Biology, detection, and clinical implications of circulating tumor cells

Simon A Joosse, Tobias M Gorges, Klaus Pantel, Simon A Joosse, Tobias M Gorges, Klaus Pantel

Abstract

Cancer metastasis is the main cause of cancer-related death, and dissemination of tumor cells through the blood circulation is an important intermediate step that also exemplifies the switch from localized to systemic disease. Early detection and characterization of circulating tumor cells (CTCs) is therefore important as a general strategy to monitor and prevent the development of overt metastatic disease. Furthermore, sequential analysis of CTCs can provide clinically relevant information on the effectiveness and progression of systemic therapies (e.g., chemo-, hormonal, or targeted therapies with antibodies or small inhibitors). Although many advances have been made regarding the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this important diagnostic approach. In this review, we discuss the biology of tumor cell dissemination, technical advances, as well as the challenges and potential clinical implications of CTC detection and characterization.

Keywords: Disseminating tumor cells (DTC); EMT; metastasis; tumor cell dormancy; tumor cell plasticity.

© 2014 The Authors. Published under the terms of the CC BY 4.0 license.

Figures

Figure 1. Metastatic cascade
Figure 1. Metastatic cascade
Tumor cells may enter the bloodstream passively or actively via biological events such as EMT or centrosomes amplification. Disseminating tumor cells must overcome several hurdles including anoikis, shear stress in the bloodstream, and the immune system in-and outside of the blood circulation. Once at a distant site, tumor cells may extravasate, undergo MET, and grow locally to become a metastasis or remain in dormancy.
Figure 2. CTC enrichment and identification
Figure 2. CTC enrichment and identification
Enrichment strategies for CTCs can be separated into label-dependent and label-independent techniques. Among label-dependent techniques, immunomagnetic-based assays targeting the EpCAM protein are the most commonly applied. Label-independent enrichment methods include size-based or density-based approaches. Additionally, negative depletion or the invasive capacity of tumor cells can be used. A combination of different enrichment strategies is also practicable. Captured tumor cells are ready for molecular characterization by immunocytochemistry (ICC) using antibodies for tumor-specific markers or by PCR approaches targeting tumor-specific mRNA or DNA sequences. Another possibility is to detect viable cells by protein secretion (EPISPOT). Additionally, fluorescence in situ hybridization (FISH) can be used for the detection of tumor-specific gene aberrations.

References

    1. Aceto N, Bardia A, Miyamoto DT, Donaldson MC, Wittner BS, Spencer JA, Yu M, Pely A, Engstrom A, Zhu H, et al., editors. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell. 2014;158:1110–1122.
    1. Alix-Panabieres C, Vendrell JP, Pelle O, Rebillard X, Riethdorf S, Muller V, Fabbro M, Pantel K. Detection and characterization of putative metastatic precursor cells in cancer patients. Clin Chem. 2007;53:537–539.
    1. Alix-Panabieres C. EPISPOT assay: detection of viable DTCs/CTCs in solid tumor patients. Recent Results Cancer Res. 2012;195:69–76.
    1. Alix-Panabieres C, Schwarzenbach H, Pantel K. Circulating tumor cells and circulating tumor DNA. Annu Rev Med. 2012;63:199–215.
    1. Alix-Panabieres C, Pantel K. Circulating tumor cells: liquid biopsy of cancer. Clin Chem. 2013;59:110–118.
    1. Alix-Panabieres C, Pantel K. Technologies for detection of circulating tumor cells: facts and vision. Lab Chip. 2014;14:57–62.
    1. Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD, Herold CI, Marcom PK, George DJ, Garcia-Blanco MA. Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res. 2011;9:997–1007.
    1. Babayan A, Hannemann J, Spotter J, Muller V, Pantel K, Joosse SA. Heterogeneity of estrogen receptor expression in circulating tumor cells from metastatic breast cancer patients. PLoS One. 2013;8:e75038.
    1. Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bauerle T, Wallwiener M, et al., editors. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol. 2013;31:539–544.
    1. Bartkowiak K, Wieczorek M, Buck F, Harder S, Moldenhauer J, Effenberger KE, Pantel K, Peter-Katalinic J, Brandt BH. Two-dimensional differential gel electrophoresis of a cell line derived from a breast cancer micrometastasis revealed a stem/progenitor cell protein profile. J Proteome Res. 2009;8:2004–2014.
    1. Bednarz-Knoll N, Alix-Panabieres C, Pantel K. Plasticity of disseminating cancer cells in patients with epithelial malignancies. Cancer Metastasis Rev. 2012;31:673–687.
    1. Bidard FC, Vincent-Salomon A, Gomme S, Nos C, de RY, Thiery JP, Sigal-Zafrani B, Mignot L, Sastre-Garau X, Pierga JY. Disseminated tumor cells of breast cancer patients: a strong prognostic factor for distant and local relapse. Clin Cancer Res. 2008;14:3306–3311.
    1. Bidard FC, Fehm T, Ignatiadis M, Smerage JB, Alix-Panabieres C, Janni W, Messina C, Paoletti C, Muller V, Hayes DF, et al., editors. Clinical application of circulating tumor cells in breast cancer: overview of the current interventional trials. Cancer Metastasis Rev. 2013a;32:179–188.
    1. Bidard FC, Pierga JY, Soria JC, Thiery JP. Translating metastasis-related biomarkers to the clinic–progress and pitfalls. Nat Rev Clin Oncol. 2013b;10:169–179.
    1. Bidard FC, Peeters DJ, Fehm T, Nole F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, et al., editors. Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient data. Lancet Oncol. 2014;15:406–414.
    1. 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;14:6302–6309.
    1. Brabletz T. To differentiate or not–routes towards metastasis. Nat Rev Cancer. 2012;12:425–436.
    1. Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C, Farina HG, Schewe DM, Aguirre-Ghiso JA. TGF-beta2 dictates disseminated tumour cell fate in target organs through TGF-beta-RIII and p38alpha/beta signalling. Nat Cell Biol. 2013;15:1351–1361.
    1. Braun S, Pantel K, Muller P, Janni W, Hepp F, Kentenich CR, Gastroph S, Wischnik A, Dimpfl T, Kindermann G, et al., editors. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med. 2000;342:525–533.
    1. Braun S, Vogl FD, Naume B, Janni W, Osborne MP, Coombes RC, Schlimok G, Diel IJ, Gerber B, Gebauer G, et al., editors. A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med. 2005;353:793–802.
    1. Budd GT, Cristofanilli M, Ellis MJ, Stopeck A, Borden E, Miller MC, Matera J, Repollet M, Doyle GV, Terstappen LW, et al., editors. Circulating tumor cells versus imaging–predicting overall survival in metastatic breast cancer. Clin Cancer Res. 2006;12:6403–6409.
    1. Camara O, Kavallaris A, Noschel H, Rengsberger M, Jorke C, Pachmann K. Seeding of epithelial cells into circulation during surgery for breast cancer: the fate of malignant and benign mobilized cells. World J Surg Oncol. 2006;4:67.
    1. Celia-Terrassa T, Meca-Cortes O, Mateo F, de Paz AM, Rubio N, Arnal-Estape A, Ell BJ, Bermudo R, Diaz A, Guerra-Rebollo M, et al., editors. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. J Clin Invest. 2012;122:1849–1868.
    1. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–572.
    1. Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse M, Mitchell E, Miller MC, et al., editors. 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.
    1. Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse MA, Mitchell E, Miller MC, et al., editors. Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol. 2009;20:1223–1229.
    1. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, et al., editors. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781–791.
    1. Deneve E, Riethdorf S, Ramos J, Nocca D, Coffy A, Daures JP, Maudelonde T, Fabre JM, Pantel K, Alix-Panabieres C. Capture of viable circulating tumor cells in the liver of colorectal cancer patients. Clin Chem. 2013;59:1384–1392.
    1. Deng G, Herrler M, Burgess D, Manna E, Krag D, Burke JF. Enrichment with anti-cytokeratin alone or combined with anti-EpCAM antibodies significantly increases the sensitivity for circulating tumor cell detection in metastatic breast cancer patients. Breast Cancer Res. 2008;10:R69.
    1. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al., editors. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369:1023–1034.
    1. Douma S, Van LT, Zevenhoven J, Meuwissen R, Van GE, Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature. 2004;430:1034–1039.
    1. El Touny LH, Vieira A, Mendoza A, Khanna C, Hoenerhoff MJ, Green JE. Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells. J Clin Invest. 2014;124:156–168.
    1. Ell B, Mercatali L, Ibrahim T, Campbell N, Schwarzenbach H, Pantel K, Amadori D, Kang Y. Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell. 2013;24:542–556.
    1. Fischer JC, Niederacher D, Topp SA, Honisch E, Schumacher S, Schmitz N, Zacarias FL, Vay C, Hoffmann I, Kasprowicz NS, et al., editors. Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients. Proc Natl Acad Sci USA. 2013;110:16580–16585.
    1. Fornvik D, Andersson I, Dustler M, Ehrnstrom R, Ryden L, Tingberg A, Zackrisson S, Aaltonen K. No evidence for shedding of circulating tumor cells to the peripheral venous blood as a result of mammographic breast compression. Breast Cancer Res Treat. 2013;141:187–195.
    1. Friedl P, Gilmour D. Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol. 2009;10:445–457.
    1. Friedl P, Wolf K. Proteolytic interstitial cell migration: a five-step process. Cancer Metastasis Rev. 2009;28:129–135.
    1. Friedl P, Alexander S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell. 2011;147:992–1009.
    1. 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;59:252–260.
    1. Gazzaniga P, de BE, Raimondi C, Gradilone A, Busetto GM, De FE, Nicolazzo C, Giovannone R, Gentile V, Cortesi E, et al., editors. Circulating tumor cells detection has independent prognostic impact in high-risk non-muscle invasive bladder cancer. Int J Cancer. 2014;135:1978–1982.
    1. Ghadimi BM, Sackett DL, Difilippantonio MJ, Schrock E, Neumann T, Jauho A, Auer G, Ried T. Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations. Genes Chromosom Cancer. 2000;27:183–190.
    1. Godinho SA, Picone R, Burute M, Dagher R, Su Y, Leung CT, Polyak K, Brugge JS, Thery M, Pellman D. Oncogene-like induction of cellular invasion from centrosome amplification. Nature. 2014;510:167–171.
    1. Gorges TM, Tinhofer I, Drosch M, Rose L, Zollner TM, Krahn T, von AO. Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition. BMC Cancer. 2012;12:178.
    1. Goss PE, Chambers AF. Does tumour dormancy offer a therapeutic target? Nat Rev Cancer. 2010;10:871–877.
    1. Gronich N, Rennert G. Beyond aspirin-cancer prevention with statins, metformin and bisphosphonates. Nat Rev Clin Oncol. 2013;10:625–642.
    1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
    1. Harb W, Fan A, Tran T, Danila DC, Keys D, Schwartz M, Ionescu-Zanetti C. Mutational Analysis of Circulating Tumor Cells Using a Novel Microfluidic Collection Device and qPCR Assay. Transl Oncol. 2013;6:528–538.
    1. Hartkopf AD, Banys M, Fehm T. HER2-positive DTCs/CTCs in breast cancer. Recent Results Cancer Res. 2012;195:203–215.
    1. Heitzer E, Auer M, Gasch C, Pichler M, Ulz P, Hoffmann EM, Lax S, Waldispuehl-Geigl J, Mauermann O, Lackner C, et al., editors. Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Res. 2013;73:2965–2975.
    1. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, Polanski R, Burt DJ, Simpson KL, Morris K, et al., editors. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med. 2014;20:897–903.
    1. Hohensee I, Lamszus K, Riethdorf S, Meyer-Staeckling S, Glatzel M, Matschke J, Witzel I, Westphal M, Brandt B, Muller V, et al., editors. Frequent genetic alterations in EGFR-and HER2-driven pathways in breast cancer brain metastases. Am J Pathol. 2013;183:83–95.
    1. Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, Priest LJ, Greystoke A, Zhou C, Morris K, et al., editors. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012;30:525–532.
    1. Hou HW, Warkiani ME, Khoo BL, Li ZR, Soo RA, Tan DS, Lim WT, Han J, Bhagat AA, Lim CT. Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci Rep. 2013;3:1259.
    1. Ignatiadis M, Rothe F, Chaboteaux C, Durbecq V, Rouas G, Criscitiello C, Metallo J, Kheddoumi N, Singhal SK, Michiels S, et al., editors. HER2-positive circulating tumor cells in breast cancer. PLoS One. 2011;6:e15624.
    1. Janni W, Vogl FD, Wiedswang G, Synnestvedt M, Fehm T, Juckstock J, Borgen E, Rack B, Braun S, Sommer H, et al., editors. Persistence of disseminated tumor cells in the bone marrow of breast cancer patients predicts increased risk for relapse–a European pooled analysis. Clin Cancer Res. 2011;17:2967–2976.
    1. Joosse SA, Hannemann J, Spotter J, Bauche A, Andreas A, Muller V, Pantel K. Changes in keratin expression during metastatic progression of breast cancer: impact on the detection of circulating tumor cells. Clin Cancer Res. 2012;18:993–1003.
    1. Joosse SA, Pantel K. Biologic challenges in the detection of circulating tumor cells. Cancer Res. 2013;73:8–11.
    1. Kang Y, Pantel K. Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell. 2013;23:573–581.
    1. Kasimir-Bauer S, Hoffmann O, Wallwiener D, Kimmig R, Fehm T. Expression of stem cell and epithelial-mesenchymal transition markers in primary breast cancer patients with circulating tumor cells. Breast Cancer Res. 2012;14:R15.
    1. Kim MY, Oskarsson T, Acharyya S, Nguyen DX, Zhang XH, Norton L, Massague J. Tumor self-seeding by circulating cancer cells. Cell. 2009;139:1315–1326.
    1. Kishi S, Bayliss PE, Hanai JI. A prospective epigenetic paradigm between cellular senescence and epithelial-mesenchymal transition in organismal development and aging. Transl Res. 2014;165:241–249.
    1. Korkaya H, Wicha MS. HER2 and breast cancer stem cells: more than meets the eye. Cancer Res. 2013;73:3489–3493.
    1. Krebs MG, Sloane R, Priest L, Lancashire L, Hou JM, Greystoke A, Ward TH, Ferraldeschi R, Hughes A, Clack G, et al., editors. Evaluation and prognostic significance of circulating tumor cells in patients with non-small-cell lung cancer. J Clin Oncol. 2011;29:1556–1563.
    1. Lewiecki EM. New targets for intervention in the treatment of postmenopausal osteoporosis. Nat Rev Rheumatol. 2011;7:631–638.
    1. Lindemann F, Schlimok G, Dirschedl P, Witte J, Riethmuller G. Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lancet. 1992;340:685–689.
    1. Lingle WL, Barrett SL, Negron VC, D'Assoro AB, Boeneman K, Liu W, Whitehead CM, Reynolds C, Salisbury JL. Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci USA. 2002;99:1978–1983.
    1. Liu Z, Fusi A, Klopocki E, Schmittel A, Tinhofer I, Nonnenmacher A, Keilholz U. Negative enrichment by immunomagnetic nanobeads for unbiased characterization of circulating tumor cells from peripheral blood of cancer patients. J Transl Med. 2011;9:70.
    1. Lohr JG, Adalsteinsson VA, Cibulskis K, Choudhury AD, Rosenberg M, Cruz-Gordillo P, Francis JM, Zhang CZ, Shalek AK, Satija R, et al., editors. Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat Biotechnol. 2014;32:479–484.
    1. Lu J, Fan T, Zhao Q, Zeng W, Zaslavsky E, Chen JJ, Frohman MA, Golightly MG, Madajewicz S, Chen WT. Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. Int J Cancer. 2010;126:669–683.
    1. Lu X, Mu E, Wei Y, Riethdorf S, Yang Q, Yuan M, Yan J, Hua Y, Tiede BJ, Lu X, et al., editors. VCAM-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging alpha4beta1-positive osteoclast progenitors. Cancer Cell. 2011;20:701–714.
    1. Lucci A, Hall CS, Lodhi AK, Bhattacharyya A, Anderson AE, Xiao L, Bedrosian I, Kuerer HM, Krishnamurthy S. Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol. 2012;13:688–695.
    1. Maheswaran S, Sequist LV, Nagrath S, Ulkus L, Brannigan B, Collura CV, Inserra E, Diederichs S, Iafrate AJ, Bell DW, et al., editors. Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med. 2008;359:366–377.
    1. McDonald DM, Baluk P. Significance of blood vessel leakiness in cancer. Cancer Res. 2002;62:5381–5385.
    1. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, et al., editors. Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res. 2004;10:8152–8162.
    1. Mitchell MJ, King MR. Computational and experimental models of cancer cell response to fluid shear stress. Front Oncol. 2013;3:44.
    1. Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzikansky A, et al., editors. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450:1235–1239.
    1. Nguyen DX, Massague J. Genetic determinants of cancer metastasis. Nat Rev Genet. 2007;8:341–352.
    1. Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013;342:1234850.
    1. Ozkumur E, Shah AM, Ciciliano JC, Emmink BL, Miyamoto DT, Brachtel E, Yu M, Chen PI, Morgan B, Trautwein J, et al., editors. Inertial focusing for tumor antigen-dependent and-independent sorting of rare circulating tumor cells. Sci Transl Med. 2013;5:179ra47.
    1. 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;85:1419–1424.
    1. Pantel K, Passlick B, Vogt J, Stosiek P, Angstwurm M, Seen-Hibler R, Haussinger K, Thetter O, Izbicki JR, Riethmuller G. Reduced expression of plakoglobin indicates an unfavorable prognosis in subsets of patients with non-small-cell lung cancer. J Clin Oncol. 1998;16:1407–1413.
    1. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer. 2004;4:448–456.
    1. Parkinson DR, Dracopoli N, Petty BG, Compton C, Cristofanilli M, Deisseroth A, Hayes DF, Kapke G, Kumar P, Lee JS, et al., editors. Considerations in the development of circulating tumor cell technology for clinical use. J Transl Med. 2012;10:138.
    1. Peeters M, Douillard JY, Van CE, Siena S, Zhang K, Williams R, Wiezorek J. Mutant KRAS codon 12 and 13 alleles in patients with metastatic colorectal cancer: assessment as prognostic and predictive biomarkers of response to panitumumab. J Clin Oncol. 2013;31:759–765.
    1. Rack B, Schindlbeck C, Juckstock J, Andergassen U, Hepp P, Zwingers T, Friedl TW, Lorenz R, Tesch H, Fasching PA, et al., editors. Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst. 2014;106 : dju066.
    1. Reymond N, d'Agua BB, Ridley AJ. Crossing the endothelial barrier during metastasis. Nat Rev Cancer. 2013;13:858–870.
    1. Riahi R, Gogoi P, Sepehri S, Zhou Y, Handique K, Godsey J, Wang Y. A novel microchannel-based device to capture and analyze circulating tumor cells (CTCs) of breast cancer. Int J Oncol. 2014;44:1870–1878.
    1. Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Janicke F, et al., editors. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the Cell Search system. Clin Cancer Res. 2007;13:920–928.
    1. Riethdorf S, Wikman H, Pantel K. Review: biological relevance of disseminated tumor cells in cancer patients. Int J Cancer. 2008;123:1991–2006.
    1. Riethdorf S, Muller V, Zhang L, Rau T, Loibl S, Komor M, Roller M, Huober J, Fehm T, Schrader I, et al., editors. Detection and HER2 expression of circulating tumor cells: prospective monitoring in breast cancer patients treated in the neoadjuvant GeparQuattro trial. Clin Cancer Res. 2010;16:2634–2645.
    1. Rink M, Chun FK, Minner S, Friedrich M, Mauermann O, Heinzer H, Huland H, Fisch M, Pantel K, Riethdorf S. Detection of circulating tumour cells in peripheral blood of patients with advanced non-metastatic bladder cancer. BJU Int. 2011;107:1668–1675.
    1. Rink M, Chun FK, Dahlem R, Soave A, Minner S, Hansen J, Stoupiec M, Coith C, Kluth LA, Ahyai SA, et al., editors. Prognostic role and HER2 expression of circulating tumor cells in peripheral blood of patients prior to radical cystectomy: a prospective study. Eur Urol. 2012;61:810–817.
    1. Saucedo-Zeni N, Mewes S, Niestroj R, Gasiorowski L, Murawa D, Nowaczyk P, Tomasi T, Weber E, Dworacki G, Morgenthaler NG, et al., editors. A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire. Int J Oncol. 2012;41:1241–1250.
    1. Stathopoulou A, Gizi A, Perraki M, Apostolaki S, Malamos N, Mavroudis D, Georgoulias V, Lianidou ES. Real-time quantification of CK-19 mRNA-positive cells in peripheral blood of breast cancer patients using the lightcycler system. Clin Cancer Res. 2003;9:5145–5151.
    1. Steinert G, Scholch S, Niemietz T, Iwata N, Garcia SA, Behrens B, Voigt A, Kloor M, Benner A, Bork U, et al., editors. Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Res. 2014;74:1694–1704.
    1. Strati A, Kasimir-Bauer S, Markou A, Parisi C, Lianidou ES. Comparison of three molecular assays for the detection and molecular characterization of circulating tumor cells in breast cancer. Breast Cancer Res. 2013;15:R20.
    1. Tam WL, Weinberg RA. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med. 2013;19:1438–1449.
    1. 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;115:581–590.
    1. Thege FI, Lannin TB, Saha TN, Tsai S, Kochman ML, Hollingsworth MA, Rhim AD, Kirby BJ. Microfluidic immunocapture of circulating pancreatic cells using parallel EpCAM and MUC1 capture: characterization, optimization and downstream analysis. Lab Chip. 2014;14:1775–1784.
    1. Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454.
    1. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–890.
    1. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 2012;22:725–736.
    1. Uhr JW, Pantel K. Controversies in clinical cancer dormancy. Proc Natl Acad Sci USA. 2011;108:12396–12400.
    1. Uppal A, Wightman SC, Ganai S, Weichselbaum RR, An G. Investigation of the essential role of platelet-tumor cell interactions in metastasis progression using an agent-based model. Theor Biol Med Model. 2014;11:17.
    1. Wan L, Pantel K, Kang Y. Tumor metastasis: moving new biological insights into the clinic. Nat Med. 2013;19:1450–1464.
    1. Wikman H, Vessella R, Pantel K. Cancer micrometastasis and tumour dormancy. APMIS. 2008;116:754–770.
    1. Wikman H, Lamszus K, Detels N, Uslar L, Wrage M, Benner C, Hohensee I, Ylstra B, Eylmann K, Zapatka M, et al., editors. Relevance of PTEN loss in brain metastasis formation in breast cancer patients. Breast Cancer Res. 2012;14:R49.
    1. Wrage M, Ruosaari S, Eijk PP, Kaifi JT, Hollmen J, Yekebas EF, Izbicki JR, Brakenhoff RH, Streichert T, Riethdorf S, et al., editors. Genomic profiles associated with early micrometastasis in lung cancer: relevance of 4q deletion. Clin Cancer Res. 2009;15:1566–1574.
    1. Wu S, Liu Z, Liu S, Lin L, Yang W, Xu J. Enrichment and enumeration of circulating tumor cells by efficient depletion of leukocyte fractions. Clin Chem Lab Med. 2014;52:243–251.
    1. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, et al., editors. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science. 2013;339:580–584.
    1. Yu M, Bardia A, Aceto N, Bersani F, Madden MW, Donaldson MC, Desai R, Zhu H, Comaills V, Zheng Z, et al., editors. Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science. 2014;345:216–220.
    1. 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;18:5701–5710.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj