Abstract
The characterization of circulating tumor cells (CTC) has the potential not only to provide important insights into molecular alterations of advanced tumor disease but also to facilitate risk prediction. Epithelial mesenchymal transition (EMT) has been discovered as important process for the development of metastases and the dissemination of tumor cells into the blood stream. In different tumor types, CTC with a mesenchymal phenotype have been reported that have presumably underwent EMT. Moreover, CTC with stem-cell like characteristics have been postulated as important drivers of tumor progression. Different platforms have been introduced to allow CTC enrichment independent of expression of epithelial antigens, as these may be downregulated in EMT- or stem-cell-like CTC. Both for CTCs with EMT- or stem-cell features different markers have been proposed. However, there is still a lack of evidence on the association of these markers with functional features and characteristics for stem cells and cells undergoing EMT.
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References
Aktas B, Tewes M, Fehm T et al (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46
Al-Hajj M, Wicha MS, Benito-Hernandez A et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988
Alix-Panabieres C, Bartkowiak K, Pantel K (2016) Functional studies on circulating and disseminated tumor cells in carcinoma patients. Mol Oncol 10(3):443–449
Alix-Panabieres C, Pantel K (2014a) The circulating tumor cells: liquid biopsy of cancer. Klinicheskaia laboratornaia diagnostika 4:60–64
Alix-Panabieres C, Pantel K (2014b) Technologies for detection of circulating tumor cells: facts and vision. Lab Chip 14(1):57–62
Alonso-Alconada L, Muinelo-Romay L, Madissoo K et al (2014) Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer. Mol Cancer 13:223
Andreopoulou E, Yang LY, Rangel KM et al (2012) Comparison of assay methods for detection of circulating tumor cells in metastatic breast cancer: AdnaGen AdnaTest BreastCancer Select/Detect versus Veridex CellSearch system. Int J Cancer 130(7):1590–1597
Armstrong AJ, Marengo MS, Oltean S et al (2011) Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res MCR 9(8):997–1007
Baccelli I, Schneeweiss A, Riethdorf S et al (2013) Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 31(6):539–544
Barber AG, Castillo-Martin M, Bonal DM et al (2015) PI3K/AKT pathway regulates E-cadherin and Desmoglein 2 in aggressive prostate cancer. Cancer Med 4(8):1258–1271
Barker N, van Es JH, Kuipers J et al (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007
Barriere G, Fici P, Gallerani G et al (2014) Circulating tumor cells and epithelial, mesenchymal and stemness markers: characterization of cell subpopulations. Annal Transl Med 2(11):109
Blassl C, Kuhlmann JD, Webers A et al (2016) Gene expression profiling of single circulating tumor cells in ovarian cancer – establishment of a multi-marker gene panel. Mol Oncol 10(7):1030–1042
Bock C, Rack B, Huober J et al (2014) Distinct expression of cytokeratin, N-cadherin and CD133 in circulating tumor cells of metastatic breast cancer patients. Future Oncol 10(10):1751–1765
Bourcy M, Suarez-Carmona M, Lambert J et al (2016) Tissue factor induced by epithelial-mesenchymal transition triggers a procoagulant state that drives metastasis of circulating tumor cells. Cancer Res 76(14):4270–4282
Braun S, Vogl FD, Naume B et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353(8):793–802
Cayrefourcq L, Mazard T, Joosse S et al (2015) Establishment and characterization of a cell line from human circulating colon cancer cells. Cancer Res 75(5):892–901
Chang K, Kong YY, Dai B et al (2015) Combination of circulating tumor cell enumeration and tumor marker detection in predicting prognosis and treatment effect in metastatic castration-resistant prostate cancer. Oncotarget 6(39):41825–41836
Clevers H (2011) The cancer stem cell: premises, promises and challenges. Nat Med 17(3):313–319
Coumans FA, Siesling S, Terstappen LW (2013) Detection of cancer before distant metastasis. BMC Cancer 13:283
De Craene B, Berx G (2013) Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer 13(2):97–110
Dinney CPNM, Melnikova VO, Pretzsch SM, Garza M, Wu W, Davis DW, Anderes KL (2014) Heterogeneity of circulating tumor cells isolated from bladder cancer patients using ApoStream and biomarkers of epithelial-mesenchymal transition. ASCO Meet Abstr 32:349
Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell 61(5):759–767
Finlay J, Roberts CM, Lowe G et al (2015) RNA-based TWIST1 inhibition via dendrimer complex to reduce breast cancer cell metastasis. Biomed Res Int 2015:382745
Freidin MB, Tay A, Freydina DV et al (2014) An assessment of diagnostic performance of a filter-based antibody-independent peripheral blood circulating tumour cell capture paired with cytomorphologic criteria for the diagnosis of cancer. Lung Cancer 85(2):182–185
Fresno Vara JA, Casado E, de Castro J et al (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30(2):193–204
Galli R, Binda E, Orfanelli U et al (2004) Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 64(19):7011–7021
Ginestier C, Hur MH, Charafe-Jauffret E et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567
Giordano A, Gao H, Anfossi S et al (2012) Epithelial-mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Mol Cancer Ther 11(11):2526–2534
Gorges TM, Kuske A, Rock K, Mauermann O, Müller V, Peine S, Verpoort K, Novosadova V, Kubista M, Riethdorf S, Pantel K (2016) Accession of tumor heterogeneity by multiplex transcriptome profiling of single circulating tumor cells. Clin Chem 62(11):1504–1515
Gradilone A, Iacovelli R, Cortesi E et al (2011) Circulating tumor cells and “suspicious objects” evaluated through CellSearch(R) in metastatic renal cell carcinoma. Anticancer Res 31(12):4219–4221
Greulich P, Simons BD (2016) Dynamic heterogeneity as a strategy of stem cell self-renewal. Proc Natl Acad Sci U S A 113(27):7509–7514
Gupta V, Jafferji I, Garza M et al (2012) ApoStream(), a new dielectrophoretic device for antibody independent isolation and recovery of viable cancer cells from blood. Biomicrofluidics 6(2):24133
Hanssen A, Wagner J, Gorges TM et al (2016) Characterization of different CTC subpopulations in non-small cell lung cancer. Sci Rep 6:28010
Hegemann M, Stenzl A, Bedke J et al (2016) Liquid biopsy: ready to guide therapy in advanced prostate cancer? BJU Int 118(6):855–863
Howard TD, Paznekas WA, Green ED et al (1997) Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat Genet 15(1):36–41
Hu L, Lau SH, Tzang CH et al (2004) Association of Vimentin overexpression and hepatocellular carcinoma metastasis. Oncogene 23(1):298–302
Hui L, Zhang S, Dong X et al (2013) Prognostic significance of twist and N-cadherin expression in NSCLC. PLoS One 8(4):e62171
Hvichia GE, Parveen Z, Wagner C et al (2016) A novel microfluidic platform for size and deformability based separation and the subsequent molecular characterization of viable circulating tumor cells. Int J Cancer 138(12):2894–2904
Hyun KA, Koo GB, Han H et al (2016) Epithelial-to-mesenchymal transition leads to loss of EpCAM and different physical properties in circulating tumor cells from metastatic breast cancer. Oncotarget 7(17):24677–24687
Kallergi G, Papadaki MA, Politaki E et al (2011) Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res 13(3):R59
Karrison TG, Ferguson DJ, Meier P (1999) Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 91(1):80–85
Khan MA, Tania M, Wei C et al (2015) Thymoquinone inhibits cancer metastasis by downregulating TWIST1 expression to reduce epithelial to mesenchymal transition. Oncotarget 6(23):19580–19591
Konigsberg R, Obermayr E, Bises G et al (2011) Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients. Acta Oncol 50(5):700–710
Krawczyk N, Meier-Stiegen F, Banys M et al (2014) Expression of stem cell and epithelial-mesenchymal transition markers in circulating tumor cells of breast cancer patients. Biomed Res Int 2014:415721
Kreso A, Dick JE (2014) Evolution of the cancer stem cell model. Cell Stem Cell 14(3):275–291
Kulemann B, Liss AS, Warshaw AL et al (2016) KRAS mutations in pancreatic circulating tumor cells: a pilot study. Tumour Biol J Int Soc Oncodevelop Biol Med 37(6):7547–7554
Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15(3):178–196
Lander AD, Kimble J, Clevers H et al (2012) What does the concept of the stem cell niche really mean today? BMC Biol 10:19
Larue L, Bellacosa A (2005) Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene 24(50):7443–7454
Li M, Zhang B, Zhang Z et al (2014) Stem cell-like circulating tumor cells indicate poor prognosis in gastric cancer. Biomed Res Int 2014:981261
Li X, Marcondes AM, Gooley TA et al (2010) The helix-loop-helix transcription factor TWIST is dysregulated in myelodysplastic syndromes. Blood 116(13):2304–2314
Lindsay CR, Le Moulec S, Billiot F et al (2016) Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer. BMC Cancer 16:168
Lu J, Fan T, Zhao Q et al (2010) Isolation of circulating epithelial and tumor progenitor cells with an invasive phenotype from breast cancer patients. Int J Cancer 126(3):669–683
Malara N, Trunzo V, Foresta U et al (2016) 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 14(1):133
Marie-Egyptienne DT, Lohse I, Hill RP (2013) Cancer stem cells, the epithelial to mesenchymal transition (EMT) and radioresistance: potential role of hypoxia. Cancer Lett 341(1):63–72
Marsden CG, Wright MJ, Pochampally R et al (2009) Breast tumor-initiating cells isolated from patient core biopsies for study of hormone action. Methods Mol Biol 590:363–375
Mascalchi M, Falchini M, Maddau C et al (2016) Prevalence and number of circulating tumour cells and microemboli at diagnosis of advanced NSCLC. J Cancer Res Clin Oncol 142(1):195–200
Mathenge EG, Dean CA, Clements D et al (2014) Core needle biopsy of breast cancer tumors increases distant metastases in a mouse model. Neoplasia 16(11):950–960
Mego M, Mani SA, Lee BN et al (2012) Expression of epithelial-mesenchymal transition-inducing transcription factors in primary breast cancer: the effect of neoadjuvant therapy. Int J Cancer 130(4):808–816
Merindol N, Riquet A, Szablewski V et al (2014) The emerging role of Twist proteins in hematopoietic cells and hematological malignancies. Blood Cancer J 4:e206
Mitra A, Mishra L, Li S (2015a) EMT, CTCs and CSCs in tumor relapse and drug-resistance. Oncotarget 6(13):10697–10711
Mitra A, Satelli A, Xia X et al (2015b) Cell-surface Vimentin: a mislocalized protein for isolating csVimentin(+) CD133(−) novel stem-like hepatocellular carcinoma cells expressing EMT markers. Int J Cancer 137(2):491–496
Mohme M, Riethdorf S, Pantel K (2016) Circulating and disseminated tumour cells – mechanisms of immune surveillance and escape. Nat Rev Clin Oncol
Nastaly P, Ruf C, Becker P et al (2014) Circulating tumor cells in patients with testicular germ cell tumors. Clin Cancer Res 20(14):3830–3841
Nieman MT, Prudoff RS, Johnson KR et al (1999) N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol 147(3):631–644
O'Brien CA, Pollett A, Gallinger S et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110
Pal SK, He M, Wilson T et al (2015) Detection and phenotyping of circulating tumor cells in high-risk localized prostate cancer. Clin Genitourin Cancer 13(2):130–136
Pantel K, Alix-Panabieres C (2016) Functional Studies on Viable Circulating Tumor Cells. Clin Chem 62(2):328–334
Pantel K, Deneve E, Nocca D et al (2012) Circulating epithelial cells in patients with benign colon diseases. Clin Chem 58(5):936–940
Papadaki MA, Kallergi G, Zafeiriou Z et al (2014) Co-expression of putative stemness and epithelial-to-mesenchymal transition markers on single circulating tumour cells from patients with early and metastatic breast cancer. BMC Cancer 14:651
Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3(12):895–902
Park S, Ang RR, Duffy SP et al (2014) Morphological differences between circulating tumor cells from prostate cancer patients and cultured prostate cancer cells. PLoS One 9(1):e85264
Patrawala L, Calhoun T, Schneider-Broussard R et al (2006) Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25(12):1696–1708
Pilati P, Mocellin S, Bertazza L et al (2012) Prognostic value of putative circulating cancer stem cells in patients undergoing hepatic resection for colorectal liver metastasis. Ann Surg Oncol 19(2):402–408
Poruk KE, Valero V 3rd, Saunders T et al (2016) Circulating tumor cell phenotype predicts recurrence and survival in pancreatic adenocarcinoma. Annal Surg 264(6):1073–1081
Powell AA, Talasaz AH, Zhang H et al (2012) Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PLoS One 7(5):e33788
Quintana E, Shackleton M, Foster HR et al (2010) Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 18(5):510–523
Rack B, Schindlbeck C, Juckstock J et al (2014) Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst 106(5)
Riaz M, Sieuwerts AM, Look MP et al (2012) High TWIST1 mRNA expression is associated with poor prognosis in lymph node-negative and estrogen receptor-positive human breast cancer and is co-expressed with stromal as well as ECM related genes. Breast Cancer Res BCR 14(5):R123
Satelli A, Brownlee Z, Mitra A et al (2015a) Circulating tumor cell enumeration with a combination of epithelial cell adhesion molecule- and cell-surface vimentin-based methods for monitoring breast cancer therapeutic response. Clin Chem 61(1):259–266
Satelli A, Mitra A, Brownlee Z et al (2015b) Epithelial-mesenchymal transitioned circulating tumor cells capture for detecting tumor progression. Clin Cancer Res Offic J Am Assoc Cancer Res 21(4):899–906
Satelli A, Mitra A, Cutrera JJ et al (2014) Universal marker and detection tool for human sarcoma circulating tumor cells. Cancer Res 74(6):1645–1650
Schilling D, Todenhofer T, Hennenlotter J et al (2012) Isolated, disseminated and circulating tumour cells in prostate cancer. Nat Rev Urol 9(8):448–463
Schulze K, Gasch C, Staufer K et al (2013) Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer 133(9):2165–2171
Shimada R, Iinuma H, Akahane T et al (2012) Prognostic significance of CTCs and CSCs of tumor drainage vein blood in Dukes’ stage B and C colorectal cancer patients. Oncol Rep 27(4):947–953
Shipitsin M, Polyak K (2008) The cancer stem cell hypothesis: in search of definitions, markers, and relevance. Lab Investig 88(5):459–463
Shmelkov SV, Butler JM, Hooper AT et al (2008) CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest 118(6):2111–2120
Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29(34):4741–4751
Sun YF, Xu Y, Yang XR et al (2013) Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology 57(4):1458–1468
Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454
Todenhofer T, Hennenlotter J, Faber F et al (2015) Significance of apoptotic and non-apoptotic disseminated tumor cells in the bone marrow of patients with clinically localized prostate cancer. Prostate 75(6):637–645
Todenhofer T, Azad A, Stewart C et al (2016a) AR-V7 transcripts in whole blood RNA of patients with metastatic castration resistant prostate cancer correlate with response to Abiraterone acetate. J Urol
Todenhofer T, Hennenlotter J, Dorner N et al (2016b) Transcripts of circulating tumor cells detected by a breast cancer-specific platform correlate with clinical stage in bladder cancer patients. J Cancer Res Clin Oncol 142(5):1013–1020
Todenhofer T, Park ES, Duffy S et al (2016c) Microfluidic enrichment of circulating tumor cells in patients with clinically localized prostate cancer. Urol Oncol 34(11):483.e9–483.e16
Uhr JW, Pantel K (2011) Controversies in clinical cancer dormancy. Proc Natl Acad Sci U S A 108(30):12396–12400
Valladares-Ayerbes M, Blanco-Calvo M, Reboredo M et al (2012) Evaluation of the adenocarcinoma-associated gene AGR2 and the intestinal stem cell marker LGR5 as biomarkers in colorectal cancer. Int J Mol Sci 13(4):4367–4387
Van der Auwera I, Peeters D, Benoy IH et al (2010) Circulating tumour cell detection: a direct comparison between the CellSearch System, the AdnaTest and CK-19/mammaglobin RT-PCR in patients with metastatic breast cancer. Br J Cancer 102(2):276–284
Vesuna F, van Diest P, Chen JH et al (2008) Twist is a transcriptional repressor of E-cadherin gene expression in breast cancer. Biochem Biophys Res Commun 367(2):235–241
Vishnoi M, Peddibhotla S, Yin W et al (2015) The isolation and characterization of CTC subsets related to breast cancer dormancy. Sci Rep 5:17533
Wang N, Shi L, Li H et al (2012) Detection of circulating tumor cells and tumor stem cells in patients with breast cancer by using flow cytometry: a valuable tool for diagnosis and prognosis evaluation. Tumour Biol 33(2):561–569
Weissenstein U, Schumann A, Reif M et al (2012) Detection of circulating tumor cells in blood of metastatic breast cancer patients using a combination of cytokeratin and EpCAM antibodies. BMC Cancer 12:206
Wu S, Liu S, Liu Z et al (2015) Classification of circulating tumor cells by epithelial-mesenchymal transition markers. PLoS One 10(4):e0123976
Wushou A, Hou J, Zhao YJ et al (2014) Twist-1 up-regulation in carcinoma correlates to poor survival. Int J Mol Sci 15(12):21621–21630
Yang MH, Imrali A, Heeschen C (2015) Circulating cancer stem cells: the importance to select. Chinese J Cancer Res = Chung-kuo yen cheng yen chiu 27(5):437–449
Ye LY, Chen W, Bai XL et al (2016) Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis. Cancer Res 76(4):818–830
Yi S, Yang ZL, Miao X et al (2014) N-cadherin and P-cadherin are biomarkers for invasion, metastasis, and poor prognosis of gallbladder carcinomas. Pathol Res Pract 210(6):363–368
Yoshida GJ, Saya H (2016) Therapeutic strategies targeting cancer stem cells. Cancer Sci 107(1):5–11
Yu M, Bardia A, Aceto N et al (2014) Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 345(6193):216–220
Zelenko Z, Gallagher EJ, Tobin-Hess A et al (2016) Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression. Oncogene
Zhang L, Huang G, Li X et al (2013) Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1alpha in hepatocellular carcinoma. BMC Cancer 13:108
Zhang P, Sun Y, Ma L (2015) ZEB1: at the crossroads of epithelial-mesenchymal transition, metastasis and therapy resistance. Cell Cycle 14(4):481–487
Zhu P, Stanton ML, Castle EP et al (2016a) Detection of tumor-associated cells in cryopreserved peripheral blood mononuclear cell samples for retrospective analysis. J Transl Med 14(1):198
Zhu QQ, Ma C, Wang Q et al (2016b) The role of TWIST1 in epithelial-mesenchymal transition and cancers. Tumour Biol J Int Soc Oncodev Biol Med 37(1):185–197
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Werner, S., Stenzl, A., Pantel, K., Todenhöfer, T. (2017). Expression of Epithelial Mesenchymal Transition and Cancer Stem Cell Markers in Circulating Tumor Cells. In: Magbanua, M., Park, J. (eds) Isolation and Molecular Characterization of Circulating Tumor Cells. Advances in Experimental Medicine and Biology, vol 994. Springer, Cham. https://doi.org/10.1007/978-3-319-55947-6_11
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