Annals of Surgical Oncology

, Volume 23, Issue 1, pp 163–170 | Cite as

Aldehyde Dehydrogenase 1 Expression Predicts Chemoresistance and Poor Clinical Outcomes in Patients with Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemotherapy Prior to Radical Hysterectomy

  • Qingsheng Xie
  • Jinxiao Liang
  • Qunxian Rao
  • Xiaofei Xie
  • Ruixin Li
  • Yunyun Liu
  • Hui Zhou
  • Jingjing Han
  • Tingting YaoEmail author
  • Zhongqiu LinEmail author
Gynecologic Oncology



Neoadjuvant chemotherapy (NAC) is an important treatment strategy for cervical cancer; however, few predictive markers of the response to NAC exist. Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, is associated with chemoresistance in a variety of cancers. This study attempted to investigate the value of ALDH1 as a predictive marker of chemosensitivity and its prognostic value in cervical cancer patients treated with NAC.


Immunohistochemistry was used to evaluate ALDH1 expression in matched pre- and post-NAC tumor samples from 52 patients with cervical cancer. Kaplan–Meier analysis and a Cox proportional hazards regression model were applied to determine overall survival (OS) and disease-free survival (DFS).


Fourteen patients (26.9 %) had ALDH1-positive tumors pre-NAC, and ALDH1 expression pre-NAC was significantly associated with a low clinical chemotherapy response rate and clinical non-response. Twenty-two patients (42.3 %) had ALDH1-positive tumors post-NAC, and ALDH1 expression post-NAC was associated with poor DFS and OS (both p = 0.004). Multivariate analysis revealed that ALDH1 expression post-NAC was an independent prognostic factor for OS (hazard ratio 3.513; p = 0.033). Moreover, we observed that ALDH1 expression was increased after NAC in 18 patients (36.7 %). Increased levels of ALDH1 expression after NAC predicted poor DFS and OS (p = 0.013 and p = 0.08, respectively).


Our findings suggest that ALDH1 expression pre-NAC may be a predictive marker for response to NAC, and ALDH1 expression post-NAC could be a prognostic marker for cervical cancer.


Overall Survival Cervical Cancer Advanced Cervical Cancer ALDH1 Expression Parametrial Invasion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to thank Dr. Bo Wang for his technical support. This work was supported by the National Natural Science Foundation of China (30672221, 30872743).

Conflict of interest

Qingsheng Xie, Jinxiao Liang, Qunxian Rao, Xiaofei Xie, Ruixin Li, Yunyun Liu, Hui Zhou, Jingjing Han, Tingting Yao, and Zhongqiu Lin declare that they have no actual or potential competing financial interests.

Supplementary material

10434_2015_4555_MOESM1_ESM.tif (1.9 mb)
Fig. S1 Identification and grading of ALDH1-positive tumor cells using immunohistochemistry. Representative images of (A) cervical cancer tissues with an ALDH1 score of 0; (B) 1+; (C) 2+; (D) and 3+; original magnification ×400. ALDH1 staining was mainly localized to the cytoplasm of the tumor cells, though faint expression was also observed in the surrounding stromal and vascular areas of the tumour tissues. Supplementary material 1 (TIFF 1985 kb)
10434_2015_4555_MOESM2_ESM.tif (984 kb)
Fig. S2 Kaplan-Meier 5-year disease-free survival (DFS) and 5-year overall survival (OS) curves for patients with cervical cancer. (A and B) Patients with ALDH1-positive tumors pre-NAC tended to have poorer DFS and OS, though this difference was not significant. (C and D) Patients who responded to NAC had significantly better DFS and OS. (E and F) Patients with ALDH1-positive tumors post-NAC had poorer 5-year DFS and 5-year OS. (G and H) Patients with increased ALDH1 expression after NAC had poorer DFS and OS than non-increased ones; however, this effect was not significant for DFS. Supplementary material 2 (TIFF 984 kb)
10434_2015_4555_MOESM3_ESM.doc (63 kb)
Supplementary material 3 (DOC 64 kb).


  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.PubMedCrossRefGoogle Scholar
  2. 2.
    Wiebe E, Denny L, Thomas G. Cancer of the cervix uteri. Int J Gynaecol Obstet. 2012;119:S100–09.PubMedCrossRefGoogle Scholar
  3. 3.
    Pareja R, Rendon GJ, Sanz-Lomana CM, Monzon O, Ramirez PT. Surgical, oncological, and obstetrical outcomes after abdominal radical trachelectomy: a systematic literature review. Gynecol Oncol. 2013;131(1):77–82.PubMedCrossRefGoogle Scholar
  4. 4.
    Marchiole P, Tigaud JD, Costantini S, et al. Neoadjuvant chemotherapy and vaginal radical trachelectomy for fertility-sparing treatment in women affected by cervical cancer (FIGO stage IB-IIA1). Gynecol Oncol. 2011;122(3):484–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Chen H, Liang C, Zhang L, Huang S, Wu X. Clinical efficacy of modified preoperative neoadjuvant chemotherapy in the treatment of locally advanced (stage IB2 to IIB) cervical cancer: randomized study. Gynecol Oncol. 2008;110(3):308–15.PubMedCrossRefGoogle Scholar
  6. 6.
    Buda A, Fossati R, Colombo N, et al. Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study. J Clin Oncol. 2005;23(18):4137–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Ye Q, Yuan HX, Chen HL. Responsiveness of neoadjuvant chemotherapy before surgery predicts favorable prognosis for cervical cancer patients: a meta-analysis. J Cancer Res Clin Oncol. 2013;139(11):1887–98.PubMedCrossRefGoogle Scholar
  8. 8.
    Wen H, Wu X, Li Z, et al. A prospective randomized controlled study on multiple neoadjuvant treatments for patients with stage IB2 to IIA cervical cancer. Int J Gynecol Cancer. 2012;22(2):296–302.PubMedCrossRefGoogle Scholar
  9. 9.
    Gong L, Lou JY, Wang P, Zhang JW, Liu H, Peng ZL. Clinical evaluation of neoadjuvant chemotherapy followed by radical surgery in the management of stage IB2-IIB cervical cancer. Int J Gynaecol Obstet. 2012;117(1):23–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Alison MR, Guppy NJ, Lim SM, Nicholson LJ. Finding cancer stem cells: are aldehyde dehydrogenases fit for purpose? J Pathol. 2010;222(4):335–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Bortolomai I, Canevari S, Facetti I, et al. Tumor initiating cells: development and critical characterization of a model derived from the A431 carcinoma cell line forming spheres in suspension. Cell Cycle. 2010;9(6):1194–206.PubMedCrossRefGoogle Scholar
  12. 12.
    Casagrande N, De Paoli M, Celegato M, et al. Preclinical evaluation of a new liposomal formulation of cisplatin, lipoplatin, to treat cisplatin-resistant cervical cancer. Gynecol Oncol. 2013;131(3):744–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Rao QX, Yao TT, Zhang BZ, et al. Expression and functional role of ALDH1 in cervical carcinoma cells. Asian Pac J Cancer Prev. 2012;13(4):1325–31.PubMedCrossRefGoogle Scholar
  14. 14.
    Liu SY, Zheng PS. High aldehyde dehydrogenase activity identifies cancer stem cells in human cervical cancer. Oncotarget. 2013;4(12):2462–75.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Tanei T, Morimoto K, Shimazu K, et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res. 2009;15(12):4234–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Avoranta ST, Korkeila EA, Ristamaki RH, et al. ALDH1 expression indicates chemotherapy resistance and poor outcome in node-negative rectal cancer. Hum Pathol. 2013;44(6):966–74.PubMedCrossRefGoogle Scholar
  17. 17.
    Minato T, Yamamoto Y, Seike J, et al. Aldehyde dehydrogenase 1 expression is associated with poor prognosis in patients with esophageal squamous cell carcinoma. Ann Surg Oncol. 2013;20(1):209–17.PubMedCrossRefGoogle Scholar
  18. 18.
    Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.PubMedCrossRefGoogle Scholar
  19. 19.
    Jin L, Shen Q, Ding S, Jiang W, Jiang L, Zhu X. Immunohistochemical expression of Annexin A2 and S100A proteins in patients with bulky stage IB-IIA cervical cancer treated with neoadjuvant chemotherapy. Gynecol Oncol. 2012;126(1):140–46.PubMedCrossRefGoogle Scholar
  20. 20.
    Lax S, Schauer G, Prein K, et al. Expression of the nuclear bile acid receptor/farnesoid X receptor is reduced in human colon carcinoma compared to nonneoplastic mucosa independent from site and may be associated with adverse prognosis. Int J Cancer. 2012;130(10):2232–39.PubMedCrossRefGoogle Scholar
  21. 21.
    Aomatsu N, Yashiro M, Kashiwagi S, et al. CD133 is a useful surrogate marker for predicting chemosensitivity to neoadjuvant chemotherapy in breast cancer. PloS One. 2012;7(9):e45865.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Choi CH, Song SY, Choi JJ, et al. Prognostic significance of VEGF expression in patients with bulky cervical carcinoma undergoing neoadjuvant chemotherapy. BMC Cancer. 2008;8:295.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Costa S, Terzano P, Bovicelli A, et al. CD44 isoform 6 (CD44v6) is a prognostic indicator of the response to neoadjuvant chemotherapy in cervical carcinoma. Gynecol Oncol. 2001;80(1):67–73.PubMedCrossRefGoogle Scholar
  24. 24.
    Park JS, Jeon EK, Chun SH, et al. ERCC1 (excision repair cross-complementation group 1) expression as a predictor for response of neoadjuvant chemotherapy for FIGO stage 2B uterine cervix cancer. Gynecol Oncol. 2011;120(2):275–79.PubMedCrossRefGoogle Scholar
  25. 25.
    Watari H, Kanuma T, Ohta Y, et al. Clusterin expression inversely correlates with chemosensitivity and predicts poor survival in patients with locally advanced cervical cancer treated with cisplatin-based neoadjuvant chemotherapy and radical hysterectomy. Pathol Oncol Res. 2010;16(3):345–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Januchowski R, Wojtowicz K, Zabel M. The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomed Pharmacother. 2013;67(7):669–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Magni M, Shammah S, Schiro R, Mellado W, Dalla-Favera R, Gianni AM. Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood. 1996;87(3):1097–103.PubMedGoogle Scholar
  28. 28.
    Greaves M, Maley CC. Clonal evolution in cancer. Nature. 2012;481(7381):306–13.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12):1253–61.PubMedCrossRefGoogle Scholar
  30. 30.
    Sakakibara M, Fujimori T, Miyoshi T, et al. Aldehyde dehydrogenase 1-positive cells in axillary lymph node metastases after chemotherapy as a prognostic factor in patients with lymph node-positive breast cancer. Cancer. 2012;118(16):3899–910.PubMedCrossRefGoogle Scholar
  31. 31.
    Gong C, Yao H, Liu Q, et al. Markers of tumor-initiating cells predict chemoresistance in breast cancer. PloS One. 2010;5(12):e15630.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Dylla SJ, Beviglia L, Park IK, et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PloS One. 2008;3(6):e2428.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2015

Authors and Affiliations

  • Qingsheng Xie
    • 1
    • 2
  • Jinxiao Liang
    • 1
    • 2
  • Qunxian Rao
    • 1
  • Xiaofei Xie
    • 1
  • Ruixin Li
    • 1
  • Yunyun Liu
    • 1
  • Hui Zhou
    • 1
  • Jingjing Han
    • 3
  • Tingting Yao
    • 1
    Email author
  • Zhongqiu Lin
    • 1
    Email author
  1. 1.Department of Gynecological Oncology, Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouPeople’s Republic of China
  2. 2.Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education InstitutesSun Yat-sen UniversityGuangzhouPeople’s Republic of China
  3. 3.Department of Pathology, Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouPeople’s Republic of China

Personalised recommendations