Circulating and disseminated tumor cells: Diagnostic tools and therapeutic targets in motion

Oncotarget

Volumn 8, Issue 1, 2017, Pages 1884-1912

  Wang, Hongxia ^a   Stoecklein, Nikolas H ^b   Lin, Peter P ^c   Gires, Olivier ^d,e  

^a SHANGHAI JIAO TONG UNIVERSITY SCHOOL OF MEDICINE   (China)

^b UNIVERSITY HOSPITAL DÜSSELDORF   (Germany)

^c Cytelligen Corporation   (United States)

^d LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^e Clinical Cooperation Group Personalized Radiotherapy of Head and Neck Tumors   (Germany)

Author keywords

CTCs; DTCs; EpCAM; Metastases; MICs

Indexed keywords

ANTINEOPLASTIC AGENT; CD47 ANTIGEN; CETUXIMAB; EPIDERMAL GROWTH FACTOR RECEPTOR 2; EPITHELIAL CELL ADHESION MOLECULE; HERMES ANTIGEN; LAPATINIB; PROGRAMMED DEATH 1 RECEPTOR; SCATTER FACTOR RECEPTOR; TRASTUZUMAB; TRASTUZUMAB EMTANSINE; TUMOR MARKER;

ADVANCED CANCER; BREAST CANCER; CANCER ADJUVANT THERAPY; CANCER STEM CELL; CELL ISOLATION; CIRCULATING TUMOR CELL; CLINICAL EFFECTIVENESS; COLORECTAL CANCER; DRUG EFFICACY; EPITHELIAL MESENCHYMAL TRANSITION; HEAD AND NECK SQUAMOUS CELL CARCINOMA; HUMAN; LUNG CANCER; METASTASIS; MOLECULARLY TARGETED THERAPY; NON SMALL CELL LUNG CANCER; NONHUMAN; PANCREAS ADENOCARCINOMA; PANCREAS CANCER; PHENOTYPE; PROSTATE CANCER; RECTUM CANCER; REVIEW; STOMACH CANCER; SYSTEMIC DISEASE; TREATMENT PLANNING; TUMOR BIOPSY; BLOOD; NEOPLASM; PATHOLOGY; PHYSIOLOGY; PROGNOSIS; TUMOR EMBOLISM; TUMOR RECURRENCE;

BIOMARKERS, TUMOR; EPITHELIAL-MESENCHYMAL TRANSITION; HUMANS; NEOPLASM METASTASIS; NEOPLASM RECURRENCE, LOCAL; NEOPLASMS; NEOPLASTIC CELLS, CIRCULATING; PROGNOSIS;

EID: 85009798294     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.12242     Document Type: Review

References (321)

1. Talmadge JE, Fidler IJ. AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res. 2010; 70: 5649-69. doi: 10.1158/0008-5472.CAN-10-1040.
2. Scott AM, Wolchok JD, Old LJ. Antibody therapy of cancer. Nat Rev Cancer. 2012; 12: 278-87. doi: 10.1038/nrc3236.
3. Wu P, Nielsen TE, Clausen MH. FDA-approved smallmolecule kinase inhibitors. Trends Pharmacol Sci. 2015; 36: 422-39. doi: 10.1016/j.tips.2015.04.005.
4. Wu P, Nielsen TE, Clausen MH. Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discov Today. 2016; 21: 5-10. doi: 10.1016/j.drudis.2015.07.008.
5. Kurtz JE, Dufour P. Adecatumumab: an anti-EpCAM monoclonal antibody, from the bench to the bedside. Expert Opin Biol Ther. 2010; 10: 951-8. doi: 10.1517/14712598.2010.482098.
6. Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I, WolffAC, Carey LA, Overmoyer BA, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015; 372: 134-41. doi: 10.1056/NEJMoa1406281.
7. Piccart-Gebhart MJ. Moving away from the "one shoe fits all" strategy: the key to future progress in chemotherapy. J Clin Oncol. 2005; 23: 1611-3. doi: 10.1200/JCO.2005.01.007.
8. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005; 353: 1659-72. doi: 10.1056/NEJMoa052306.
9. Puglisi F, Piccart M. Trastuzumab and breast cancer. Are we just beyond the prologue of a fascinating story? Onkologie. 2005; 28: 547-9. doi: 10.1159/000088849.
10. Driemel C, Kremling H, Schumacher S, Will D, Wolters J, Lindenlauf N, Mack B, Baldus SA, Hoya V, Pietsch JM, Panagiotidou P, Raba K, Vay C, et al. Contextdependent adaption of EpCAM expression in early systemic esophageal cancer. Oncogene. 2013. doi: 10.1038/onc.2013.441.
11. Gires O, Stoecklein NH. Dynamic EpCAM expression on circulating and disseminating tumor cells: causes and consequences. Cell Mol Life Sci. 2014. doi: 10.1007/s00018-014-1693-1.
12. Punnoose EA, Atwal SK, Spoerke JM, Savage H, Pandita A, Yeh RF, Pirzkall A, Fine BM, Amler LC, Chen DS, Lackner MR. Molecular biomarker analyses using circulating tumor cells. PLoS One. 2010; 5: e12517. doi: 10.1371/journal.pone.0012517.
13. Meng S, Tripathy D, Shete S, Ashfaq R, Haley B, Perkins S, Beitsch P, Khan A, Euhus D, Osborne C, Frenkel E, Hoover S, Leitch M, et al. HER-2 gene amplification can be acquired as breast cancer progresses. Proc Natl Acad Sci U S A. 2004; 101: 9393-8. doi: 10.1073/pnas.0402993101.
14. Hayes DF, Walker TM, Singh B, Vitetta ES, Uhr JW, Gross S, Rao C, Doyle GV, Terstappen LW. Monitoring expression of HER-2 on circulating epithelial cells in patients with advanced breast cancer. Int J Oncol. 2002; 21: 1111-7.
15. Stoecklein NH, Fischer JC, Niederacher D, Terstappen LW. Challenges for CTC-based liquid biopsies: low CTC frequency and diagnostic leukapheresis as a potential solution. Expert Rev Mol Diagn. 2015: 1-18. doi: 10.1586/14737159.2016.1123095.
16. Joosse SA, Gorges TM, Pantel K. Biology, detection, and clinical implications of circulating tumor cells. EMBO Mol Med. 2015; 7: 1-11. doi: 10.15252/emmm.201303698.
17. Leversha MA, Han J, Asgari Z, Danila DC, Lin O, Gonzalez-Espinoza R, Anand A, Lilja H, Heller G, Fleisher M, Scher HI. Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin Cancer Res. 2009; 15: 2091-7. doi: 10.1158/1078-0432. CCR-08-2036.
18. Riethdorf S, Pantel K. Advancing personalized cancer therapy by detection and characterization of circulating carcinoma cells. Ann N Y Acad Sci. 2010; 1210: 66-77. doi: 10.1111/j.1749-6632.2010.05779.x.
19. Pantel K, Alix-Panabieres C. Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res. 2013; 73: 6384-8. doi: 10.1158/0008-5472.CAN-13-2030.
20. Wan L, Pantel K, Kang Y. Tumor metastasis: moving new biological insights into the clinic. Nat Med. 2013; 19: 1450-64. doi: 10.1038/nm.3391.
21. Janni W, Rack B, Terstappen LW, Pierga JY, Taran FA, Fehm T, Hall C, de Groot M, Bidard FC, Friedl TW, Fasching PA, Brucker SY, Pantel K, et al. Pooled Analysis of the Prognostic Relevance of Circulating Tumor Cells in Primary Breast Cancer. Clin Cancer Res. 2016. doi: 10.1158/1078-0432.CCR-15-1603.
22. Klein CA. Cancer. The metastasis cascade. Science. 2008; 321: 1785-7. doi: 321/5897/1785 [pii]10.1126/science.1164853.
23. Khoo BL, Lee SC, Kumar P, Tan TZ, Warkiani ME, Ow SG, Nandi S, Lim CT, Thiery JP. Short-term expansion of breast circulating cancer cells predicts response to anti-cancer therapy. Oncotarget. 2015; 6: 15578-93. doi: 10.18632/oncotarget.3903.
24. Yu M, Bardia A, Aceto N, Bersani F, Madden MW, Donaldson MC, Desai R, Zhu H, Comaills V, Zheng Z, Wittner BS, Stojanov P, Brachtel E, et al. Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science. 2014; 345: 216-20. doi: 10.1126/science.1253533.
25. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, IsakoffSJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013; 339: 580-4. doi: 10.1126/science.1228522.
26. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J, Schwabe RF, Vahdat LT, Altorki NK, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015; 527: 472-6. doi: 10.1038/nature15748.
27. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R. Epithelial-tomesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015; 527: 525-30. doi: 10.1038/nature16064.
28. Miyamoto DT, Lee RJ, Stott SL, Ting DT, Wittner BS, Ulman M, Smas ME, Lord JB, Brannigan BW, Trautwein J, Bander NH, Wu CL, Sequist LV, et al. Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. Cancer Discov. 2012; 2: 995-1003. doi: 10.1158/2159-8290.CD-12-0222.
29. Bork U, Rahbari NN, Scholch S, Reissfelder C, Kahlert C, Buchler MW, Weitz J, Koch M. Circulating tumour cells and outcome in non-metastatic colorectal cancer: a prospective study. Br J Cancer. 2015; 112: 1306-13. doi: 10.1038/bjc.2015.88.
30. Pecqueux M, Fritzmann J, Adamu M, Thorlund K, Kahlert C, Reissfelder C, Weitz J, Rahbari NN. Free intraperitoneal tumor cells and outcome in gastric cancer patients: a systematic review and meta-analysis. Oncotarget. 2015; 6: 35564-78. doi: 10.18632/oncotarget.5595.
31. Rahbari NN, Bork U, Motschall E, Thorlund K, Buchler MW, Koch M, Weitz J. Molecular detection of tumor cells in regional lymph nodes is associated with disease recurrence and poor survival in node-negative colorectal cancer: a systematic review and meta-analysis. J Clin Oncol. 2012; 30: 60-70. doi: 10.1200/JCO.2011.36.9504.
32. Tinhofer I, Hristozova T, Stromberger C, Keilhoiz U, Budach V. Monitoring of circulating tumor cells and their expression of EGFR/phospho-EGFR during combined radiotherapy regimens in locally advanced squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012; 83: e685-90. doi: 10.1016/j.ijrobp.2012.02.009.
33. Tinhofer I, Konschak R, Stromberger C, Raguse JD, Dreyer JH, Johrens K, Keilholz U, Budach V. Detection of circulating tumor cells for prediction of recurrence after adjuvant chemoradiation in locally advanced squamous cell carcinoma of the head and neck. Ann Oncol. 2014; 25: 2042-7. doi: 10.1093/annonc/mdu271.
34. Smerage JB, Barlow WE, Hortobagyi GN, Winer EP, Leyland-Jones B, Srkalovic G, Tejwani S, Schott AF, O'Rourke MA, Lew DL, Doyle GV, Gralow JR, Livingston RB, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. 2014; 32: 3483-9. doi: 10.1200/JCO.2014.56.2561.
35. Gorges TM, Tinhofer I, Drosch M, Rose L, Zollner TM, Krahn T, von Ahsen O. Circulating tumour cells escape from EpCAM-based detection due to epithelial-tomesenchymal transition. BMC Cancer. 2012; 12: 178. doi: 1471-2407-12-178 [pii]10.1186/1471-2407-12-178.
36. Hanssen A, Wagner J, Gorges TM, Taenzer A, Uzunoglu FG, Driemel C, Stoecklein NH, Knoefel WT, Angenendt S, Hauch S, Atanackovic D, Loges S, Riethdorf S, et al. Characterization of different CTC subpopulations in nonsmall cell lung cancer. Sci Rep. 2016; 6: 28010. doi: 10.1038/srep28010.
37. Ignatiadis M, Rack B, Rothe F, Riethdorf S, Decraene C, Bonnefoi H, Dittrich C, Messina C, Beauvois M, Trapp E, Goulioti T, Tryfonidis K, Pantel K, et al. Liquid biopsybased clinical research in early breast cancer: The EORTC 90091-10093 Treat CTC trial. Eur J Cancer. 2016; 63: 97-104. doi: 10.1016/j.ejca.2016.04.024.
38. Alix-Panabieres C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014; 14: 623-31. doi: 10.1038/nrc3820.
39. Fischer JC, Niederacher D, Topp SA, Honisch E, Schumacher S, Schmitz N, Zacarias Fohrding L, Vay C, Hoffmann I, Kasprowicz NS, Hepp PG, Mohrmann S, Nitz U, et al. Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients. Proc Natl Acad Sci U S A. 2013; 110: 16580-5. doi: 10.1073/pnas.1313594110.
40. Ma M, Zhu H, Zhang C, Sun X, Gao X, Chen G. "Liquid biopsy"-ctDNA detection with great potential and challenges. Ann Transl Med. 2015; 3: 235. doi: 10.3978/j. issn.2305-5839.2015.09.29.
41. Kato K, Uchida J, Kukita Y, Kumagai T, Nishino K, Inoue T, Kimura M, Oba S, Imamura F. Numerical indices based on circulating tumor DNA for the evaluation of therapeutic response and disease progression in lung cancer patients. Sci Rep. 2016; 6: 29093. doi: 10.1038/srep29093.
42. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, et al. Detection of circulating tumor DNA in early-and late-stage human malignancies. Sci Transl Med. 2014; 6: 224ra24. doi: 10.1126/scitranslmed.3007094.
43. Newman AM, Bratman SV, To J, Wynne JF, Eclov NC, Modlin LA, Liu CL, Neal JW, Wakelee HA, Merritt RE, Shrager JB, Loo BW, Jr., Alizadeh AA, et al. An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage. Nat Med. 2014; 20: 548-54. doi: 10.1038/nm.3519.
44. Dawson SJ, Rosenfeld N, Caldas C. Circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013; 369: 93-4. doi: 10.1056/NEJMc1306040.
45. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, Dunning MJ, Gale D, Forshew T, Mahler-Araujo B, Rajan S, Humphray S, Becq J, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med. 2013; 368: 1199-209. doi: 10.1056/NEJMoa1213261.
46. Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bauerle T, Wallwiener M, Holland-Letz T, Hofner T, Sprick M, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013; 31: 539-44. doi: 10.1038/nbt.2576.
47. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004; 351: 781-91. doi: 10.1056/NEJMoa040766.
48. Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW. 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: 4218-24. doi: 10.1158/1078-0432.CCR-05-2821.
49. de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, Doyle GV, Terstappen LW, Pienta KJ, Raghavan D. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008; 14: 6302-9. doi: 10.1158/1078-0432.CCR-08-0872.
50. Yap TA, Lorente D, Omlin A, Olmos D, de Bono JS. Circulating tumor cells: a multifunctional biomarker. Clin Cancer Res. 2014; 20: 2553-68. doi: 10.1158/1078-0432. CCR-13-2664.
51. Moreno JG, O'Hara SM, Gross S, Doyle G, Fritsche H, Gomella LG, Terstappen LW. Changes in circulating carcinoma cells in patients with metastatic prostate cancer correlate with disease status. Urology. 2001; 58: 386-92.
52. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, Tibbe AG, Uhr JW, Terstappen LW. 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: 6897-904. doi: 10.1158/1078-0432.CCR-04-0378.
53. Budd GT, Cristofanilli M, Ellis MJ, Stopeck A, Borden E, Miller MC, Matera J, Repollet M, Doyle GV, Terstappen LW, Hayes DF. Circulating tumor cells versus imaging predicting overall survival in metastatic breast cancer. Clin Cancer Res. 2006; 12: 6403-9. doi: 10.1158/1078-0432. CCR-05-1769.
54. Pantel K, Alix-Panabieres C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med. 2010; 16: 398-406. doi: S1471-4914(10)00096-1 [pii]10.1016/j.molmed.2010.07.001.
55. Cristofanilli M. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. Semin Oncol. 2006; 33: S9-14. doi: 10.1053/j.seminoncol.2006.03.016.
56. Coumans FA, Ligthart ST, Uhr JW, Terstappen LW. Challenges in the enumeration and phenotyping of CTC. Clin Cancer Res. 2012; 18: 5711-8. doi: 10.1158/1078-0432.CCR-12-1585.
57. Coumans FA, Siesling S, Terstappen LW. Detection of cancer before distant metastasis. BMC Cancer. 2013; 13:283. doi: 10.1186/1471-2407-13-283.
58. Pantel K, Alix-Panabieres C. The potential of circulating tumor cells as a liquid biopsy to guide therapy in prostate cancer. Cancer Discov. 2012; 2: 974-5. doi: 10.1158/2159-8290.CD-12-0432.
59. Jacob K, Sollier C, Jabado N. Circulating tumor cells: detection, molecular profiling and future prospects. Expert Rev Proteomics. 2007; 4: 741-56. doi: 10.1586/14789450.4.6.741.
60. Tewes M, Aktas B, Welt A, Mueller S, Hauch S, Kimmig R, Kasimir-Bauer S. Molecular profiling and predictive value of circulating tumor cells in patients with metastatic breast cancer: an option for monitoring response to breast cancer related therapies. Breast Cancer Res Treat. 2009; 115: 581-90. doi: 10.1007/s10549-008-0143-x.
61. Husemann Y, Geigl JB, Schubert F, Musiani P, Meyer M, Burghart E, Forni G, Eils R, Fehm T, Riethmuller G, Klein CA. Systemic spread is an early step in breast cancer. Cancer Cell. 2008; 13: 58-68.
62. Klein CA, Blankenstein TJ, Schmidt-Kittler O, Petronio M, Polzer B, Stoecklein NH, Riethmuller G. Genetic heterogeneity of single disseminated tumour cells in minimal residual cancer. Lancet. 2002; 360: 683-9.
63. Klein CA, Seidl S, Petat-Dutter K, Offner S, Geigl JB, Schmidt-Kittler O, Wendler N, Passlick B, Huber RM, Schlimok G, Baeuerle PA, Riethmuller G. Combined transcriptome and genome analysis of single micrometastatic cells. Nat Biotechnol. 2002; 20: 387-92.
64. Polzer B, Medoro G, Pasch S, Fontana F, Zorzino L, Pestka A, Andergassen U, Meier-Stiegen F, Czyz ZT, Alberter B, Treitschke S, Schamberger T, Sergio M, et al. Molecular profiling of single circulating tumor cells with diagnostic intention. EMBO Mol Med. 2014; 6: 1371-86. doi: 10.15252/emmm.201404033.
65. Schardt JA, Meyer M, Hartmann CH, Schubert F, Schmidt-Kittler O, Fuhrmann C, Polzer B, Petronio M, Eils R, Klein CA. Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell. 2005; 8: 227-39.
66. Schmidt-Kittler O, Ragg T, Daskalakis A, Granzow M, Ahr A, Blankenstein TJ, Kaufmann M, Diebold J, Arnholdt H, Muller P, BischoffJ, Harich D, Schlimok G, et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci U S A. 2003; 100: 7737-42.
67. Stoecklein NH, Hosch SB, Bezler M, Stern F, Hartmann CH, Vay C, Siegmund A, Scheunemann P, Schurr P, Knoefel WT, Verde PE, Reichelt U, Erbersdobler A, et al. Direct genetic analysis of single disseminated cancer cells for prediction of outcome and therapy selection in esophageal cancer. Cancer Cell. 2008; 13: 441-53. doi: S1535-6108(08)00124-4 [pii]10.1016/j.ccr.2008.04.005.
68. Stoecklein NH, Klein CA. Genetic disparity between primary tumours, disseminated tumour cells, and manifest metastasis. Int J Cancer. 2010; 126: 589-98. doi: 10.1002/ijc.24916.
69. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer. 2009; 9: 302-12. doi: 10.1038/nrc2627.
70. Alix-Panabieres C, Riethdorf S, Pantel K. Circulating tumor cells and bone marrow micrometastasis. Clin Cancer Res. 2008; 14: 5013-21. doi: 14/16/5013 [pii]10.1158/1078-0432.CCR-07-5125.
71. Kang Y, Pantel K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell. 2013; 23: 573-81. doi: 10.1016/j. ccr.2013.04.017.
72. Muller V, Riethdorf S, Rack B, Janni W, Fasching PA, Solomayer E, Aktas B, Kasimir-Bauer S, Pantel K, Fehm T, on behalf of the Dsg. Prognostic impact of circulating tumor cells assessed with the CellSearch System and AdnaTest Breast in metastatic breast cancer patients: the DETECT study. Breast Cancer Res. 2012; 14: R118. doi: 10.1186/bcr3243.
73. Muller V, Stahmann N, Riethdorf S, Rau T, Zabel T, Goetz A, Janicke F, Pantel K. Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin Cancer Res. 2005; 11: 3678-85.
74. Pantel K, BrakenhoffRH, Brandt B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer. 2008; 8: 329-40.
75. Pantel K, Woelfle U. Detection and molecular characterisation of disseminated tumour cells: implications for anti-cancer therapy. Biochim Biophys Acta. 2005; 1756: 53-64.
76. Rack B, Schindlbeck C, Juckstock J, Andergassen U, Hepp P, Zwingers T, Friedl TW, Lorenz R, Tesch H, Fasching PA, Fehm T, Schneeweiss A, Lichtenegger W, et al. Circulating tumor cells predict survival in early average-tohigh risk breast cancer patients. J Natl Cancer Inst. 2014; 106. doi: 10.1093/jnci/dju066.
77. Schulze K, Gasch C, Staufer K, Nashan B, Lohse AW, Pantel K, Riethdorf S, Wege H. Presence of EpCAMpositive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer. 2013; 133: 2165-71. doi: 10.1002/ijc.28230.
78. Wallwiener M, Hartkopf AD, Baccelli I, Riethdorf S, Schott S, Pantel K, Marme F, Sohn C, Trumpp A, Rack B, Aktas B, Solomayer EF, Muller V, et al. The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast Cancer Res Treat. 2013; 137: 503-10. doi: 10.1007/s10549-012-2382-0.
79. Zhang L, Riethdorf S, Wu G, Wang T, Yang K, Peng G, Liu J, Pantel K. Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res. 2012; 18: 5701-10. doi: 10.1158/1078-0432.CCR-12-1587.
80. Onstenk W, Gratama JW, Foekens JA, Sleijfer S. Towards a personalized breast cancer treatment approach guided by circulating tumor cell (CTC) characteristics. Cancer Treat Rev. 2013; 39: 691-700. doi: 10.1016/j.ctrv.2013.04.001.
81. Goss PE, Chambers AF. Does tumour dormancy offer a therapeutic target? Nat Rev Cancer. 2010; 10: 871-7. doi: 10.1038/nrc2933.
82. Janni W, Rack B, Schindlbeck C, Strobl B, Rjosk D, Braun S, Sommer H, Pantel K, Gerber B, Friese K. The persistence of isolated tumor cells in bone marrow from patients with breast carcinoma predicts an increased risk for recurrence. Cancer. 2005; 103: 884-91.
83. Pantel K, Alix-Panabieres C, Riethdorf S. Cancer micrometastases. Nat Rev Clin Oncol. 2009; 6: 339-51. doi: nrclinonc.2009.44 [pii]10.1038/nrclinonc.2009.44.
84. Riethdorf S, Wikman H, Pantel K. Review: Biological relevance of disseminated tumor cells in cancer patients. Int J Cancer. 2008; 123: 1991-2006. doi: 10.1002/ijc.23825.
85. Klein CA, Stoecklein NH. Lessons from an aggressive cancer: evolutionary dynamics in esophageal carcinoma. Cancer Res. 2009; 69: 5285-8. doi: 0008-5472.CAN-08-4586 [pii]10.1158/0008-5472.CAN-08-4586.
86. Klein CA. The systemic progression of human cancer: a focus on the individual disseminated cancer cell the unit of selection. Adv Cancer Res. 2003; 89: 35-67.
87. Riethdorf S, Pantel K. Disseminated tumor cells in bone marrow and circulating tumor cells in blood of breast cancer patients: current state of detection and characterization. Pathobiology. 2008; 75: 140-8. doi: 000123852 [pii]10.1159/000123852.
88. Hosch S, Kraus J, Scheunemann P, Izbicki JR, Schneider C, Schumacher U, Witter K, Speicher MR, Pantel K. Malignant potential and cytogenetic characteristics of occult disseminated tumor cells in esophageal cancer. Cancer Res. 2000; 60: 6836-40. doi:
89. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, Polanski R, Burt DJ, Simpson KL, Morris K, Pepper SD, Nonaka D, Greystoke A, et al. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med. 2014; 20: 897-903. doi: 10.1038/nm.3600.
90. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, Brannigan BW, Kapur R, Stott SL, et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014; 158: 1110-22. doi: 10.1016/j. cell.2014.07.013.
91. Morrow CJ, Trapani F, Metcalf RL, Bertolini G, Hodgkinson CL, Khandelwal G, Kelly P, Galvin M, Carter L, Simpson KL, Williamson S, Wirth C, Simms N, et al. Tumourigenic non-small-cell lung cancer mesenchymal circulating tumour cells: a clinical case study. Ann Oncol. 2016; 27: 1155-60. doi: 10.1093/annonc/mdw122.
92. Girotti MR, Gremel G, Lee R, Galvani E, Rothwell D, Viros A, Mandal AK, Lim KH, Saturno G, Furney SJ, Baenke F, Pedersen M, Rogan J, et al. Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma. Cancer Discov. 2016; 6: 286-99. doi: 10.1158/2159-8290.CD-15-1336.
93. Fidler IJ. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res. 1978; 38: 2651-60.
94. Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle. 2007; 6: 2332-8.
95. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, et al. The epithelialmesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133: 704-15. doi: S0092-8674(08)00444-3 [pii]10.1016/j.cell.2008.03.027.
96. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009; 9: 265-73. doi: 10.1038/nrc2620.
97. Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007; 11: 259-73.
98. Brouwer A, De Laere B, Peeters D, Peeters M, Salgado R, Dirix L, Van Laere S. Evaluation and consequences of heterogeneity in the circulating tumor cell compartment. Oncotarget. 2016. doi: 10.18632/oncotarget.8015.
99. Tam WL, Weinberg RA. The epigenetics of epithelialmesenchymal plasticity in cancer. Nat Med. 2013; 19: 1438-49. doi: 10.1038/nm.3336.
100. Lujambio A, Esteller M. How epigenetics can explain human metastasis: a new role for microRNAs. Cell Cycle. 2009; 8: 377-82.
101. Nierodzik ML, Karpatkin S. Thrombin induces tumor growth, metastasis, and angiogenesis: Evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell. 2006; 10: 355-62. doi: 10.1016/j.ccr.2006.10.002.
102. Barkan D, Kleinman H, Simmons JL, Asmussen H, Kamaraju AK, HoenorhoffMJ, Liu ZY, Costes SV, Cho EH, Lockett S, Khanna C, Chambers AF, Green JE. Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res. 2008; 68: 6241-50. doi: 10.1158/0008-5472.CAN-07-6849.
103. Quesnel B. Dormant tumor cells as a therapeutic target? Cancer Lett. 2008; 267: 10-7. doi: 10.1016/j. canlet.2008.02.055.
104. Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nat Rev Cancer. 2014; 14: 611-22. doi: 10.1038/nrc3793.
105. Ghajar CM. Metastasis prevention by targeting the dormant niche. Nat Rev Cancer. 2015; 15: 238-47. doi: 10.1038/nrc3910.
106. Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A, Hajjar KA, Stainier DY, Chen EI, Lyden D, Bissell MJ. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013; 15: 807-17. doi: 10.1038/ncb2767.
107. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelialmesenchymal transitions in development and disease. Cell. 2009; 139: 871-90. doi: 10.1016/j.cell.2009.11.007.
108. Thiery JP, Lim CT. Tumor dissemination: an EMT affair. Cancer Cell. 2013; 23: 272-3. doi: 10.1016/j. ccr.2013.03.004.
109. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011; 331: 1559-64. doi: 10.1126/science.1203543.
110. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-74. doi: S0092-8674(11)00127-9 [pii]10.1016/j.cell.2011.02.013.
111. Braun S, Hepp F, Sommer HL, Pantel K. Tumor-antigen heterogeneity of disseminated breast cancer cells: implications for immunotherapy of minimal residual disease. Int J Cancer. 1999; 84: 1-5. doi:
112. Thurm H, Ebel S, Kentenich C, Hemsen A, Riethdorf S, Coith C, Wallwiener D, Braun S, OberhoffC, Janicke F, Pantel K. Rare expression of epithelial cell adhesion molecule on residual micrometastatic breast cancer cells after adjuvant chemotherapy. Clin Cancer Res. 2003; 9: 2598-604.
113. Weigelt B, Glas AM, Wessels LF, Witteveen AT, Peterse JL, van't Veer LJ. Gene expression profiles of primary breast tumors maintained in distant metastases. Proc Natl Acad Sci U S A. 2003; 100: 15901-5. doi: 10.1073/pnas.2634067100.
114. Weigelt B, Hu Z, He X, Livasy C, Carey LA, Ewend MG, Glas AM, Perou CM, Van't Veer LJ. Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. Cancer Res. 2005; 65: 9155-8. doi: 10.1158/0008-5472.CAN-05-2553.
115. Hao X, Sun B, Hu L, Lahdesmaki H, Dunmire V, Feng Y, Zhang SW, Wang H, Wu C, Wang H, Fuller GN, Symmans WF, Shmulevich I, et al. Differential gene and protein expression in primary breast malignancies and their lymph node metastases as revealed by combined cDNA microarray and tissue microarray analysis. Cancer. 2004; 100: 1110-22. doi: 10.1002/cncr.20095.
116. Bukholm IK, Nesland JM, Borresen-Dale AL. Reexpression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients [seecomments]. J Pathol. 2000; 190: 15-9. doi: 10.1002/(SICI)1096-9896(200001)190:1<15::AIDPATH489>3.0.CO;2-L.
117. Weigelt B, Peterse JL, van't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005; 5: 591-602. doi: 10.1038/nrc1670.
118. Nacht M, Ferguson AT, Zhang W, Petroziello JM, Cook BP, Gao YH, Maguire S, Riley D, Coppola G, Landes GM, Madden SL, Sukumar S. Combining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancer. Cancer Res. 1999; 59: 5464-70. doi:
119. Iwatsuki M, Toyoshima K, Watanabe M, Hayashi N, Ishimoto T, Eto K, Iwagami S, Baba Y, Yoshida N, Hayashi A, Ohta Y, Baba H. Frequency of HER2 expression of circulating tumour cells in patients with metastatic or recurrent gastrointestinal cancer. Br J Cancer. 2013; 109: 2829-32. doi: 10.1038/bjc.2013.680.
120. Solomayer EF, Becker S, Pergola-Becker G, Bachmann R, Kramer B, Vogel U, Neubauer H, Wallwiener D, Huober J, Fehm TN. Comparison of HER2 status between primary tumor and disseminated tumor cells in primary breast cancer patients. Breast Cancer Res Treat. 2006; 98: 179-84. doi: 10.1007/s10549-005-9147-y.
121. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, Digumarthy S, Muzikansky A, Irimia D, et al. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008; 359: 366-77. doi: 10.1056/NEJMoa0800668.
122. Polzer B, Klein CA. Metastasis awakening: the challenges of targeting minimal residual cancer. Nat Med. 2013; 19: 274-5. doi: 10.1038/nm.3121.
123. Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003; 33: 49-54. doi: 10.1038/ng1060.
124. Barradas AM, Terstappen LW. Towards the Biological Understanding of CTC: Capture Technologies, Definitions and Potential to Create Metastasis. Cancers (Basel). 2013; 5: 1619-42. doi: 10.3390/cancers5041619.
125. Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse M, Mitchell E, Miller MC, Doyle GV, Tissing H, Terstappen LW, et al. Relationship of circulating tumor cells to tumor response, progressionfree survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26: 3213-21. doi: 10.1200/JCO.2007.15.8923.
126. Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse MA, Mitchell E, Miller MC, Doyle GV, Tissing H, Terstappen LW, et al. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol. 2009; 20: 1223-9. doi: 10.1093/annonc/mdn786.
127. Hiltermann TJ, Pore MM, van den Berg A, Timens W, Boezen HM, Liesker JJ, Schouwink JH, Wijnands WJ, Kerner GS, Kruyt FA, Tissing H, Tibbe AG, Terstappen LW, et al. Circulating tumor cells in small-cell lung cancer: a predictive and prognostic factor. Ann Oncol. 2012; 23: 2937-42. doi: 10.1093/annonc/mds138.
128. Powell AA, Talasaz AH, Zhang H, Coram MA, Reddy A, Deng G, Telli ML, Advani RH, Carlson RW, Mollick JA, Sheth S, Kurian AW, Ford JM, et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One. 2012; 7: e33788. doi: 10.1371/journal.pone.0033788.
129. Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Janicke F, Jackson S, Gornet T, Cristofanilli M, 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: 920-8.
130. Zoller M. CD44: can a cancer-initiating cell profit from an Cancer Res. 2013; 73: 4112-22. doi: 10.1158/0008-5472. CAN-12-3801.
131. Nagahara M, Mimori K, Kataoka A, Ishii H, Tanaka F, Nakagawa T, Sato T, Ono S, Sugihara K, Mori M. Correlated expression of CD47 and SIRPA in bone marrow and in peripheral blood predicts recurrence in breast cancer patients. Clin Cancer Res. 2010; 16: 4625-35. doi: 10.1158/1078-0432.CCR-10-0349.
132. Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol. 2010; 11: 834-48. doi: 10.1038/nrm3012.
133. Gires O, Klein CA, Baeuerle PA. On the abundance of EpCAM on cancer stem cells. Nat Rev Cancer. 2009; 9: 143; author reply doi: nrc2499-c1 [pii]10.1038/nrc2499-c1.
134. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008; 8: 755-68. doi:
135. Gires O. Lessons from common markers of tumor-initiating cells in solid cancers. Cell Mol Life Sci. 2011. doi: 10.1007/s00018-011-0772-9.
136. Munz M, Baeuerle PA, Gires O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res. 2009; 69: 5627-9. doi: 0008-5472.CAN-09-0654 [pii]10.1158/0008-5472.CAN-09-0654.
137. Du L, Wang H, He L, Zhang J, Ni B, Wang X, Jin H, Cahuzac N, Mehrpour M, Lu Y, Chen Q. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 2008; 14: 6751-60. doi: 10.1158/1078-0432. CCR-08-1034.
138. Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, Schutte M, Martens JW, Gratama JW, Sleijfer S, Foekens JA. Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst. 2009; 101: 61-6. doi: 10.1093/jnci/djn419.
139. Went P, Vasei M, Bubendorf L, Terracciano L, Tornillo L, Riede U, Kononen J, Simon R, Sauter G, Baeuerle PA. Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers. Br J Cancer. 2006; 94: 128-35.
140. Went PT, Lugli A, Meier S, Bundi M, Mirlacher M, Sauter G, Dirnhofer S. Frequent EpCam protein expression in human carcinomas. Hum Pathol. 2004; 35: 122-8.
141. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells-an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005; 5: 744-9. doi: nrc1694 [pii]10.1038/nrc1694.
142. Liu WF, Nelson CM, Pirone DM, Chen CS. E-cadherin engagement stimulates proliferation via Rac1. J Cell Biol. 2006; 173: 431-41. doi: 10.1083/jcb.200510087.
143. van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008; 65: 3756-88. doi: 10.1007/s00018-008-8281-1.
144. Cavallaro U, Schaffhauser B, Christofori G. Cadherins and the tumour progression: is it all in a switch? Cancer Lett. 2002; 176: 123-8.
145. Kolijn K, Verhoef EI, van Leenders GJ. Morphological and immunohistochemical identification of epithelialto-mesenchymal transition in clinical prostate cancer. Oncotarget. 2015; 6: 24488-98.
146. Canel M, Serrels A, Frame MC, Brunton VG. E-cadherinintegrin crosstalk in cancer invasion and metastasis. J Cell Sci. 2013; 126: 393-401. doi: 10.1242/jcs.100115.
147. de Wit S, van Dalum G, Lenferink AT, Tibbe AG, Hiltermann TJ, Groen HJ, van Rijn CJ, Terstappen LW. The detection of EpCAM(+) and EpCAM(-) circulating tumor cells. Sci Rep. 2015; 5: 12270. doi: 10.1038/srep12270.
148. Rao CG, Chianese D, Doyle GV, Miller MC, Russell T, Sanders RA, Jr., Terstappen LW. Expression of epithelial cell adhesion molecule in carcinoma cells present in blood and primary and metastatic tumors. Int J Oncol. 2005; 27: 49-57.
149. Mikolajczyk SD, Millar LS, Tsinberg P, Coutts SM, Zomorrodi M, Pham T, BischoffFZ, Pircher TJ. Detection of EpCAM-Negative and Cytokeratin-Negative Circulating Tumor Cells in Peripheral Blood. J Oncol. 2011; 2011:252361 doi: 10.1155/2011/252361.
150. Konigsberg R, Obermayr E, Bises G, Pfeiler G, Gneist M, Wrba F, de Santis M, Zeillinger R, Hudec M, Dittrich C. Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients. Acta Oncol. 2012; 50: 700-10. doi: 10.3109/0284186X.2010.549151.
151. Schneck H, Gierke B, Uppenkamp F, Behrens B, Niederacher D, Stoecklein NH, Templin MF, Pawlak M, Fehm T, Neubauer H, Disseminated Cancer Cell Network D. EpCAM-Independent Enrichment of Circulating Tumor Cells in Metastatic Breast Cancer. PLoS One. 2015; 10: e0144535. doi: 10.1371/journal.pone.0144535.
152. Kim MJ, Choi NY, Lee EK, Kang MS. Identification of novel markers that outperform EpCAM in quantifying circulating tumor cells. Cell Oncol (Dordr). 2014; 37: 235-43. doi: 10.1007/s13402-014-0178-4.
153. Chaves-Perez A, Mack B, Maetzel D, Kremling H, Eggert C, Harreus U, Gires O. EpCAM regulates cell cycle progression via control of cyclin D1 expression. Oncogene. 2013; 32: 641-50. doi: 10.1038/onc.2012.75.
154. Imrich S, Hachmeister M, Gires O. EpCAM and its potential role in tumor-initiating cells. Cell Adh Migr. 2012; 6: 30-8. doi: 18953 [pii]10.4161/cam.18953.
155. Maetzel D, Denzel S, Mack B, Canis M, Went P, Benk M, Kieu C, Papior P, Baeuerle PA, Munz M, Gires O. Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol. 2009; 11: 162-71. doi:
156. Maaser K, Borlak J. A genome-wide expression analysis identifies a network of EpCAM-induced cell cycle regulators. Br J Cancer. 2008; 99: 1635-43. doi:
157. Tsaktanis T, Kremling H, Pavsic M, von Stackelberg R, Mack B, Fukumori A, Steiner H, Vielmuth F, Spindler V, Huang Z, Jakubowski J, Stoecklein NH, Luxenburger E, et al. Cleavage and Cell Adhesion Properties of Human Epithelial Cell Adhesion Molecule hEpCAM. J Biol Chem. 2015 doi: 10.1074/jbc. M115.662700.
158. Gosens MJ, van Kempen LC, van de Velde CJ, van Krieken JH, Nagtegaal ID. Loss of membranous Ep-CAM in budding colorectal carcinoma cells. Mod Pathol. 2007; 20: 221-32. doi: 10.1038/modpathol.3800733.
159. Biddle A, Liang X, Gammon L, Fazil B, Harper LJ, Emich H, Costea DE, Mackenzie IC. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res. 2011; 71: 5317-26. doi: 0008-5472.CAN-11-1059 [pii]10.1158/0008-5472.CAN-11-1059.
160. Maghzal N, Vogt E, Reintsch W, Fraser JS, Fagotto F. The tumor-associated EpCAM regulates morphogenetic movements through intracellular signaling. J Cell Biol. 2010; 191: 645-59. doi: jcb.201004074 [pii]10.1083/jcb.201004074.
161. Maghzal N, Kayali HA, Rohani N, Kajava AV, Fagotto F. EpCAM controls actomyosin contractility and cell adhesion by direct inhibition of PKC. Dev Cell. 2013; 27: 263-77. doi: 10.1016/j.devcel.2013.10.003.
162. Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA, Cole DJ, Gillanders WE. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res. 2004; 64: 5818-24.
163. Sankpal NV, Willman MW, Fleming TP, Mayfield JD, Gillanders WE. Transcriptional Repression of Epithelial Cell Adhesion Molecule Contributes to p53 Control of Breast Cancer Invasion. Cancer Res. 2009.
164. Munz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene. 2004; 23: 5748-58.
165. Baeuerle PA, Gires O. EpCAM (CD326) finding its role in cancer. Br J Cancer. 2007; 96: 417-23.
166. Carpenter G, Red Brewer M. EpCAM: Another Surface-to-Nucleus Missile. Cancer Cell. 2009; 15: 165-6. doi: S1535-6108(09)00038-5 [pii]10.1016/j.ccr.2009.02.005.
167. Pickersgill H. Journey into the center of the cell. Science. 2009; 323.
168. Lu TY, Lu RM, Liao MY, Yu J, Chung CH, Kao CF, Wu HC. Epithelial cell adhesion molecule regulation is associated with the maintenance of the undifferentiated phenotype of human embryonic stem cells. J Biol Chem. 2010; 285: 8719-32. doi: M109.077081 [pii]10.1074/jbc. M109.077081.
169. Huang HP, Chen PH, Yu CY, Chuang CY, Stone L, Hsiao WC, Li CL, Tsai SC, Chen KY, Chen HF, Ho HN, Kuo HC. Epithelial cell adhesion molecule (EpCAM) complex proteins promote transcription factor-mediated pluripotency reprogramming. J Biol Chem. 2011; 286: 33520-32. doi: M111.256164 [pii]10.1074/jbc. M111.256164.
170. Gonzalez B, Denzel S, Mack B, Conrad M, Gires O. EpCAM Is Involved in Maintenance of the Murine Embryonic Stem Cell Phenotype. Stem Cells. 2009; 27: 1782-91. doi: 10.1002/stem.97.
171. Weller P, Nel I, Hassenkamp P, Gauler T, Schlueter A, Lang S, Dountsop P, Hoffmann AC, Lehnerdt G. Detection of circulating tumor cell subpopulations in patients with head and neck squamous cell carcinoma (HNSCC). PLoS One. 2014; 9: e113706. doi: 10.1371/journal.pone.0113706.
172. Coumans FA, van Dalum G, Beck M, Terstappen LW. Filtration parameters influencing circulating tumor cell enrichment from whole blood. PLoS One. 2013; 8: e61774. doi: 10.1371/journal.pone.0061774.
173. Ge F, Zhang H, Wang DD, Li L, Lin PP. Enhanced detection and comprehensive in situ phenotypic characterization of circulating and disseminated heteroploid epithelial and glioma tumor cells. Oncotarget. 2015; 6: 27049-64. doi: 10.18632/oncotarget.4819.
174. Jiang J, Wang DD, Yang M, Chen D, Pang L, Guo S, Cai J, Wery JP, Li L, Li HQ, Lin PP. Comprehensive characterization of chemotherapeutic efficacy on metastases in the established gastric neuroendocrine cancer patient derived xenograft model. Oncotarget. 2015; 6: 15639-51. doi: 10.18632/oncotarget.3712.
175. Li Y, Zhang X, Ge S, Gao J, Gong J, Lu M, Zhang Q, Cao Y, Wang DD, Lin PP, Shen L. Clinical significance of phenotyping and karyotyping of circulating tumor cells in patients with advanced gastric cancer. Oncotarget. 2014; 5: 6594-602. doi: 10.18632/oncotarget.2175.
176. Menard S, Pupa SM, Campiglio M, Tagliabue E. Biologic and therapeutic role of HER2 in cancer. Oncogene. 2003; 22: 6570-8.
177. Elster N, Collins DM, Toomey S, Crown J, Eustace AJ, Hennessy BT. HER2-family signalling mechanisms, clinical implications and targeting in breast cancer. Breast Cancer Res Treat. 2015; 149: 5-15. doi: 10.1007/s10549-014-3250-x.
178. Hudziak RM, Lewis GD, Shalaby MR, Eessalu TE, Aggarwal BB, Ullrich A, Shepard HM. Amplified expression of the HER2/ERBB2 oncogene induces resistance to tumor necrosis factor alpha in NIH 3T3 cells. Proc Natl Acad Sci U S A. 1988; 85: 5102-6.
179. Hudziak RM, Lewis GD, Winget M, Fendly BM, Shepard HM, Ullrich A. p185HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989; 9: 1165-72.
180. Sarup JC, Johnson RM, King KL, Fendly BM, Lipari MT, Napier MA, Ullrich A, Shepard HM. Characterization of an anti-p185HER2 monoclonal antibody that stimulates receptor function and inhibits tumor cell growth. Growth Regul. 1991; 1: 72-82.
181. Lee J, Dull TJ, Lax I, Schlessinger J, Ullrich A. HER2 cytoplasmic domain generates normal mitogenic and transforming signals in a chimeric receptor. EMBO J. 1989; 8: 167-73. doi:
182. Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med. 2005; 353: 1734-6. doi: 10.1056/NEJMe058196.
183. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Jr., Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005; 353: 1673-84. doi: 10.1056/NEJMoa052122.
184. Shepard HM, Lewis GD, Sarup JC, Fendly BM, Maneval D, Mordenti J, Figari I, Kotts CE, Palladino MA, Jr., Ullrich A, et al. Monoclonal antibody therapy of human cancer: taking the HER2 protooncogene to the clinic. J Clin Immunol. 1991; 11: 117-27.
185. Liu Y, Liu Q, Wang T, Bian L, Zhang S, Hu H, Li S, Hu Z, Wu S, Liu B, Jiang Z. Circulating tumor cells in HER2-positive metastatic breast cancer patients: a valuable prognostic and predictive biomarker. BMC Cancer. 2013; 13: 202. doi: 10.1186/1471-2407-13-202.
186. Riethdorf S, Muller V, Zhang L, Rau T, Loibl S, Komor M, Roller M, Huober J, Fehm T, Schrader I, Hilfrich J, Holms F, Tesch H, et al. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res. 2010; 16: 2634-45. doi: 10.1158/1078-0432.CCR-09-2042.
187. Klijn JG, Berns PM, Schmitz PI, Foekens JA. The clinical significance of epidermal growth factor receptor (EGF-R) in human breast cancer: a review on 5232 patients. Endocr Rev. 1992; 13: 3-17. doi: 10.1210/edrv-13-1-3.
188. Di Fiore PP, Pierce JH, Fleming TP, Hazan R, Ullrich A, King CR, Schlessinger J, Aaronson SA. Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell. 1987; 51: 1063-70.
189. Fischer OM, Hart S, Gschwind A, Ullrich A. EGFR signal transactivation in cancer cells. Biochem Soc Trans. 2003; 31: 1203-8. doi: 10.1042/.
190. Yarden Y, Shilo BZ. SnapShot: EGFR signaling pathway. Cell. 2007; 131: 1018. doi: 10.1016/j.cell.2007.11.013.
191. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000; 19: 6550-65. doi: 10.1038/sj.onc.1204082.
192. Carpenter G, King L, Jr., Cohen S. Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro. Nature. 1978; 276: 409-10. doi:
193. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006; 7: 505-16. doi: 10.1038/nrm1962.
194. Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001; 37 Suppl 4: S3-8. doi:
195. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006; 366: 2-16. doi: 10.1016/j. gene.2005.10.018.
196. Bogdan S, Klambt C. Epidermal growth factor receptor signaling. Curr Biol. 2001; 11: R292-5.
197. Lo HW, Ali-Seyed M, Wu Y, Bartholomeusz G, Hsu SC, Hung MC. Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1. J Cell Biochem. 2006; 98: 1570-83. doi: 10.1002/jcb.20876.
198. Lo HW, Hsu SC, Hung MC. EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Res Treat. 2006; 95: 211-8. doi: 10.1007/s10549-005-9011-0.
199. Lo HW, Hung MC. Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. Br J Cancer. 2006; 94: 184-8. doi: 10.1038/sj.bjc.6602941.
200. Lin SY, Makino K, Xia W, Matin A, Wen Y, Kwong KY, Bourguignon L, Hung MC. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol. 2001; 3: 802-8. doi: 10.1038/ncb0901-802.
201. Liao HJ, Carpenter G. Regulated intramembrane cleavage of the EGF receptor. Traffic. 2012; 13: 1106-12. doi: 10.1111/j.1600-0854.2012.01371.x.
202. Perez-Torres M, Valle BL, Maihle NJ, Negron-Vega L, Nieves-Alicea R, Cora EM. Shedding of epidermal growth factor receptor is a regulated process that occurs with overexpression in malignant cells. Exp Cell Res. 2008; 314: 2907-18. doi: 10.1016/j.yexcr.2008.07.013.
203. Sanderson MP, Keller S, Alonso A, Riedle S, Dempsey PJ, Altevogt P. Generation of novel, secreted epidermal growth factor receptor (EGFR/ErbB1) isoforms via metalloprotease-dependent ectodomain shedding and exosome secretion. J Cell Biochem. 2008; 103: 1783-97. doi: 10.1002/jcb.21569.
204. Gasch C, Bauernhofer T, Pichler M, Langer-Freitag S, Reeh M, Seifert AM, Mauermann O, Izbicki JR, Pantel K, Riethdorf S. Heterogeneity of epidermal growth factor receptor status and mutations of KRAS/PIK3CA in circulating tumor cells of patients with colorectal cancer. Clin Chem. 2013; 59: 252-60. doi: 10.1373/clinchem.2012.188557.
205. Breitenbuecher F, Hoffarth S, Worm K, Cortes-Incio D, Gauler TC, Kohler J, Herold T, Schmid KW, Freitag L, Kasper S, Schuler M. Development of a highly sensitive and specific method for detection of circulating tumor cells harboring somatic mutations in non-small-cell lung cancer patients. PLoS One. 2014; 9: e85350. doi: 10.1371/journal. pone.0085350.
206. Kuboki Y, Matsusaka S, Minowa S, Shibata H, Suenaga M, Shinozaki E, Mizunuma N, Ueno M, Yamaguchi T, Hatake K. Circulating tumor cell (CTC) count and epithelial growth factor receptor expression on CTCs as biomarkers for cetuximab efficacy in advanced colorectal cancer. Anticancer Res. 2013; 33: 3905-10. doi:
207. Payne RE, Yague E, Slade MJ, Apostolopoulos C, Jiao LR, Ward B, Coombes RC, Stebbing J. Measurements of EGFR expression on circulating tumor cells are reproducible over time in metastatic breast cancer patients. Pharmacogenomics. 2009; 10: 51-7. doi: 10.2217/14622416.10.1.51.
208. Kalykaki A, Agelaki S, Kallergi G, Xyrafas A, Mavroudis D, Georgoulias V. Elimination of EGFR-expressing circulating tumor cells in patients with metastatic breast cancer treated with gefitinib. Cancer Chemother Pharmacol. 2014; 73: 685-93. doi: 10.1007/s00280-014-2387-y.
209. Serrano MJ, Ortega FG, Alvarez-Cubero MJ, Nadal R, Sanchez-Rovira P, Salido M, Rodriguez M, Garcia-Puche JL, Delgado-Rodriguez M, Sole F, Garcia MA, Peran M, Rosell R, et al. EMT and EGFR in CTCs cytokeratin negative non-metastatic breast cancer. Oncotarget. 2014; 5: 7486-97. doi: 10.18632/oncotarget.2217.
210. Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011; 3: 99ra86. doi: 10.1126/scitranslmed.3002442.
211. Herrlich P, Zoller M, Pals ST, Ponta H. CD44 splice variants: metastases meet lymphocytes. Immunol Today. 1993; 14: 395-9. doi: 10.1016/0167-5699(93)90141-7.
212. Koopman G, Griffioen AW, Ponta H, Herrlich P, van den Berg F, Manten-Horst E, Pals ST. CD44 splice variants; expression on lymphocytes and in neoplasia. Res Immunol. 1993; 144: 750-4; discussion 4-62.
213. Pals ST, Koopman G, Heider KH, Griffioen A, Adolf GR, Van den Berg F, Ponta H, Herrlich P, Horst E. CD44 splice variants: expression during lymphocyte activation and tumor progression. Behring Inst Mitt. 1993: 273-7.
214. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003; 4: 33-45.
215. Underhill C. CD44: the hyaluronan receptor. J Cell Sci. 1992; 103 (Pt 2): 293-8.
216. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990; 61: 1303-13.
217. Bourguignon LY, Spevak CC, Wong G, Xia W, Gilad E. Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker Nanog and the Production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J Biol Chem. 2009; 284: 26533-46. doi: M109.027466 [pii]10.1074/jbc. M109.027466.
218. Bourguignon LY, Wong G, Earle C, Krueger K, Spevak CC. Hyaluronan-CD44 Interaction Promotes c-Src-mediated Twist Signaling, MicroRNA-10b Expression, and RhoA/RhoC Up-regulation, Leading to Rho-kinase-associated Cytoskeleton Activation and Breast Tumor Cell Invasion. J Biol Chem. 2010; 285: 36721-35. doi: M110.162305 [pii]10.1074/jbc. M110.162305.
219. Bourguignon LY, Xia W, Wong G. Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates betacatenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells. J Biol Chem. 2009; 284: 2657-71. doi: M806708200 [pii]10.1074/jbc. M806708200.
220. Marhaba R, Bourouba M, Zoller M. CD44v6 promotes proliferation by persisting activation of MAP kinases. Cell Signal. 2005; 17: 961-73.
221. Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 1991; 65: 13-24. doi:
222. Okamoto I, Kawano Y, Tsuiki H, Sasaki J, Nakao M, Matsumoto M, Suga M, Ando M, Nakajima M, Saya H. CD44 cleavage induced by a membrane-associated metalloprotease plays a critical role in tumor cell migration. Oncogene. 1999; 18: 1435-46.
223. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A. 2007; 104: 10158-63.
224. Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, Li J. Cancer stem/progenitor cells are highly enriched in CD133+CD44+ population in hepatocellular carcinoma. Int J Cancer. 2010; 126: 2067-78. doi: 10.1002/ijc.24868.
225. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A. 2007; 104: 973-8.
226. Leung EL, Fiscus RR, Tung JW, Tin VP, Cheng LC, Sihoe AD, Fink LM, Ma Y, Wong MP. Non-small cell lung cancer cells expressing CD44 are enriched for stem celllike properties. PLoS One. 2010; 5: e14062. doi: 10.1371/journal.pone.0014062.
227. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identification of pancreatic cancer stem cells. Cancer Res. 2007; 67: 1030-7.
228. Naor D, Wallach-Dayan SB, Zahalka MA, Sionov RV. Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin Cancer Biol. 2008; 18: 260-7.
229. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006; 12: 1167-74. doi: nm1483 [pii]10.1038/nm1483.
230. Jacobs PP, Sackstein R. CD44 and HCELL: preventing hematogenous metastasis at step 1. FEBS Lett. 2011; 585: 3148-58. doi: 10.1016/j.febslet.2011.07.039.
231. Burdick MM, Chu JT, Godar S, Sackstein R. HCELL is the major E-and L-selectin ligand expressed on LS174T colon carcinoma cells. J Biol Chem. 2006; 281: 13899-905. doi: 10.1074/jbc. M513617200.
232. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012; 109: 6662-7. doi: 10.1073/pnas.1121623109.
233. Baccelli I, Stenzinger A, Vogel V, Pfitzner BM, Klein C, Wallwiener M, ScharpffM, Saini M, Holland-Letz T, Sinn HP, Schneeweiss A, Denkert C, Weichert W, et al. Co-expression of MET and CD47 is a novel prognosticator for survival of luminal breast cancer patients. Oncotarget. 2014; 5: 8147-60. doi: 10.18632/oncotarget.2385.
234. Yap TA, Olmos D, Brunetto AT, Tunariu N, Barriuso J, Riisnaes R, Pope L, Clark J, Futreal A, Germuska M, Collins D, deSouza NM, Leach MO, et al. Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. J Clin Oncol. 2011; 29: 1271-9. doi: 10.1200/JCO.2010.31.0367.
235. Yap TA, Sandhu SK, Alam SM, de Bono JS. HGF/c-MET targeted therapeutics: novel strategies for cancer medicine. Curr Drug Targets. 2011; 12: 2045-58.
236. Steinert G, Scholch S, Niemietz T, Iwata N, Garcia SA, Behrens B, Voigt A, Kloor M, Benner A, Bork U, Rahbari NN, Buchler MW, Stoecklein NH, et al. Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Res. 2014; 74: 1694-704. doi: 10.1158/0008-5472.CAN-13-1885.
237. van Noort V, Scholch S, Iskar M, Zeller G, Ostertag K, Schweitzer C, Werner K, Weitz J, Koch M, Bork P. Novel drug candidates for the treatment of metastatic colorectal cancer through global inverse gene-expression profiling. Cancer Res. 2014; 74: 5690-9. doi: 10.1158/0008-5472. CAN-13-3540.
238. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest. 2015; 125: 3384-91. doi: 10.1172/JCI80011.
239. Sheppard KA, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, Qiu Y, Jussif JM, Carter LL, Wood CR, Chaudhary D. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004; 574: 37-41. doi: 10.1016/j.febslet.2004.07.083.
240. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000; 192: 1027-34.
241. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002; 99: 12293-7. doi: 10.1073/pnas.192461099.
242. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002; 8: 793-800. doi: 10.1038/nm730.
243. Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol. 2000; 74: 181-273. doi:
244. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007; 104: 3360-5. doi: 10.1073/pnas.0611533104.
245. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, Tamada K, Chen L. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005; 65: 1089-96. doi:
246. Wu P, Wu D, Li L, Chai Y, Huang J. PD-L1 and Survival in Solid Tumors: A Meta-Analysis. PLoS One. 2015; 10: e0131403. doi: 10.1371/journal.pone.0131403.
247. Hamanishi J, Mandai M, Matsumura N, Abiko K, Baba T, Konishi I. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. Int J Clin Oncol. 2016; 21: 462-73. doi: 10.1007/s10147-016-0959-z.
248. Mandai M, Hamanishi J, Abiko K, Matsumura N, Baba T, Konishi I. Anti-PD-L1/PD-1 immune therapies in ovarian cancer: basic mechanism and future clinical application. Int J Clin Oncol. 2016; 21: 456-61. doi: 10.1007/s10147-016-0968-y.
249. Swaika A, Hammond WA, Joseph RW. Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy. Mol Immunol. 2015; 67: 4-17. doi: 10.1016/j. molimm.2015.02.009.
250. Mazel M, Jacot W, Pantel K, Bartkowiak K, Topart D, Cayrefourcq L, Rossille D, Maudelonde T, Fest T, Alix-Panabieres C. Frequent expression of PD-L1 on circulating breast cancer cells. Mol Oncol. 2015; 9: 1773-82. doi: 10.1016/j.molonc.2015.05.009.
251. David R. PD-L1 expression by circulating breast cancer cells. Lancet Oncol. 2015; 16: e321. doi: 10.1016/S1470-2045(15)00074-1.
252. Oliveira-Costa JP, de Carvalho AF, da Silveira da GG, Amaya P, Wu Y, Park KJ, Gigliola MP, Lustberg M, Buim ME, Ferreira EN, Kowalski LP, Chalmers JJ, Soares FA, et al. Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells. Oncotarget. 2015; 6: 20902-20. doi: 10.18632/oncotarget.3939.
253. Satelli A, Batth IS, Brownlee Z, Rojas C, Meng QH, Kopetz S, Li S. Potential role of nuclear PD-L1 expression in cell-surface vimentin positive circulating tumor cells as a prognostic marker in cancer patients. Sci Rep. 2016; 6:28910 doi: 10.1038/srep28910.
254. Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, Baba T, Yamaguchi K, Murakami R, Yamamoto A, Kharma B, Kosaka K, Konishi I. PD-L1 on tumor cells is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL dysfunction. Clin Cancer Res. 2013; 19: 1363-74. doi: 10.1158/1078-0432.CCR-12-2199.
255. Mocellin S, Hoon D, Ambrosi A, Nitti D, Rossi CR. The prognostic value of circulating tumor cells in patients with melanoma: a systematic review and meta-analysis. Clin Cancer Res. 2006; 12: 4605-13. doi: 10.1158/1078-0432. CCR-06-0823.
256. Khan MS, Kirkwood A, Tsigani T, Garcia-Hernandez J, Hartley JA, Caplin ME, Meyer T. Circulating tumor cells as prognostic markers in neuroendocrine tumors. J Clin Oncol. 2013; 31: 365-72. doi: 10.1200/JCO.2012.44.2905.
257. Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, Greystoke A, Ward TH, Ferraldeschi R, Hughes A, Clack G, Ranson M, Dive C, Blackhall FH. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol. 2011; 29: 1556-63. doi: 10.1200/JCO.2010.28.7045.
258. Han L, Chen W, Zhao Q. Prognostic value of circulating tumor cells in patients with pancreatic cancer: a metaanalysis. Tumour Biol. 2014; 35: 2473-80. doi: 10.1007/s13277-013-1327-5.
259. Wu XL, Tu Q, Faure G, Gallet P, Kohler C, Bittencourt Mde C. Diagnostic and Prognostic Value of Circulating Tumor Cells in Head and Neck Squamous Cell Carcinoma: a systematic review and meta-analysis. Sci Rep. 2016; 6:20210 doi: 10.1038/srep20210.
260. Hyun KA, Goo KB, Han H, Sohn J, Choi W, Kim SI, Jung HI, Kim YS. Epithelial-to-mesenchymal transition leads to loss of EpCAM and different physical properties in circulating tumor cells from metastatic breast cancer. Oncotarget. 2016. doi: 10.18632/oncotarget.8250.
261. Theodoropoulos PA, Polioudaki H, Agelaki S, Kallergi G, Saridaki Z, Mavroudis D, Georgoulias V. Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer. Cancer Lett. 2010; 288: 99-106. doi: 10.1016/j.canlet.2009.06.027.
262. Balasubramanian P, Lang JC, Jatana KR, Miller B, Ozer E, Old M, Schuller DE, Agrawal A, Teknos TN, Summers TA, Jr., Lustberg MB, Zborowski M, Chalmers JJ. Multiparameter analysis, including EMT markers, on negatively enriched blood samples from patients with squamous cell carcinoma of the head and neck. PLoS One. 2012; 7: e42048. doi: 10.1371/journal.pone.0042048.
263. Giordano A, Gao H, Anfossi S, Cohen E, Mego M, Lee BN, Tin S, De Laurentiis M, Parker CA, Alvarez RH, Valero V, Ueno NT, De Placido S, et al. Epithelial-mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Mol Cancer Ther. 2012; 11: 2526-34. doi: 10.1158/1535-7163.MCT-12-0460.
264. Alonso-Alconada L, Muinelo-Romay L, Madissoo K, Diaz-Lopez A, Krakstad C, Trovik J, Wik E, Hapangama D, Coenegrachts L, Cano A, Gil-Moreno A, Chiva L, Cueva J, et al. Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer. Mol Cancer. 2014; 13: 223. doi: 10.1186/1476-4598-13-223.
265. Toyoshima K, Hayashi A, Kashiwagi M, Hayashi N, Iwatsuki M, Ishimoto T, Baba Y, Baba H, Ohta Y. Analysis of circulating tumor cells derived from advanced gastric cancer. Int J Cancer. 2015; 137: 991-8. doi: 10.1002/ijc.29455.
266. 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. doi: 10.1186/bcr2333.
267. Malara N, Trunzo V, Foresta U, Amodio N, De Vitis S, Roveda L, Fava M, Coluccio M, Macri R, Di Vito A, Costa N, Mignogna C, Britti D, et al. Ex-vivo characterization of circulating colon cancer cells distinguished in stem and differentiated subset provides useful biomarker for personalized metastatic risk assessment. J Transl Med. 2016; 14: 133. doi: 10.1186/s12967-016-0876-y.
268. Nel I, Gauler TC, Bublitz K, Lazaridis L, Goergens A, Giebel B, Schuler M, Hoffmann AC. Circulating Tumor Cell Composition in Renal Cell Carcinoma. PLoS One. 2016; 11: e0153018. doi: 10.1371/journal.pone.0153018.
269. Shimada R, Iinuma H, Akahane T, Horiuchi A, Watanabe T. Prognostic significance of CTCs and CSCs of tumor drainage vein blood in Dukes' stage B and C colorectal cancer patients. Oncol Rep. 2012; 27: 947-53. doi: 10.3892/or.2012.1649.
270. Nel I, Jehn U, Gauler T, Hoffmann AC. Individual profiling of circulating tumor cell composition in patients with nonsmall cell lung cancer receiving platinum based treatment. Transl Lung Cancer Res. 2014; 3: 100-6. doi: 10.3978/j. issn.2218-6751.2014.03.05.
271. Sun YF, Xu Y, Yang XR, Guo W, Zhang X, Qiu SJ, Shi RY, Hu B, Zhou J, Fan J. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology. 2013; 57: 1458-68. doi: 10.1002/hep.26151.
272. Nadal R, Ortega FG, Salido M, Lorente JA, Rodriguez-Rivera M, Delgado-Rodriguez M, Macia M, Fernandez A, Corominas JM, Garcia-Puche JL, Sanchez-Rovira P, Sole F, Serrano MJ. CD133 expression in circulating tumor cells from breast cancer patients: potential role in resistance to chemotherapy. Int J Cancer. 2013; 133: 2398-407. doi: 10.1002/ijc.28263.
273. Alix-Panabieres C. EPISPOT assay: detection of viable DTCs/CTCs in solid tumor patients. Recent Results Cancer Res. 2012; 195: 69-76. doi: 10.1007/978-3-642-28160-0_6.
274. Kolostova K, Pinkas M, Jakabova A, Pospisilova E, Svobodova P, Spicka J, Cegan M, Matkowski R, Bobek V. Molecular characterization of circulating tumor cells in ovarian cancer. Am J Cancer Res. 2016; 6: 973-80. doi:
275. Kubisch I, de Albuquerque A, Schuppan D, Kaul S, Schaich M, Stolzel U. Prognostic Role of a Multimarker Analysis of Circulating Tumor Cells in Advanced Gastric and Gastroesophageal Adenocarcinomas. Oncology. 2015; 89: 294-303. doi: 10.1159/000437373.
276. de Albuquerque A, Kaul S, Breier G, Krabisch P, Fersis N. Multimarker Analysis of Circulating Tumor Cells in Peripheral Blood of Metastatic Breast Cancer Patients: A Step Forward in Personalized Medicine. Breast Care (Basel). 2012; 7: 7-12. doi: 10.1159/000336548.
277. Zhang T, Boominathan R, Foulk B, Rao C, Kemeny G, Strickler JH, Abbruzzese JL, Harrison MR, Hsu DS, Healy P, Li J, Pi C, Prendergast KM, et al. Development of a novel c-MET based CTC detection platform. Mol Cancer Res. 2016. doi: 10.1158/1541-7786.MCR-16-0011.
278. Lu Y, Liang H, Yu T, Xie J, Chen S, Dong H, Sinko PJ, Lian S, Xu J, Wang J, Yu S, Shao J, Yuan B, et al. Isolation and characterization of living circulating tumor cells in patients by immunomagnetic negative enrichment coupled with flow cytometry. Cancer. 2015; 121: 3036-45. doi: 10.1002/cncr.29444.
279. Aktas B, Kasimir-Bauer S, Heubner M, Kimmig R, Wimberger P. Molecular profiling and prognostic relevance of circulating tumor cells in the blood of ovarian cancer patients at primary diagnosis and after platinum-based chemotherapy. Int J Gynecol Cancer. 2011; 21: 822-30. doi: 10.1097/IGC.0b013e318216cb91.
280. Pestrin M, Bessi S, Puglisi F, Minisini AM, Masci G, Battelli N, Ravaioli A, Gianni L, Di Marsico R, Tondini C, Gori S, Coombes CR, Stebbing J, et al. Final results of a multicenter phase II clinical trial evaluating the activity of single-agent lapatinib in patients with HER2-negative metastatic breast cancer and HER2-positive circulating tumor cells. A proof-of-concept study. Breast Cancer Res Treat. 2012; 134: 283-9. doi: 10.1007/s10549-012-2045-1.
281. Zhang L, Ridgway LD, Wetzel MD, Ngo J, Yin W, Kumar D, Goodman JC, Groves MD, Marchetti D. The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl Med. 2013; 5: 180ra48. doi: 10.1126/scitranslmed.3005109.
282. Lankiewicz S, Rother E, Zimmermann S, Hollmann C, Korangy F, Greten TF. Tumour-associated transcripts and EGFR deletion variants in colorectal cancer in primary tumour, metastases and circulating tumour cells. Cell Oncol. 2008; 30: 463-71.
283. Kolostova K, Matkowski R, Gurlich R, Grabowski K, Soter K, Lischke R, Schutzner J, Bobek V. Detection and cultivation of circulating tumor cells in gastric cancer. Cytotechnology. 2015. doi: 10.1007/s10616-015-9866-9.
284. Grisanti S, Almici C, Consoli F, Buglione M, Verardi R, Bolzoni-Villaret A, Bianchetti A, Ciccarese C, Mangoni M, Ferrari L, Biti G, Marini M, Ferrari VD, et al. Circulating tumor cells in patients with recurrent or metastatic head and neck carcinoma: prognostic and predictive significance. PLoS One. 2014; 9: e103918. doi: 10.1371/journal. pone.0103918.
285. Shaffer DR, Leversha MA, Danila DC, Lin O, Gonzalez-Espinoza R, Gu B, Anand A, Smith K, Maslak P, Doyle GV, Terstappen LW, Lilja H, Heller G, et al. Circulating tumor cell analysis in patients with progressive castrationresistant prostate cancer. Clin Cancer Res. 2007; 13: 2023-9. doi: 10.1158/1078-0432.CCR-06-2701.
286. Sundaresan TK, Sequist LV, Heymach JV, Riely GJ, Janne PA, Koch WH, Sullivan JP, Fox DB, Maher R, Muzikansky A, Webb A, Tran HT, Giri U, et al. Detection of T790M, the Acquired Resistance EGFR Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses. Clin Cancer Res. 2016; 22: 1103-10. doi: 10.1158/1078-0432.CCR-15-1031.
287. Stebbing J, Payne R, Reise J, Frampton AE, Avery M, Woodley L, Di Leo A, Pestrin M, Krell J, Coombes RC. The efficacy of lapatinib in metastatic breast cancer with HER2 non-amplified primary tumors and EGFR positive circulating tumor cells: a proof-of-concept study. PLoS One. 2013; 8: e62543. doi: 10.1371/journal.pone.0062543.
288. Theodoro TR, de Matos LL, Sant Anna AV, Fonseca FL, Semedo P, Martins LC, Nader HB, Del Giglio A, da Silva Pinhal MA. Heparanase expression in circulating lymphocytes of breast cancer patients depends on the presence of the primary tumor and/or systemic metastasis. Neoplasia. 2007; 9: 504-10.
289. Scher HI, Lu D, Schreiber NA, Louw J, Graf RP, Vargas HA, Johnson A, Jendrisak A, Bambury R, Danila D, McLaughlin B, Wahl J, Greene SB, et al. Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer. JAMA Oncol. 2016. doi: 10.1001/jamaoncol.2016.1828.
290. Goldkorn A, Ely B, Tangen CM, Tai YC, Xu T, Li H, Twardowski P, Veldhuizen PJ, Agarwal N, Carducci MA, Monk JP, 3rd, Garzotto M, Mack PC, et al. Circulating tumor cell telomerase activity as a prognostic marker for overall survival in SWOG 0421: a phase III metastatic castration resistant prostate cancer trial. Int J Cancer. 2015; 136: 1856-62. doi: 10.1002/ijc.29212.
291. Ma Y, Hao S, Wang S, Zhao Y, Lim B, Lei M, Spector DJ, El-Deiry WS, Zheng SY, Zhu J. A Combinatory Strategy for Detection of Live CTCs Using Microfiltration and a New Telomerase-Selective Adenovirus. Mol Cancer Ther. 2015; 14: 835-43. doi: 10.1158/1535-7163.MCT-14-0693.
292. Yabusaki M, Sato J, Kohyama A, Kojima T, Nobuoka D, Yoshikawa T, Sawada Y, Murakami K, Gohda K, Okegawa T, Nakamura M, Takamatsu K, Ito M, et al. Detection and preliminary evaluation of circulating tumor cells in the peripheral blood of patients with eight types of cancer using a telomerase-specific adenovirus. Oncol Rep. 2014; 32: 1772-8. doi: 10.3892/or.2014.3436.
293. Lindsay CR, Le Moulec S, Billiot F, Loriot Y, Ngo-Camus M, Vielh P, Fizazi K, Massard C, Farace F. Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer. BMC Cancer. 2016; 16:168. doi: 10.1186/s12885-016-2192-6.
294. Wang HY, Ahn S, Kim S, Park S, Jung D, Park S, Han H, Sohn J, Kim S, Lee H. Detection of circulating tumor cell-specific markers in breast cancer patients using the quantitative RT-PCR assay. Int J Clin Oncol. 2015; 20: 878-90. doi: 10.1007/s10147-015-0798-3.
295. Paoletti C, Muniz MC, Thomas DG, Griffith KA, Kidwell KM, Tokudome N, Brown ME, Aung K, Miller MC, Blossom DL, Schott AF, Henry NL, Rae JM, et al. Development of circulating tumor cell-endocrine therapy index in patients with hormone receptor-positive breast cancer. Clin Cancer Res. 2015; 21: 2487-98. doi: 10.1158/1078-0432.CCR-14-1913.
296. Kallergi G, Konstantinidis G, Markomanolaki H, Papadaki MA, Mavroudis D, Stournaras C, Georgoulias V, Agelaki S. Apoptotic circulating tumor cells in early and metastatic breast cancer patients. Mol Cancer Ther. 2013; 12: 1886-95. doi: 10.1158/1535-7163.MCT-12-1167.
297. Vishnoi M, Peddibhotla S, Yin W, A TS, George GC, Hong DS, Marchetti D. The isolation and characterization of CTC subsets related to breast cancer dormancy. Sci Rep. 2015; 5:17533 doi: 10.1038/srep17533.
298. Meng S, Tripathy D, Shete S, Ashfaq R, Saboorian H, Haley B, Frenkel E, Euhus D, Leitch M, Osborne C, Clifford E, Perkins S, Beitsch P, et al. uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues. Proc Natl Acad Sci U S A. 2006; 103: 17361-5. doi: 10.1073/pnas.0608113103.
299. Balic M, Lin H, Young L, Hawes D, Giuliano A, McNamara G, Datar RH, Cote RJ. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res. 2006; 12: 5615-21. doi: 10.1158/1078-0432.CCR-06-0169.
300. Wu P, Tang RN, Zou JH, Wang FC. The prognostic role of disseminated tumor cells detected in peripheral blood and bone marrow of colorectal cancer. Hepatogastroenterology. 2012; 59: 2164-7. doi: 10.5754/hge12539.
301. Tjensvoll K, Oltedal S, Heikkila R, Kvaloy JT, Gilje B, Reuben JM, Smaaland R, Nordgard O. Persistent tumor cells in bone marrow of non-metastatic breast cancer patients after primary surgery are associated with inferior outcome. BMC Cancer. 2012; 12: 190. doi: 10.1186/1471-2407-12-190.
302. Gilje B, Nordgard O, Tjensvoll K, Borgen E, Synnestvedt M, Smaaland R, Naume B. Comparison of molecular and immunocytochemical methods for detection of disseminated tumor cells in bone marrow from early breast cancer patients. BMC Cancer. 2014; 14: 514. doi: 10.1186/1471-2407-14-514.
303. Thomas C, Wiesner C, Melchior SW, Schmidt F, Gillitzer R, ThuroffJW, Pfitzenmaier J. Urokinase-plasminogenactivator receptor expression in disseminated tumour cells in the bone marrow and peripheral blood of patients with clinically localized prostate cancer. BJU Int. 2009; 104: 29-34. doi: 10.1111/j.1464-410X.2008.08298.x.
304. Schindlbeck C, Jeschke U, Schulze S, Karsten U, Janni W, Rack B, Sommer H, Friese K. Characterisation of disseminated tumor cells in the bone marrow of breast cancer patients by the Thomsen-Friedenreich tumor antigen. Histochem Cell Biol. 2005; 123: 631-7. doi: 10.1007/s00418-005-0781-6.
305. Schindlbeck C, Hantschmann P, Zerzer M, Jahns B, Rjosk D, Janni W, Rack B, Sommer H, Friese K. Prognostic impact of KI67, p53, human epithelial growth factor receptor 2, topoisomerase IIalpha, epidermal growth factor receptor, and nm23 expression of ovarian carcinomas and disseminated tumor cells in the bone marrow. Int J Gynecol Cancer. 2007; 17: 1047-55. doi: 10.1111/j.1525-1438.2007.00920.x.
306. Schindlbeck C, Kampik T, Janni W, Rack B, Jeschke U, Krajewski S, Sommer H, Friese K. Prognostic relevance of disseminated tumor cells in the bone marrow and biological factors of 265 primary breast carcinomas. Breast Cancer Res. 2005; 7: R1174-85. doi: 10.1186/bcr1360.
307. Hartkopf AD, Banys M, Meier-Stiegen F, Hahn M, Rohm C, Hoffmann J, Helms G, Taran FA, Wallwiener M, Walter C, Neubauer H, Wallwiener D, Fehm T. The HER2 status of disseminated tumor cells in the bone marrow of early breast cancer patients is independent from primary tumor and predicts higher risk of relapse. Breast Cancer Res Treat. 2013; 138: 509-17. doi: 10.1007/s10549-013-2470-9.
308. Braun S, Schlimok G, Heumos I, Schaller G, Riethdorf L, Riethmuller G, Pantel K. ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I-III breast cancer patients. Cancer Res. 2001; 61: 1890-5.
309. Jager BA, Finkenzeller C, Bock C, Majunke L, Jueckstock JK, Andergassen U, Neugebauer JK, Pestka A, Friedl TW, Jeschke U, Janni W, Doisneau-Sixou SF, Rack BK. Estrogen Receptor and HER2 Status on Disseminated Tumor Cells and Primary Tumor in Patients with Early Breast Cancer. Transl Oncol. 2015; 8: 509-16. doi: 10.1016/j.tranon.2015.11.009.
310. Zhang J, Shen KW, Liu G, Zhou J, Shen Q, Shen ZZ, Shao ZM. Antigenic profiles of disseminated breast tumour cells and microenvironment in bone marrow. Eur J Surg Oncol. 2003; 29: 121-6.
311. Pantel K, Schlimok G, Braun S, Kutter D, Lindemann F, Schaller G, Funke I, Izbicki JR, Riethmuller G. Differential expression of proliferation-associated molecules in individual micrometastatic carcinoma cells. J Natl Cancer Inst. 1993; 85: 1419-24.
312. Zieglschmid V, Hollmann C, Mannel J, Albert W, Jaeschke-Melli S, Eckstein B, Hillemann T, Greten TF, Gross E, Bocher O. Tumor-associated gene expression in disseminated tumor cells correlates with disease progression and tumor stage in colorectal cancer. Anticancer Res. 2007; 27: 1823-32.
313. Silva HA, Abraul E, Raimundo D, Dias MF, Marques C, Guerra C, de Oliveira CF, Regateiro FJ. Molecular detection of EGFRvIII-positive cells in the peripheral blood of breast cancer patients. Eur J Cancer. 2006; 42: 2617-22. doi: 10.1016/j.ejca.2006.03.033.
314. Chery L, Lam HM, Coleman I, Lakely B, Coleman R, Larson S, Aguirre-Ghiso JA, Xia J, Gulati R, Nelson PS, Montgomery B, Lange P, Snyder LA, et al. Characterization of single disseminated prostate cancer cells reveals tumor cell heterogeneity and identifies dormancy associated pathways. Oncotarget. 2014; 5: 9939-51. doi: 10.18632/oncotarget.2480.
315. Dardaei L, Shahsavani R, Ghavamzadeh A, Behmanesh M, Aslankoohi E, Alimoghaddam K, Ghaffari SH. The detection of disseminated tumor cells in bone marrow and peripheral blood of gastric cancer patients by multimarker (CEA, CK20, TFF1 and MUC2) quantitative real-time PCR. Clin Biochem. 2011; 44: 325-30. doi: 10.1016/j. clinbiochem.2010.11.005.
316. Berois N, Varangot M, Aizen B, Estrugo R, Zarantonelli L, Fernandez P, Krygier G, Simonet F, Barrios E, Muse I, Osinaga E. Molecular detection of cancer cells in bone marrow and peripheral blood of patients with operable breast cancer. Comparison of CK19, MUC1 and CEA using RT-PCR. Eur J Cancer. 2000; 36: 717-23.
317. Rud AK, Boye K, Fodstad O, Juell S, Jorgensen LH, Solberg S, Helland A, Brustugun OT, Maelandsmo GM. Detection of disseminated tumor cells in lymph nodes from patients with early stage non-small cell lung cancer. Diagn Pathol. 2016; 11: 50. doi: 10.1186/s13000-016-0504-4.
318. Dhayat S, Sorescu S, Vallbohmer D, Kraus S, Baldus SE, Rehders A, Kropil F, Krieg A, Knoefel WT, Stoecklein NH. Prognostic Significance of EpCAM-Positive Disseminated Tumor Cells in Rectal Cancer Patients With Stage I Disease. Am J Surg Pathol. 2012; 36: 1809-16. doi: 10.1097/PAS.0b013e318265288c.
319. Wimberger P, Heubner M, Otterbach F, Fehm T, Kimmig R, Kasimir-Bauer S. Influence of platinum-based chemotherapy on disseminated tumor cells in blood and bone marrow of patients with ovarian cancer. Gynecol Oncol. 2007; 107: 331-8. doi: 10.1016/j.ygyno.2007.07.073.
320. Braun S, Hepp F, Kentenich CR, Janni W, Pantel K, Riethmuller G, Willgeroth F, Sommer HL. Monoclonal antibody therapy with edrecolomab in breast cancer patients: monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clin Cancer Res. 1999; 5: 3999-4004.
321. Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, Pierga JY, Marth C, Oruzio D, et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005; 353: 793-802.