at stages IIIB–IVA, 51 % of the tumors were negative for the expression of CD44 and 49 % showed variable CD44 expression. Patients who had CD44-positive tumors had statistically significant shorter disease-free (p ≤ 0.001) and overall survival (p ≤ 0.001) intervals compared with patients with CD44-negative tumors. The hazard ratio for death was 6.8 (95 % confidence interval 2.4–19.2, p ≤ 0.001) among the patients with CD44-positive tumors. A multivariate analysis showed that carboplatin-resistant or carboplatin-refractory EOC was the only independent predictive factor for death.

Conclusions

CD44 expression contributes to the development of carboplatin resistance in advanced serous EOC, and it may contribute to worse prognoses for patients, but it is neither an independent predictor of survival nor of recurrence.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • AGO-Leitlinienkommission (2013) S3-Leitlinie Diagnostik, Therapie und Nachsorge maligner Ovarialtumoren

  • Ataseven B, Grimm C, Harter P, Heitz F, Traut A, Prader S, du Bois A (2015) Prognostic impact of debulking surgery and residual tumor in patients with epithelial ovarian cancer FIGO stage IV. Gynecol Oncol. doi:10.1016/j.ygyno.2015.12.007

    Google Scholar 

  • Baba T et al (2009) Epigenetic regulation of CD133 and tumorigenicity of CD133 + ovarian cancer cells. Oncogene 28:209–218. doi:10.1038/onc.2008.374

    Article  CAS  PubMed  Google Scholar 

  • Berner HS et al (2000) Expression of CD44 in effusions of patients diagnosed with serous ovarian carcinoma–diagnostic and prognostic implications. Clin Exp Metastasis 18:197–202

    Article  CAS  PubMed  Google Scholar 

  • Bonneau C et al (2015) Predictive markers of chemoresistance in advanced stages epithelial ovarian carcinoma. Gynecol Oncol 136:112–120. doi:10.1016/j.ygyno.2014.10.024

    Article  CAS  PubMed  Google Scholar 

  • Bourguignon LY (2008) Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression. Semin Cancer Biol 18:251–259. doi:10.1016/j.semcancer.2008.03.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cannistra SA (2004) Cancer of the ovary. N Engl J Med 351:2519–2529. doi:10.1056/NEJMra041842

    Article  CAS  PubMed  Google Scholar 

  • du Bois A et al (2003) A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 95:1320–1329

    Article  PubMed  Google Scholar 

  • du Bois A, Reuss A, Pujade-Lauraine E, Harter P, Ray-Coquard I, Pfisterer J (2009) Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials. Cancer 115:1234–1244. doi:10.1002/cncr.24149

    Article  PubMed  Google Scholar 

  • Friedlander M et al (2011) Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer 21:771–775. doi:10.1097/IGC.0b013e31821bb8aa

    Article  PubMed  Google Scholar 

  • Gao L et al (2011) Enhancive effects of Lewis y antigen on CD44-mediated adhesion and spreading of human ovarian cancer cell line RMG-I. J Exp Clin Cancer Res 30:15. doi:10.1186/1756-9966-30-15

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao Y et al (2015) Up-regulation of CD44 in the development of metastasis, recurrence and drug resistance of ovarian cancer. Oncotarget 6:9313–9326

    Article  PubMed  PubMed Central  Google Scholar 

  • Garcia M, Jemal A, Ward E, Center M, Hao Y, Siegel R, Thun M (2007) Global cancer facts & figures. American Cancer Society, Atlanta

    Google Scholar 

  • Hoskins WJ et al (1994) The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. American journal of obstetrics and gynecology 170:974–979 (discussion 979–980)

    Article  CAS  PubMed  Google Scholar 

  • Hu Z et al (2013) High expression of Lewis y antigen and CD44 is correlated with resistance to chemotherapy in epithelial ovarian cancers. PLoS One 8:e57250. doi:10.1371/journal.pone.0057250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaatsch P et al (2013) Krebs in Deutschland 2009/2010. 9 edn. Robert Koch-Institut und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V., Berlin

  • McGuire WP et al (1996) Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1–6. doi:10.1056/nejm199601043340101

    Article  CAS  PubMed  Google Scholar 

  • Naumann RW, Coleman RL (2011) Management strategies for recurrent platinum-resistant ovarian cancer. Drugs 71:1397–1412. doi:10.2165/11591720-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  • Ohashi R et al (2007) Interaction between CD44 and hyaluronate induces chemoresistance in non-small cell lung cancer cell. Cancer Lett 252:225–234. doi:10.1016/j.canlet.2006.12.025

    Article  CAS  PubMed  Google Scholar 

  • Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern cooperative oncology group. Am J Clin Oncol 5:649–655

    Article  CAS  PubMed  Google Scholar 

  • Omura G, Blessing JA, Ehrlich CE, Miller A, Yordan E, Creasman WT, Homesley HD (1986) A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. A gynecologic oncology group study. Cancer 57:1725–1730

    Article  CAS  PubMed  Google Scholar 

  • Ozols RF et al (2003) Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer. A gynecologic oncology group study. J Clin Oncol 21:3194–3200. doi:10.1200/JCO.2003.02.153

    Article  CAS  PubMed  Google Scholar 

  • Piccart MJ et al (2000) Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 92:699–708

    Article  CAS  PubMed  Google Scholar 

  • Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108. doi:10.3322/caac.21262

    Article  PubMed  Google Scholar 

  • Trimbos JB et al (2003) Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European organisation for research and treatment of cancer-adjuvant chemotherapy in ovarian neoplasm trial. J Natl Cancer Inst 95:113–125

    Article  CAS  PubMed  Google Scholar 

  • Wang C et al (2011) Overexpression of Lewis(y) antigen protects ovarian cancer RMG-1 cells from carboplatin-induced apoptosis by the upregulation of Topo-I and Topo-II beta. Anat Rec 294:961–969. doi:10.1002/ar.21398

    Article  CAS  Google Scholar 

  • Zagorianakou N, Stefanou D, Makrydimas G, Zagorianakou P, Briasoulis E, Karavasilis B, Agnantis NJ (2004) CD44s expression, in benign, borderline and malignant tumors of ovarian surface epithelium. Correlation with p53, steroid receptor status, proliferative indices (PCNA, MIB1) and survival. Anticancer Res 24:1665–1670

    CAS  PubMed  Google Scholar 

  • Zhang S et al (2008) Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 68:4311–4320. doi:10.1158/0008-5472.CAN-08-0364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amr A. Soliman.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest regarding this study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Alaa A. Elzarkaa and Bassma El Sabaa have contributed equally to the manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Elzarkaa, A.A., Sabaa, B.E., Abdelkhalik, D. et al. Clinical relevance of CD44 surface expression in advanced stage serous epithelial ovarian cancer: a prospective study. J Cancer Res Clin Oncol 142, 949–958 (2016). https://doi.org/10.1007/s00432-016-2116-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-016-2116-5

Keywords

Navigation