Current Colorectal Cancer Reports

, Volume 6, Issue 4, pp 212–220 | Cite as

Circulating Tumor Cells and Colorectal Cancer

  • Joshua E. Allen
  • Wafik S. El-DeiryEmail author


The significance of circulating tumor cells (CTCs) has been discussed for more than a century. The advent of modern technology has allowed for more reliable detection of CTCs, and recent studies have provided compelling evidence that CTCs predict clinical response in metastatic colorectal cancer (mCRC). Combination of CTC analysis with independent prognostic factors has demonstrated powerful synergy in some studies. The ability of CTCs to predict metastasis and therapy-specific response has high potential clinical utility, with early studies showing promising results in colorectal cancer (CRC). Reliable CTC detection has also allowed for examination of tumor cell dissemination during surgery, and there appears to be a heavy dependence on the approach chosen. This review discusses the evidence for CTC significance, with particular focus on detection methods, novel markers, and clinical outcomes in CRC. Numerous opportunities exist for preclinical, clinical, and translational studies to explore molecular determinants within CTCs, as well as the value of CTCs in directing targeted therapeutics.


Circulating tumor cells Colorectal cancer CRC Colon cancer Rectal cancer CTC detection CTC enrichment Stratification Prognosis Overall survival Progression-free survival Clinical response Hepatic resection Liver resection Hepatic ablation Hepatic metastasis Liver metastasis Cytokeratin Tumor cell dissemination Epithelial cell adhesion molecule EpCAM Survivin Cetuximab KRAS 



No potential conflicts of interest relevant to this article were reported.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Jemal A, Siegel R, Ward E, et al.: Cancer Statistics, 2009. CA Cancer J Clin 2009, 59:225–249.CrossRefPubMedGoogle Scholar
  2. 2.
    Lievre A, Bachet JB, Le Corre D, et al.: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 2006, 66:3992–3995.CrossRefPubMedGoogle Scholar
  3. 3.
    Ashworth T: A case of cancer in which cells similar to those in the tumours were seen in the blood after death. Aust Med J 1869.Google Scholar
  4. 4.
    Engell HC: Cancer cells in the circulating blood: a clinical study on the occurrence of cancer cells in the peripheral blood and in venous blood draining the tumour area at operation. Ugeskr Laeger 1955, 117:822–823.PubMedGoogle Scholar
  5. 5.
    Engell HC: Cancer cells in the blood: a five to nine year follow up study. Ann Surg 1959, 149:457–461.CrossRefPubMedGoogle Scholar
  6. 6.
    Roberts S, Jonasson O, Long L, et al.: Clinical significance of cancer cells in the circulating blood: two to five-year survival. Ann Surg 1961, 154:362–370.CrossRefPubMedGoogle Scholar
  7. 7.
    Negin B, Cohen S: Circulating tumor cells in colorectal cancer: past, present, and future challenges. Curr Treat Options Oncol 2010 Feb 9 (Epub ahead of print)]. This concise review describes current detection methods for CTCs.Google Scholar
  8. 8.
    Allard WJ, Matera J, Miller MC, et al.: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 2004, 10:6897–6904.CrossRefPubMedGoogle Scholar
  9. 9.
    Riethdorf S, Fritsche H, Müller V, et al.: Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the CellSearch System. Clin Cancer Res 2007, 13:920–928.CrossRefPubMedGoogle Scholar
  10. 10.
    Hayes DF, Cristofanilli M, Budd G, et al.: Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 2006, 12:4218–4224.CrossRefPubMedGoogle Scholar
  11. 11.
    Danila DC, Heller G, Gignac GA, et al.: Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 2007, 13:7053–7058.CrossRefPubMedGoogle Scholar
  12. 12.
    •• Cohen SJ, Punt CJA, Iannotti N, et al.: Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol 2009, 20:1223–1229. This was the first large-scale mCRC patient study examining CTCs. CTC level was shown to correlate with PFS and OS.CrossRefPubMedGoogle Scholar
  13. 13.
    Sastre J, Maestro ML, Puente J, et al.: Circulating tumor cells in colorectal cancer: correlation with clinical and pathological variables. Ann Oncol 2008, 19:935–938.CrossRefPubMedGoogle Scholar
  14. 14.
    Katsuno H, Zacharakis E, Aziz O, et al.: Does the presence of circulating tumor cells in the venous drainage of curative colorectal cancer resections determine prognosis? A meta-analysis. Ann Surg Oncol 2008, 15:3083–3091.CrossRefPubMedGoogle Scholar
  15. 15.
    •• Cohen SJ, Punt CJA, Iannotti N, et al.: Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 2008, 26:3213–3221. This extended analysis of a previous study provides updated follow-up time points. The impact of CTCs on prognosis is examined in several subgroups of patients.CrossRefPubMedGoogle Scholar
  16. 16.
    Tol J, Koopman M, Miller MC, et al.: Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents. Ann Oncol 2009, 21:1006–1012.CrossRefPubMedGoogle Scholar
  17. 17.
    Garrigós N, Gallego J, Guillén-Ponce C, et al.: Circulating tumour cell analysis as an early marker for relapse in stage II and III colorectal cancer patients: a pilot study. Clin Transl Oncol 2010, 12:142–147. This small study demonstrated the potential of CTCs to predict metastasis in CRC.CrossRefPubMedGoogle Scholar
  18. 18.
    Ronzoni M, Manzoni M, Mariucci S, et al.: Circulating endothelial cells and endothelial progenitors as predictive markers of clinical response to bevacizumab-based first-line treatment in advanced colorectal cancer patients. Ann Oncol 2010 May 23 (Epub ahead of print).Google Scholar
  19. 19.
    Findeisen P, Matthias R, Matthias N, et al.: Systematic identification and validation of candidate genes for detection of circulating tumor cells in peripheral blood specimens of colorectal cancer patients. Int J Oncol 2008, 33:1001–1010.PubMedGoogle Scholar
  20. 20.
    Yie SM, Lou B, Ye S, et al.: Detection of survivin-expressing circulating cancer cells (CCCs) in peripheral blood of patients with gastric and colorectal cancer reveals high risks of relapse. Ann Surg Oncol 2008, 15:3073–3082.CrossRefPubMedGoogle Scholar
  21. 21.
    Wong CSC, Cheung MT, Ma BBY, et al.: Isolated tumor cells and circulating CK20 mRNA in pN0 colorectal cancer patients. Int J Surg Pathol 2008, 16:119–126.CrossRefPubMedGoogle Scholar
  22. 22.
    Wong SCC, Chan CML, Ma BBY, et al.: Clinical significance of cytokeratin 20-positive circulating tumor cells detected by a refined immunomagnetic enrichment assay in colorectal cancer patients. Clin Cancer Res 2009, 15:1005–1012.CrossRefPubMedGoogle Scholar
  23. 23.
    Schmidt T, Koch M, Antolovic D, et al.: Influence of two different resection techniques (conventional liver resection versus anterior approach) of liver metastases from colorectal cancer on hematogenous tumor cell dissemination—prospective randomized multicenter trial. BMC Surg 2008, 8:6.CrossRefPubMedGoogle Scholar
  24. 24.
    Koyanagi K, Bilchik AJ, Saha S, et al.: Prognostic relevance of occult nodal micrometastases and circulating tumor cells in colorectal cancer in a prospective multicenter trial. Clin Cancer Res 2008, 14:7391–7396.CrossRefPubMedGoogle Scholar
  25. 25.
    Gervasoni A, Monasterio Muñoz RM, Wengler GS, et al.: Molecular signature detection of circulating tumor cells using a panel of selected genes. Cancer Lett 2008, 263:267–279.CrossRefPubMedGoogle Scholar
  26. 26.
    Shen C, Hu L, Xia L, et al.: Quantitative real-time RT-PCR detection for survivin, CK20 and CEA in peripheral blood of colorectal cancer patients. Jpn J Clin Oncol 2008, 38:770–776.CrossRefPubMedGoogle Scholar
  27. 27.
    Königsberg R, Gneist M, Jahn-Kuch D, et al.: Circulating tumor cells in metastatic colorectal cancer: efficacy and feasibility of different enrichment methods. Cancer Lett 2010, 293:117–123.CrossRefPubMedGoogle Scholar
  28. 28.
    Chen YF, Wang JY, Wu CH, et al.: Detection of circulating cancer cells with K-ras oncogene using membrane array. Cancer Lett 2005, 229:115–122.CrossRefPubMedGoogle Scholar
  29. 29.
    Yen LC, Yeh YS, Chen CW, et al.: Detection of KRAS oncogene in peripheral blood as a predictor of the response to cetuximab plus chemotherapy in patients with metastatic colorectal cancer. Clin Cancer Res 2009, 15:4508–4513. This study demonstrated the clinical feasibility of a novel membrane array for detecting CTCs and the importance of KRAS in CTCs for predicting cetuximab response.CrossRefPubMedGoogle Scholar
  30. 30.
    Yang MJ, Chiu HH, Wang HW, et al.: Enhancing detection of circulating tumor cells with activating KRAS oncogene in patients with colorectal cancer by weighted chemiluminescent membrane array method. Ann Surg Oncol 2010, 17:624–633.CrossRefPubMedGoogle Scholar
  31. 31.
    Antolovic D, Galindo L, Carstens A, et al.: Heterogeneous detection of circulating tumor cells in patients with colorectal cancer by immunomagnetic enrichment using different EpCAM-specific antibodies. BMC Biotechnol 2010, 10:35. This study demonstrated the significant impact of CTC identification method on CTC enumeration.CrossRefPubMedGoogle Scholar
  32. 32.
    Uen YH, Lu CY, Tsai HL, et al.: Persistent presence of postoperative circulating tumor cells is a poor prognostic factor for patients with stage I–III colorectal cancer after curative resection. Ann Surg Oncol 2008, 15:2120–2128.CrossRefPubMedGoogle Scholar
  33. 33.
    Papavasiliou P, Fisher T, Kuhn J, et al.: Circulating tumor cells in patients undergoing surgery for hepatic metastases from colorectal cancer. Proc (Bayl Univ Med Cent) 2010, 23:11–14. This study found that RFA significantly increases the level of intraoperative CTCs.Google Scholar
  34. 34.
    Tralhão JG, Hoti E, Serôdio M, et al.: Perioperative tumor cell dissemination in patients with primary or metastatic colorectal cancer. Eur J Surg Oncol (EJSO) 2010, 36:125–129.CrossRefGoogle Scholar
  35. 35.
    Pang R, Law WL, Chu ACY: A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 2010, 6:603–617.CrossRefPubMedGoogle Scholar
  36. 36.
    Paget S: The distribution of secondary growths in cancer of the breast. Lancet 1889, 1:571–572.CrossRefGoogle Scholar
  37. 37.
    Fidler IJ: The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer 2003, 3:453–458.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Penn State Hershey Cancer InstituteHersheyUSA
  2. 2.Hematology/Oncology DivisionPenn State Hershey Medical Center and Cancer InstituteHersheyUSA

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