Lung

, Volume 193, Issue 2, pp 157–171 | Cite as

Circulating Tumor Cells in Lung Cancer: Detection Methods and Clinical Applications

Article

Abstract

Circulating tumor cells (CTCs) are tumor cells that have disseminated from primary and metastatic sites, and circulate in the bloodstream. Advanced immunological and molecular-based methods can be used to detect and analyze the cells with the characteristics of tumor cells, and can be detected and analyzed in the blood of cancer patients. The most commonly used methods in lung cancer combine the processes of immunomagnetic enrichment and immunocytochemical detection, morphology-based enrichment coupled with reverse transcriptase polymerase chain reaction (RT-PCR), and RT-PCR alone. CTC analysis is considered a liquid biopsy approach for early diagnosis, risk stratification, evaluation of curative efficacy, and early detection of lung cancer relapse. In this review, we discuss the present techniques for analyzing CTCs, and the restrictions of using these methods in lung cancer. We also review the clinical studies in lung cancer and discuss the underlying associations between these studies and their future applications to this disease.

Keywords

Circulating tumor cells Detection methods Clinical significance Lung cancer Review 

Notes

Acknowledgments

This work was supported by Chongqing Science and Technology Commission (cstc2013yykfA10002). The recipient of this Grant is Xiaokui Tang.

Conflicts of interest

No potential conflicts of interest were disclosed.

References

  1. 1.
    Mitas M et al (2003) Lunx is a superior molecular marker for detection of non-small cell lung cancer in peripheral blood. J Mol Diagn 5(4):237–242CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Martin OA et al (2014) Mobilization of Viable Tumor Cells Into the Circulation During Radiation Therapy. Int J Radiat Oncol Biol Phys 88(2):395–403CrossRefPubMedGoogle Scholar
  3. 3.
    Lecharpentier A et al (2011) Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. Br J Cancer 105(9):1338–1341CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Vona G et al (2000) Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol 156(1):57–63CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Chen Q et al (2013) Lung cancer circulating tumor cells isolated by the EpCAM-independent enrichment strategy correlate with Cytokeratin 19-derived CYFRA21-1 and pathological staging. Clin Chim Acta 419:57–61CrossRefPubMedGoogle Scholar
  6. 6.
    Nezos A et al (2009) Molecular markers detecting circulating melanoma cells by reverse transcription polymerase chain reaction: methodological pitfalls and clinical relevance. Clin Chem Lab Med 47(1):1–11CrossRefPubMedGoogle Scholar
  7. 7.
    Armakolas A et al (2010) Detection of the circulating tumor cells in cancer patients. Future Oncol 6(12):1849–1856CrossRefPubMedGoogle Scholar
  8. 8.
    Devriese LA et al (2012) Circulating tumor cell detection in advanced non-small cell lung cancer patients by multi-marker QPCR analysis. Lung Cancer 75(2):242–247CrossRefPubMedGoogle Scholar
  9. 9.
    Pailler E et al (2013) Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK-positive non-small-cell lung cancer. J Clin Oncol 31(18):2273–2281CrossRefPubMedGoogle Scholar
  10. 10.
    Ilie M et al (2012) ALK-gene rearrangement: a comparative analysis on circulating tumour cells and tumour tissue from patients with lung adenocarcinoma. Ann Oncol 23(11):2907–2913CrossRefPubMedGoogle Scholar
  11. 11.
    Wolff AC et al (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25(1):118–145CrossRefPubMedGoogle Scholar
  12. 12.
    Chen YY, Xu GB (2014) Effect of circulating tumor cells combined with negative enrichment and CD45-FISH identification in diagnosis, therapy monitoring and prognosis of primary lung cancer. Med Oncol 31(12):240CrossRefPubMedGoogle Scholar
  13. 13.
    Ning N et al (2014) Improvement of specific detection of circulating tumor cells using combined CD45 staining and fluorescence in situ hybridization. Clin Chim Acta 433:69–75CrossRefPubMedGoogle Scholar
  14. 14.
    Allard WJ et al (2004) Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10(20):6897–6904CrossRefPubMedGoogle Scholar
  15. 15.
    Li Q et al (2011) Detection of micrometastases in peripheral blood of non-small cell lung cancer with a refined immunomagnetic nanoparticle enrichment assay. Int J Nanomed 6:2175–2181CrossRefGoogle Scholar
  16. 16.
    Yu Y et al (2013) Combination of four gene markers to detect circulating tumor cells in the peripheral blood of patients with advanced lung adenocarcinoma using real-time PCR. Oncol Lett 5(4):1400–1406PubMedCentralPubMedGoogle Scholar
  17. 17.
    Zhu WF et al (2014) Prognostic value of EpCAM/MUC1 mRNA-positive cells in non-small cell lung cancer patients. Tumour Biol 35(2):1211–1219CrossRefPubMedGoogle Scholar
  18. 18.
    Shi WL et al (2013) CK-19 mRNA-positive cells in peripheral blood predict treatment efficacy and survival in small-cell lung cancer patients. Med Oncol 30(4):755CrossRefPubMedGoogle Scholar
  19. 19.
    Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4(6):448–456CrossRefPubMedGoogle Scholar
  20. 20.
    Sawabata N et al (2007) Circulating tumor cells in peripheral blood caused by surgical manipulation of non-small-cell lung cancer: pilot study using an immunocytology method. Gen Thorac Cardiovasc Surg 55(5):189–192CrossRefPubMedGoogle Scholar
  21. 21.
    Truini A et al (2014) Clinical applications of circulating tumor cells in lung cancer patients by Cell Search System. Front Oncol 4:242CrossRefPubMedCentralPubMedGoogle Scholar
  22. 22.
    Tanaka F et al (2009) Circulating tumor cell as a diagnostic marker in primary lung cancer. Clin Cancer Res 15(22):6980–6986CrossRefPubMedGoogle Scholar
  23. 23.
    Naito T et al (2012) Prognostic impact of circulating tumor cells in patients with small cell lung cancer. J Thorac Oncol 7(3):512–519CrossRefPubMedGoogle Scholar
  24. 24.
    Hou JM et al (2012) Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol 30(5):525–532CrossRefPubMedGoogle Scholar
  25. 25.
    Kurusu Y, Yamashita J, Ogawa M (1999) Detection of circulating tumor cells by reverse transcriptase-polymerase chain reaction in patients with resectable non-small-cell lung cancer. Surgery 126(5):820–826CrossRefPubMedGoogle Scholar
  26. 26.
    Ge M et al (2005) Fluctuation of circulating tumor cells in patients with lung cancer by real-time fluorescent quantitative-PCR approach before and after radiotherapy. J Cancer Res Ther 1(4):221–226CrossRefPubMedGoogle Scholar
  27. 27.
    Yoon SO et al (2011) TTF-1 mRNA-positive circulating tumor cells in the peripheral blood predict poor prognosis in surgically resected non-small cell lung cancer patients. Lung Cancer 71(2):209–216CrossRefPubMedGoogle Scholar
  28. 28.
    Wendel M et al (2012) Fluid biopsy for circulating tumor cell identification in patients with early-and late-stage non-small cell lung cancer: a glimpse into lung cancer biology. Phys Biol 9(1):016005CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Hayes DC et al (2006) Multigene real-time PCR detection of circulating tumor cells in peripheral blood of lung cancer patients. Anticancer Res 26(2B):1567–1575PubMedGoogle Scholar
  30. 30.
    Katseli A et al (2013) Multiplex PCR-based detection of circulating tumor cells in lung cancer patients using CK19, PTHrP, and LUNX specific primers. Clin Lung Cancer 14(5):513–520CrossRefPubMedGoogle Scholar
  31. 31.
    Ma XL et al (2012) Meta-analysis of circulating tumor cells as a prognostic marker in lung cancer. Asian Pac J Cancer Prev 13(4):1137–1144CrossRefPubMedGoogle Scholar
  32. 32.
    Isobe K et al (2012) Clinical significance of circulating tumor cells and free DNA in non-small cell lung cancer. Anticancer Res 32(8):3339–3344PubMedGoogle Scholar
  33. 33.
    Punnoose EA et al (2012) Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib. Clin Cancer Res 18(8):2391–2401CrossRefPubMedGoogle Scholar
  34. 34.
    Nemunaitis J et al (2009) Phase II trial of Belagenpumatucel-L, a TGF-beta2 antisense gene modified allogeneic tumor vaccine in advanced non small cell lung cancer (NSCLC) patients. Cancer Gene Ther 16(8):620–624CrossRefPubMedGoogle Scholar
  35. 35.
    Li J et al (2014) LUNX mRNA-positive cells at different time points predict prognosis in patients with surgically resected nonsmall cell lung cancer. Transl Res 163(1):27–35CrossRefPubMedGoogle Scholar
  36. 36.
    Yamashita JI et al (2000) Detection of circulating tumor cells in patients with non-small cell lung cancer undergoing lobectomy by video-assisted thoracic surgery: a potential hazard for intraoperative hematogenous tumor cell dissemination. J Thorac Cardiovasc Surg 119(5):899–905CrossRefPubMedGoogle Scholar
  37. 37.
    Yamashita J et al (2002) Preoperative evidence of circulating tumor cells by means of reverse transcriptase-polymerase chain reaction for carcinoembryonic antigen messenger RNA is an independent predictor of survival in non-small cell lung cancer: a prospective study. J Thorac Cardiovasc Surg 124(2):299–305CrossRefPubMedGoogle Scholar
  38. 38.
    Krebs MG et al (2011) Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol 29(12):1556–1563CrossRefPubMedGoogle Scholar
  39. 39.
    Juan O et al (2014) Prognostic significance of circulating tumor cells in advanced non-small cell lung cancer patients treated with docetaxel and gemcitabine. Clin Transl Oncol 16(7):637–643CrossRefPubMedGoogle Scholar
  40. 40.
    Hirose T et al (2012) Relationship of circulating tumor cells to the effectiveness of cytotoxic chemotherapy in patients with metastatic non-small-cell lung cancer. Oncol Res 20(2–3):131–137CrossRefPubMedGoogle Scholar
  41. 41.
    Wu C et al (2009) Preliminary investigation of the clinical significance of detecting circulating tumor cells enriched from lung cancer patients. J Thorac Oncol 4(1):30–36CrossRefPubMedGoogle Scholar
  42. 42.
    Maheswaran S et al (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359(4):366–377CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Howard EW et al (2008) Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer. Clin Exp Metastasis 25(5):497–508CrossRefPubMedGoogle Scholar
  44. 44.
    Brodbeck T et al (2014) Perforin-dependent direct cytotoxicity in natural killer cells induces considerable knockdown of spontaneous lung metastases and computer modelling-proven tumor cell dormancy in a HT29 human colon cancer xenograft mouse model. Mol Cancer 13:244CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Tarumi S et al (2013) Innovative method using circulating tumor cells for prediction of the effects of induction therapy on locally advanced non-small cell lung cancer. J Cardiothorac Surg 8:175CrossRefPubMedCentralPubMedGoogle Scholar
  46. 46.
    Okumura Y et al (2009) Circulating tumor cells in pulmonary venous blood of primary lung cancer patients. Ann Thorac Surg 87(6):1669–1675CrossRefPubMedGoogle Scholar
  47. 47.
    Huang TH et al (2007) Clinical significance of enrichment and detection of circulating tumor cells in NSCLC patients with immunomagnetic beads. Zhonghua Zhong Liu Za Zhi 29(9):676–680PubMedGoogle Scholar
  48. 48.
    Wang XG, Hu H, Liu YN (2004) Detection of circulating tumor cells by nano-immunomagnetic enrichment in early lung cancer. Zhonghua Yi Xue Za Zhi 84(16):1393–1395PubMedGoogle Scholar
  49. 49.
    Nair VS et al (2013) An observational study of circulating tumor cells and (18)F-FDG PET uptake in patients with treatment-naive non-small cell lung cancer. PLoS One 8(7):e67733CrossRefPubMedCentralPubMedGoogle Scholar
  50. 50.
    Wang Y et al (2012) Detection of micrometastases in lung cancer with magnetic nanoparticles and quantum dots. Int J Nanomed 7:2315–2324Google Scholar
  51. 51.
    Pirozzi G et al (2013) Prognostic value of cancer stem cells, epithelial-mesenchymal transition and circulating tumor cells in lung cancer. Oncol Rep 29(5):1763–1768PubMedGoogle Scholar
  52. 52.
    Fleischhacker M et al (2001) Detection of amplifiable messenger RNA in the serum of patients with lung cancer. Ann N. Y. Acad Sci 945:179–188CrossRefPubMedGoogle Scholar
  53. 53.
    Moss AC et al (2009) SCG3 transcript in peripheral blood is a prognostic biomarker for REST-deficient small cell lung cancer. Clin Cancer Res 15(1):274–283CrossRefPubMedGoogle Scholar
  54. 54.
    De Luca A et al (2000) Detection of circulating tumor cells in carcinoma patients by a novel epidermal growth factor receptor reverse transcription-PCR assay. Clin Cancer Res 6(4):1439–1444PubMedGoogle Scholar
  55. 55.
    Xi L et al (2007) Optimal markers for real-time quantitative reverse transcription PCR detection of circulating tumor cells from melanoma, breast, colon, esophageal, head and neck, and lung cancers. Clin Chem 53(7):1206–1215CrossRefPubMedGoogle Scholar
  56. 56.
    Nordgard O et al (2013) Novel molecular tumor cell markers in regional lymph nodes and blood samples from patients undergoing surgery for non-small cell lung cancer. PLoS One 8(5):e62153CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Guo Y, Wang J, Huang P (2009) Clinical significance of CK20, CK19, CEA mRNAs in peripheral blood from lung cancer patients. Zhongguo Fei Ai Za Zhi 12(9):1013–1017PubMedGoogle Scholar
  58. 58.
    Qi ZL et al (2002) Expression and clinical significance of surfactant protein D mRNA in peripheral blood of lung cancer patients. Ai Zheng 21(7):772–775PubMedGoogle Scholar
  59. 59.
    Qu YM et al (2010) Clinical significance of expressions of tumor markers in peripheral blood in non-small cell lung cancer. Zhonghua Yi Xue Za Zhi 90(28):1958–1962PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Respiratory DiseaseThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
  2. 2.Department of Clinical LaboratoryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina

Personalised recommendations