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Clinical and Translational Oncology

, Volume 19, Issue 9, pp 1147–1153 | Cite as

Mesenchymal circulating tumor cells (CTCs) and OCT4 mRNA expression in CTCs for prognosis prediction in patients with non-small-cell lung cancer

  • S. Li
  • Q. Chen
  • H. Li
  • Y. Wu
  • J. Feng
  • Y. YanEmail author
Research Article

Abstract

Purpose

Circulating tumor cells (CTCs) with epithelial-to-mesenchymal transition (EMT) phenotypes might be related to tumor progression while OCT4 expression is involved in tumor metastasis and poor prognosis. But the possible clinical significance of EMT phenotypes of CTCs from non-small-cell lung cancer (NSCLC) patients has still to be demonstrated. Furthermore, none has been investigated the expression of OCT4 in CTCs. We therefore identified the EMT phenotype-based subsets of CTCs and determined the OCT4 expression status of CTCs in NSCLC patients, to explore their possible clinical relevance.

Methods

37 NSCLC patients and ten healthy volunteers were enrolled, respectively. The Canpatrol™ CTC enrichment technique was used to isolate and identify the EMT phenotype-based subsets of CTCs. OCT4 expression in each CTC was also determined. Results were correlated with patients’ clinico-pathological features.

Results

CTCs were detected in 33 of 37 (89.2%) NSCLC patients, and no CTCs were identified in ten healthy volunteers. Three CTCs phenotypes, including epithelial, biophenotypic, and mesenchymal CTCs were identified based on the expression of EMT markers. Mesenchymal CTCs were more commonly found in patients with distant metastasis. Patients with distant metastasis tended to have a higher median CTCs number. OCT4-positive was observed in 21 of 28 (75.0%) patients. High expression of OCT4 tended to occur in advanced patients as well as in distant metastatic patients.

Conclusions

The findings suggest that identification of CTCs by EMT markers as well as evaluation of OCT4 expression status by assessment of OCT4 expression in CTCs could serve as potential adjuncts for evaluating metastasis and prognosis in NSCLC patients.

Keywords

NSCLC Circulating tumor cells (CTCs) Epithelial–mesenchymal transition (EMT) OCT4 

Notes

Acknowledgements

The authors would like to thank SurExam Bio-Tech Co., Ltd., Guangzhou, China for the technical support.

Compliance with ethical standards

Conflict of interest

None declared.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Andre F, Mardis E, Salm M, Soria JC, Siu LL, Swanton C. Prioritizing targets for precision cancer medicine. Ann Oncol. 2014;25(12):2295–303.CrossRefPubMedGoogle Scholar
  3. 3.
    Budd GT, Cristofanilli M, Ellis MJ, Stopeck A, Borden E, Miller MC, et al. Circulating tumor cells versus imaging—predicting overall survival in metastatic breast cancer. Clin Cancer Res. 2006;12(21):6403–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Stott SL, Lee RJ, Nagrath S, Yu M, Miyamoto DT, Ulkus L, et al. Isolation and characterization of circulating tumor cells from patients with localized and metastatic prostate cancer. Sci Transl Med. 2010;2:25.CrossRefGoogle Scholar
  5. 5.
    Tanaka F, Yoneda K, Kondo N, Hashimoto M, Takuwa T, Matsumoto S, et al. Circulating tumor cell as a diagnostic marker in primary lung cancer. Clin Cancer Res. 2009;15(22):6980–6.CrossRefPubMedGoogle Scholar
  6. 6.
    Negin BP, Cohen SJ. Circulating tumor cells in colorectal cancer: past, present, and future challenges. Curr Treat Options Oncol. 2010;11:1–13.CrossRefPubMedGoogle Scholar
  7. 7.
    Alama A, Truini A, Coco S, Genova C, Grossi F. Prognostic and predictive relevance of circulating tumor cells in patients with non-small-cell lung cancer. Drug Discov Today. 2014;19:1671–6.CrossRefPubMedGoogle Scholar
  8. 8.
    O’Flaherty JD, Gray S, Richard D, Fennell D, O’Leary JJ, Blackhall FH, et al. Circulating tumour cells, their role in metastasis and their clinical utility in lung cancer. Lung Cancer. 2012;76:19–25.CrossRefPubMedGoogle Scholar
  9. 9.
    Wu C, Hao H, Li L, Zhou X, Guo Z, Zhang L, et al. Preliminary investigation of the clinical significance of detecting circulating tumor cells enriched from lung cancer patients. J Thorac Oncol. 2009;4:30–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Normanno N, Rossi A, Morabito A, Signoriello S, Bevilacqua S, Di Maio M, et al. Prognostic value of circulating tumor cells’ reduction in patients with extensive small-cell lung cancer. Lung Cancer. 2014;85(2):314–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359(4):366–77.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Pailler E, Adam J, Barthélémy A, Oulhen M, Auger N, Valent A, et al. Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non-small-cell lung cancer. J Clin Oncol. 2013;31(18):2273–81.CrossRefPubMedGoogle Scholar
  13. 13.
    Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer. 2004;4(6):448–56.CrossRefPubMedGoogle Scholar
  14. 14.
    Barrière G, Tartary M, Rigaud M. Epithelial mesenchymal transition: a new insight into the detection of circulating tumor cells. ISRN Oncol. 2012. doi: 10.5402/2012/382010.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339(6119):580–4.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Chen Y-C, Hsu H-S, Chen Y-W, Tsai T-H, How C-K, Wang C-Y, et al. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS ONE. 2008;3(7):e2637.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998;95(3):379–91.CrossRefPubMedGoogle Scholar
  18. 18.
    Li X, Wang J, Xu Z, Ahmad A, Li E, Wang Y, et al. Expression of Sox2 and Oct4 and their clinical significance in human non-small-cell lung cancer. Int J Mol Sci. 2012;13(6):7663–75.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zhang X, Han B, Huang J, Zheng B, Geng Q, Aziz F, et al. Prognostic significance of OCT4 expression in adenocarcinoma of the lung. Jpn J Clin Oncol. 2010;40(10):961–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Chiou S-H, Wang M-L, Chou Y-T, Chen C-J, Hong C-F, Hsieh W-J, et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial–mesenchymal transdifferentiation. Cancer Res. 2010;70(24):10433–44.CrossRefPubMedGoogle Scholar
  21. 21.
    Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S. Stem cell and epithelial–mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009;11:R46.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Raimondi C, Gradilone A, Naso G, Vincenzi B, Petracca A, Nicolazzo C, et al. Epithelial–mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat. 2011;130(2):449–55.CrossRefPubMedGoogle Scholar
  23. 23.
    Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Wu S, Liu S, Liu Z, Huang J, Pu X, Li J, et al. Classification of circulating tumor cells by epithelial–mesenchymal transition markers. PLoS ONE. 2015;10(4):e0123976.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wan L, Pantel K, Kang Y. Tumor metastasis: moving new biological insights into the clinic. Nat Med. 2013;19(11):1450–64.CrossRefPubMedGoogle Scholar
  26. 26.
    Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331(6024):1559–64.CrossRefPubMedGoogle Scholar
  27. 27.
    Bidard FC, Fehm T, Ignatiadis M, Smerage JB, Alix-Panabières C, Janni W, et al. Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev. 2013;32:179–88.CrossRefPubMedGoogle Scholar
  28. 28.
    Miller MC, Gross S, Allard WJ, Terstappen LW, Gomella LG, Moreno JG. Circulating tumor cells (CTC) predict survival in patients with metastatic prostate cancer. Cancer Res. 2004;64:1215.CrossRefGoogle Scholar
  29. 29.
    Gorges TM, Tinhofer I, Drosch M, Röse L, Zollner TM, Krahn T, et al. Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition. BMC Cancer. 2012;12:178.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Farace F, Massard C, Vimond N, Drusch F, Jacques N, Billiot F, et al. A direct comparison of Cell Search and ISET for circulating tumour-cell detection in patients with metastatic carcinomas. Brit J Cancer. 2011;105(6):847–53.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Li YM, Xu SC, Li J, Han KQ, Pi HF, Zheng L, et al. Epithelial–mesenchymal transition markers expressed in circulating tumor cells in hepatocellular carcinoma patients with different stages of disease. Cell Death Dis. 2013;4(10):e831.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Chen X, Wang X, He H, Liu Z, Hu JF, Li W. Combination of circulating tumor cells with serum carcinoembryonic antigen enhances clinical prediction of non-small cell lung cancer. PLoS ONE. 2015;10(5):e0126276.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Das M, Riess JW, Frankel P, Schwartz E, Bennis R, Hsieh HB, et al. ERCC1 expression in circulating tumor cells (CTCs) using a novel detection platform correlates with progression-free survival (PFS) in patients with metastatic non-small-cell lung cancer (NSCLC) receiving platinum chemotherapy. Lung Cancer. 2012;77(2):421–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Yu M, Stott S, Toner M, Maheswaran S, Haber DA. Circulating tumor cells: approaches to isolation and characterization. J Cell Biol. 2011;192(3):373–82.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2017

Authors and Affiliations

  1. 1.Department of Cardiothoracic SurgeryZhujiang Hospital of Southern Medical UniversityGuangzhouPeople’s Republic of China

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