Advertisement

Tumor Biology

, Volume 36, Issue 10, pp 7623–7630 | Cite as

Clinicopathological significance and prognostic value of the expression of the cancer stem cell marker CD133 in hepatocellular carcinoma: a meta-analysis

  • Chen Zhong
  • Jin-Dao Wu
  • Ming-Ming Fang
  • Li-Yong Pu
Research Article

Abstract

To conduct a meta-analysis to assess the association between CD133 expression and clinicopathological significance and prognostic value in hepatocellular carcinoma patients. Studies were identified via an electronic comprehensive literature search through the Pubmed, Chinese CNKI, and Wanfang databases. This meta-analysis was performed using Stata statistical software version 12.0. The outcomes included various clinicopathological and survival parameters (P < 0.05 was consider to indicate a statistical significance). A total of 21 studies comprising 2592 patients were included in this meta-analysis. CD133 overexpression was significantly associated with a series of clinicopathological parameters, such as low tumor differentiation (pooled odds ratio (OR) = 2.26, 95% CI: 1.59–3.21, P < 0.00001), advanced tumor stage (pooled OR = 2.17, 95% CI: 1.70–2.77, P < 0.00001), vascular invasion (pooled OR = 2.06, 95% CI: 1.25–3.39, P = 0.005), and vascular thrombosis (pooled OR = 1.47, 95% CI: 1.08–1.99, P = 0.015). However, CD133 expression was not correlated with hepatitis, cirrhosis, α-fetoprotein level, tumor number, tumor size, encapsulation, or metastasis. Regarding survival outcome, CD133 overexpression was significantly correlated with poor overall survival (pooled hazard ratio (HR) = 2.01, 95% CI: 1.45–2.80, P = 0.00002) and poor disease-free survival (pooled HR = 1.82, 95% CI: 1.45–2.29, P < 0.00001). This meta-analysis indicated that CD133 overexpression is significantly associated with clinicopathological factors and poorer survival outcome.

Keywords

Cancer stem cells CD133 Hepatocellular carcinoma Meta-analysis Prognosis Clinicopathological features 

Notes

Acknowledgments

This study was supported by National Natural Science foundation of China (81273261). The authors would like to thank Nature Publishing Group Language Editing for revising the English text.

Conflicts of interest

None

References

  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Ma YC, Yang JY, Yan LN. Relevant markers of cancer stem cells indicate a poor prognosis in hepatocellular carcinoma patients: a meta-analysis. Eur J Gastroenterol Hepatol. 2013;25:1007–16.CrossRefPubMedGoogle Scholar
  3. 3.
    Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020–2.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ho CM, Wu CY, Lee PH, Lai HS, Ho MC, Wu YM, et al. Analysis of the risk factors of untransplantable recurrence after primary curative resection for patients with hepatocellular carcinoma. Ann Surg Oncol. 2013;20:2526–33.CrossRefPubMedGoogle Scholar
  5. 5.
    Poon RT, Fan ST, Lo CM, Liu CL, Lam CM, Yuen WK, et al. Extended hepatic resection for hepatocellular carcinoma in patients with cirrhosis: is it justified? Ann Surg. 2002;236:602–11.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Tung-Ping Poon R, Fan ST, Wong J. Risk factors, prevention, and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg. 2000;232:10–24.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ding X, Yang LY, Huang GW, Yang JQ, Liu HL, Wang W, et al. Role of AFP mRNA expression in peripheral blood as a predictor for postsurgical recurrence of hepatocellular carcinoma: a systematic review and meta-analysis. World J Gastroenterol. 2005;11:2656–61.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Chun JM, Kwon HJ, Sohn J, Kim SG, Park JY, Bae HI, et al. Prognostic factors after early recurrence in patients who underwent curative resection for hepatocellular carcinoma. J Surg Oncol. 2011;103:148–51.CrossRefPubMedGoogle Scholar
  9. 9.
    Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359:1995–2004.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Hixson DC, Brown J, McBride AC, Affigne S. Differentiation status of rat ductal cells and ethionine-induced hepatic carcinomas defined with surface-reactive monoclonal antibodies. Exp Mol Pathol. 2000;68:152–69.CrossRefPubMedGoogle Scholar
  11. 11.
    Libbrecht L, Roskams T. Hepatic progenitor cells in human liver diseases. Semin Cell Dev Biol. 2002;13:389–96.CrossRefPubMedGoogle Scholar
  12. 12.
    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11.CrossRefPubMedGoogle Scholar
  13. 13.
    Ailles LE, Weissman IL. Cancer stem cells in solid tumors. Curr Opin Biotechnol. 2007;18:460–6.CrossRefPubMedGoogle Scholar
  14. 14.
    Wang K, Liu L, Zhang T, Zhu YL, Qiu F, Wu XG, et al. Oxaliplatin-incorporated micelles eliminate both cancer stem-like and bulk cell populations in colorectal cancer. Int J Nanomedicine. 2011;6:3207–18.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Wang W, Chen Y, Deng J, Zhou J, Zhou Y, Wang S, et al. The prognostic value of CD133 expression in non-small cell lung cancer: a meta-analysis. Tumor Biol. 2014;35:9769–75.CrossRefGoogle Scholar
  16. 16.
    Wang K, Xu J, Zhang J, Huang J. Prognostic role of CD133 expression in colorectal cancer: a meta-analysis. BMC Cancer. 2012;12:573.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Chen S, Song X, Chen Z, Li X, Li M, Liu H, et al. CD133 expression and the prognosis of colorectal cancer: systematic review and meta-analysis. PLoS One. 2013;8, e56380. doi: 10.1371/journal.pone.0056380.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wen L, Chen XZ, Yang K, Chen ZX, Zhang B, Chen JP, et al. Prognostic value of cancer stem cell marker CD133 expression in gastric cancer: a systematic review. PLoS One. 2013;8, e59154. doi: 10.1371/journal.pone.0059154.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Song W, Li H, Tao K, Li R, Song Z, Zhao Q, et al. Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int J Clin Pract. 2008;62:1212–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Tsuchiya A, Kamimura H, Takamura M, Yamagiwa S, Matsuda Y, Sato Y, et al. Clinicopathological analysis of CD133 and NCAM human hepatic stem/progenitor cells in damaged livers and hepatocellular carcinomas. Hepatol Res. 2009;39:1080–90.CrossRefPubMedGoogle Scholar
  21. 21.
    Yeh CT, Kuo CJ, Lai MW, Chen TC, Lin CY, Yeh TS, et al. CD133-positive hepatocellular carcinoma in an area endemic for hepatitis B virus infection. BMC Cancer. 2009;9:324.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zhang H, Gao ZH, Xu TY, Zhu JF, Zhang Y. Expression of CD133 in hepatocellular carcinoma and its clinical significance. Cancer Res Clin. 2009;21:440–3.Google Scholar
  23. 23.
    Lingala S, Cui YY, Chen X, Ruebner BH, Qian XF, Zern MA, et al. Immunohistochemical staining of cancer stem cell markers in hepatocellular carcinoma. Exp Mol Pathol. 2010;89:27–35.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sasaki A, Kamiyama T, Yokoo H, Nakanishi K, Kubota K, Haga H, et al. Cytoplasmic expression of CD133 is an important risk factor for overall survival in hepatocellular carcinoma. Oncol Rep. 2010;24:537–46.CrossRefPubMedGoogle Scholar
  25. 25.
    Yang XR, Xu Y, Yu B, Zhou J, Qiu SJ, Shi GM, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut. 2010;59:953–62.CrossRefPubMedGoogle Scholar
  26. 26.
    Guo XD, Wang HB, Qu F, Liu LM, Zhang JL, Li XX, et al. Expression of CD133 in hepatocellular carcinoma and its relationship with clinical pathological features. Clin J Lab Diagn. 2011;15:78–80.Google Scholar
  27. 27.
    Wu XH, Wang SX, Cui DP, Li JK, Yang BM. Expression and significance of CD133 and CD90 in hepatocellular carcinoma. Clin J Hepatol. 2011;19:376–7.Google Scholar
  28. 28.
    Zen C, Zen Y, Mitry RR, Corbeil D, Karbanová J, O’Grady J, et al. Mixed phenotype hepatocellular carcinoma after transarterial chemoembolization and liver transplantation. Liver Transpl. 2011;17:943–54.CrossRefPubMedGoogle Scholar
  29. 29.
    Pan QX, Su ZJ, Wang CR, Zhuang JN. Expression of tumor stem cell markers EpCAM and CD133 in human primary hepatocellular carcinoma and their value in prognostic prediction. Tumori. 2012;32:628–33.Google Scholar
  30. 30.
    Zeng XC, Zhang D, Fu BS, Chen W, Chen GZ, Li H, et al. Expression of CD133 as a tumor stem cell surface marker in hepatocellular and its significance in the prognosis of liver transplantation patients. Chin J Hepat Surg (Electronic Edition). 2012;1:51–6.Google Scholar
  31. 31.
    Liu LL, Li W, Li YJ. Expression of CD133 and CD90 in hepatocellular carcinoma tissue and their clinical significance. Acta Academiae Medicinae Qindao Universitatis. 2013;49:393–6.Google Scholar
  32. 32.
    Tian J, Gong XM. Expression and their relationship to clinicopathological significance of CD133 and maspin in hepatocellular carcinoma. Chinese Journal of Histochemistry and Cytochemistry. 2013;22:528–32.Google Scholar
  33. 33.
    Wu LM, Cheng CT, Chen XX, Wang JH, Liu HY, Tian L. Prognostic significance of expression of CD133, VEGF and CD34 in hepatocellular carcinoma. Clin J Cancer Prev Treat. 2013;20:998–1002.Google Scholar
  34. 34.
    Chan AW, Tong JH, Chan SL, Lai PB, To KF. Expression of stemness markers (CD133 and EpCAM) in prognostication of hepatocellular carcinoma. Histopathology. 2014;64:935–50.CrossRefPubMedGoogle Scholar
  35. 35.
    Chen K, Li ZH, Jiang P, Zhang X, Zhang YJ, Jiang Y, et al. CD44, CD133 and TF correlate with formation of portal vein tumor thrombus and poor prognosis in patients with hepatocellular carcinoma. J Third Mil Med Univ. 2014;36:1068–73.Google Scholar
  36. 36.
    Guo Z, Li LQ, Jiang JH, Ou C, Zeng LX, Xiang BD. Cancer stem cell markers correlate with early recurrence and survival in hepatocellular carcinoma. World J Gastroenterol. 2014;20:2098–106.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ye F, Jing YY, Guo SW, Yu GF, Fan QM, Qu FF, et al. Proliferative ductular reactions correlate with hepatic progenitor cell and predict recurrence in HCC patients after curative resection. Cell Biosci. 2014;4:50.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Yilmaz G, Akyol G, Cakir A, Ilhan M. Investigation of diagnostic utility and expression profiles of stem cell markers (CD133 and CD90) in hepatocellular carcinoma, small cell dysplasia, and cirrhosis. Pathol Res Pract. 2014;210:419–25.CrossRefPubMedGoogle Scholar
  39. 39.
    Zhao MY. Immunohistochemical analysis of CD133 and CD90 expression in hepatocellular carcinoma and its clinicopathological significance. Med Lab Sci. 2014; 104–5.Google Scholar
  40. 40.
    Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Zhang L, Li H, Ge C, Li M, Zhao FY, Hou HL, et al. Inhibitory effects of transcription factor Ikaros no the expression of liver cancer stem cell marker CD133 in hepatocellular carcinoma. Oncotarget. 2014;5:10621–35.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM, et al. CD133(+) liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology. 2012;55:807–20.CrossRefPubMedGoogle Scholar
  43. 43.
    Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H. Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun. 2006;351:820–4.CrossRefPubMedGoogle Scholar
  44. 44.
    Ji J, Wang XW. Clinical implications of cancer stem cell biology in hepatocellular carcinoma. Semin Oncol. 2012;39:461–72.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Armeanu-Ebinger S, Wenz J, Seitz G, Leuschner I, Handgretinger R, Mau-Holzmann UA, et al. Characterisation of the cell line HC-AFW1 derived from a pediatric hepatocellular carcinoma. PLoS One. 2012;7, e38223. doi: 10.1371/journal.pone.0038223.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, et al. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res. 2008;6:1146–53.CrossRefPubMedGoogle Scholar
  47. 47.
    Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, et al. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer. 2010;126:2067–78.CrossRefPubMedGoogle Scholar
  48. 48.
    Zheng YW, Tsuchida T, Shimao T, Li B, Takebe T, Zhang RR, et al. The CD133+ CD44+ precancerous subpopulation of oval cells is a therapeutic target for hepatocellular carcinoma. Stem Cells Dev. 2014;23:2237–49.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Chen Zhong
    • 1
  • Jin-Dao Wu
    • 1
  • Ming-Ming Fang
    • 2
  • Li-Yong Pu
    • 1
  1. 1.Department of Liver Transplantation Center, and Key Laboratory of Living Donor Liver Transplantation of Ministry of Public HealthThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of Neurology, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Jiangsu Branch of the China Academy of Chinese Medical SciencesThe First Medical College of Nanjing University of Chinese MedicineNanjingChina

Personalised recommendations