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Advancing Techniques and Insights in Circulating Tumor Cell (CTC) Research

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Ex Vivo Engineering of the Tumor Microenvironment

Abstract

Cancer is a major cause of mortality worldwide, with a disease burden estimated to grow over the coming decades. Circulating tumor cells (CTCs) are rare cancer cells released from the primary or metastatic tumors and transported though the peripheral circulatory system to their specific secondary locations. The presence of CTCs in the a cancer patient’s blood has been used as a prognostic biomarker, with lower CTC count correlating with greater overall survival [1]. In spite of its clinical potential, the isolation and detection of CTCs has been a challenging task due to its rare presence amongst other blood cells (as low as 1–10 CTCs per billions of blood cells) and variability in terms of both morphological and biochemical markers. Recent developments of microfluidics technology have paved the way for better isolation and characterization of CTCs due to several advantages such as lower sample volume, higher sensitivity and throughput and lesser production cost [2, 3]. In this chapter, various CTC isolation devices are classified under two major categories: microfluidics and conventional macro-scale devices, as illustrated in Fig. 1. We will be discussing both label-free methods and antibody-dependent methods for CTC isolation, and will provide discussion and future perspectives on the advantages and drawbacks of both these techniques on potential clinical applications. Advancement in these technologies for CTCs and associated components, such as exosomes, led to an unraveling of tumor variation, ranging histology, molecular, proteomic and functional heterogeneity, which will be discussed in the subsequent sections.

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References

  1. Allen JE, El-Deiry WS (2010) Circulating tumor cells and colorectal cancer. Curr Colorectal Cancer Rep 6(4):212–220

    Article  PubMed  PubMed Central  Google Scholar 

  2. Majid EW, Lim CT (2013) Microfluidic platforms for human disease cell mechanics studies. In: Buehler MJ, Ballarini R (eds) Materiomics: multiscale mechanics of biological materials and structures. Springer, New York, pp 107–119

    Chapter  Google Scholar 

  3. Chaudhuri PK et al (2016) Microfluidics for research and applications in oncology. Analyst 141(2):504–524

    Article  CAS  PubMed  Google Scholar 

  4. Low WS, Wan Abu Bakar WA (2015) Benchtop technologies for circulating tumor cells separation based on biophysical properties. BioMed Res Int 2015:239362

    PubMed  PubMed Central  Google Scholar 

  5. Alix-Panabières C, Pantel K (2014) Technologies for detection of circulating tumor cells: facts and vision. Lab Chip 14(1):57–62

    Article  PubMed  Google Scholar 

  6. Zabaglo L et al (2003) Cell filtration-laser scanning cytometry for the characterisation of circulating breast cancer cells. Cytometry A 55(2):102–108

    Article  PubMed  Google Scholar 

  7. Allard WJ et al (2004) Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin Cancer Res 10(20):6897–6904

    Article  PubMed  Google Scholar 

  8. Zheng S et al (2011) 3D microfilter device for viable circulating tumor cell (CTC) enrichment from blood. Biomed Microdevices 13(1):203–213

    Article  PubMed  Google Scholar 

  9. Zhou MD et al (2014) Separable bilayer microfiltration device for viable label-free enrichment of circulating tumour cells. Sci Rep 4:7392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Adams DL et al (2014) The systematic study of circulating tumor cell isolation using lithographic microfilters. RSC Adv 4(9):4334–4342

    Article  CAS  Google Scholar 

  11. Chung J et al (2012) Microfluidic cell sorter (μFCS) for on-chip capture and analysis of single cells. Adv Healthcare Mater 1(4):432–436

    Article  CAS  Google Scholar 

  12. Khoo BL et al (2014) Clinical validation of an ultra high-throughput spiral microfluidics for the detection and enrichment of viable circulating tumor cells. PLoS One 9(7), e99409

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Hou S et al (2013) Capture and stimulated release of circulating tumor cells on polymer-grafted silicon nanostructures. Adv Mater 25(11):1547–1551

    Article  CAS  PubMed  Google Scholar 

  14. Saucedo-Zeni N et al (2012) 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 41(4):1241–1250

    PubMed  PubMed Central  Google Scholar 

  15. Tan SJ et al (2009) Microdevice for the isolation and enumeration of cancer cells from blood. Biomed Microdevices 11(4):883–892

    Article  PubMed  Google Scholar 

  16. Tan SJ et al (2010) Versatile label free biochip for the detection of circulating tumor cells from peripheral blood in cancer patients. Biosens Bioelectron 26(4):1701–1705

    Article  CAS  PubMed  Google Scholar 

  17. Desitter I et al (2011) A new device for rapid isolation by size and characterization of rare circulating tumor cells. Anticancer Res 31(2):427–441

    PubMed  Google Scholar 

  18. Vona G et al (2000) Isolation by size of epithelial tumor cells: a new method for the immunomorphological and molecular characterization of circulating tumor cells. Am J Pathol 156(1):57–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kuo JS et al (2010) Deformability considerations in filtration of biological cells. Lab Chip 10(7):837–842

    Article  CAS  PubMed  Google Scholar 

  20. Alunni-Fabbroni M, Sandri MT (2010) Circulating tumour cells in clinical practice: methods of detection and possible characterization. Methods 50(4):289–297

    Article  CAS  PubMed  Google Scholar 

  21. Shim S et al (2013) Antibody-independent isolation of circulating tumor cells by continuous-flow dielectrophoresis. Biomicrofluidics 7(1):011807

    Article  PubMed Central  CAS  Google Scholar 

  22. Huang C-T et al (2012) Selectively concentrating cervical carcinoma cells from red blood cells utilizing dielectrophoresis with circular ITO electrodes in stepping electric fields. J Med Biol Eng 33(1):51–58

    Article  CAS  Google Scholar 

  23. Gupta V et al (2012) ApoStream™, a new dielectrophoretic device for antibody independent isolation and recovery of viable cancer cells from blood. Biomicrofluidics 6(2):024133

    Article  PubMed Central  Google Scholar 

  24. Loutherback K et al (2012) Deterministic separation of cancer cells from blood at 10 mL/min. AIP Adv 2(4):042107

    Article  PubMed Central  CAS  Google Scholar 

  25. Sollier E et al (2014) Size-selective collection of circulating tumor cells using Vortex technology. Lab Chip 14(1):63–77

    Article  CAS  PubMed  Google Scholar 

  26. Hou HW et al (2013) Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci Rep 3

    Google Scholar 

  27. Warkiani ME et al (2014) Slanted spiral microfluidics for the ultra-fast, label-free isolation of circulating tumor cells. Lab Chip 14(1):128–137

    Article  CAS  PubMed  Google Scholar 

  28. Lee MG et al (2013) Label-free cancer cell separation from human whole blood using inertial microfluidics at low shear stress. Anal Chem 85(13):6213–6218

    Article  CAS  PubMed  Google Scholar 

  29. Zborowski M, Chalmers JJ (2011) Rare cell separation and analysis by magnetic sorting. Anal Chem 83(21):8050–8056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fehm T et al (2009) Detection and characterization of circulating tumor cells in blood of primary breast cancer patients by RT-PCR and comparison to status of bone marrow disseminated cells. Breast Cancer Res 11(4):R59

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Punnoose EA et al (2010) Molecular biomarker analyses using circulating tumor cells. PLoS One 5(9), e12517

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Hoshino K et al (2011) Microchip-based immunomagnetic detection of circulating tumor cells. Lab Chip 11(20):3449–3457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pamme N (2012) On-chip bioanalysis with magnetic particles. Curr Opin Chem Biol 16(3):436–443

    Article  CAS  PubMed  Google Scholar 

  34. Kang JH et al (2012) A combined micromagnetic-microfluidic device for rapid capture and culture of rare circulating tumor cells. Lab Chip 12(12):2175–2181

    Article  CAS  PubMed  Google Scholar 

  35. Wang S, Owens GE, Tseng HR (2011) Nano “fly paper” technology for the capture of circulating tumor cells. Methods Mol Biol 726:141–150

    Article  CAS  PubMed  Google Scholar 

  36. Lu J 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Smith JP et al (2012) Microfluidic transport in microdevices for rare cell capture. Electrophoresis 33(21):3133–3142

    Article  CAS  PubMed  Google Scholar 

  38. Nagrath S et al (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173):1235–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Stott SL et al (2010) Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci 107(43):18392–18397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sheng W et al (2014) Capture, release and culture of circulating tumor cells from pancreatic cancer patients using an enhanced mixing chip. Lab Chip 14(1):89–98

    Article  CAS  PubMed  Google Scholar 

  41. Yoon HJ et al (2013) Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets. Nat Nanotechnol 8(10):735–741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ozkumur E et al (2013) Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci Transl Med 5(179):179ra47

    Google Scholar 

  43. Liu Z et al (2013) High throughput capture of circulating tumor cells using an integrated microfluidic system. Biosens Bioelectron 47:113–119

    Article  CAS  PubMed  Google Scholar 

  44. Seal S (1959) Silicone flotation: a simple quantitative method for the isolation of free-floating cancer cells from the blood. Cancer 12(3):590–595

    Article  CAS  PubMed  Google Scholar 

  45. Gertler R et al (2003) Detection of circulating tumor cells in blood using an optimized density gradient centrifugation. In: Allgayer H, Heiss M (eds) Molecular staging of cancer. Springer, Berlin, pp 149–155

    Chapter  Google Scholar 

  46. Königsberg R et al (2011) Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients. Acta Oncol 50(5):700–710

    Article  PubMed  Google Scholar 

  47. Naume B et al (2004) Detection of isolated tumor cells in peripheral blood and in BM: evaluation of a new enrichment method. Cytotherapy 6(3):244–252

    Article  CAS  PubMed  Google Scholar 

  48. Seal S (1964) A sieve for the isolation of cancer cells and other large cells from the blood. Cancer 17(5):637–642

    Article  CAS  PubMed  Google Scholar 

  49. Riethdorf S et al (2007) 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 13(3):920–928

    Article  CAS  PubMed  Google Scholar 

  50. Diamandis EP (2002) Tumor markers: physiology, pathobiology, technology, and clinical applications. American Association for Clinical Chemistry, Washington

    Google Scholar 

  51. Cristofanilli M et al (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791

    Article  CAS  PubMed  Google Scholar 

  52. Cristofanilli M et al (2005) Circulating tumor cells: a novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23(7):1420–1430

    Article  PubMed  Google Scholar 

  53. Giordano A et al (2013) Establishment and validation of circulating tumor cell-based prognostic nomograms in first-line metastatic breast cancer patients. Clin Cancer Res 19(6):1596–1602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Talasaz AH et al (2009) Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device. Proc Natl Acad Sci 106(10):3970–3975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Cruz I et al (2005) Evaluation of multiparameter flow cytometry for the detection of breast cancer tumor cells in blood samples. Am J Clin Pathol 123(1):66–74

    Article  PubMed  Google Scholar 

  56. Yu M et al (2011) Circulating tumor cells: approaches to isolation and characterization. J Cell Biol 192(3):373–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lee HJ et al (2013) Efficient isolation and accurate in situ analysis of circulating tumor cells using detachable beads and a high-pore-density filter. Angew Chem Int Ed 52(32):8337–8340

    Article  CAS  Google Scholar 

  58. McCarthy N (2014) The cancer kaleidoscope. Nat Rev Cancer 14:151–152

    Article  CAS  PubMed  Google Scholar 

  59. Chapman PB et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364(26):2507–2516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kwak EL et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363(18):1693–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Singh AK et al (2015) Tumor heterogeneity and cancer stem cell paradigm: updates in concept, controversies and clinical relevance. Int J Cancer 136(9):1991–2000

    Article  CAS  PubMed  Google Scholar 

  62. Marrinucci D et al (2010) Cytomorphology of circulating colorectal tumor cells: a small case series. J Oncol 2010:861341. doi:10.1155/2010/861341

    Article  PubMed  PubMed Central  Google Scholar 

  63. Khoo BL et al (2016c) Liquid biopsy and therapeutic response: circulating tumor cell cultures for evaluation of anticancer treatment. Sci Adv 2, e1600274

    Google Scholar 

  64. Alix-Panabieres C et al (2009) Full-length cytokeratin-19 is released by human tumor cells: a potential role in metastatic progression of breast cancer. Breast Cancer Res 11(3):R39

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Weichselbaum RR, Hellman S (2011) Oligometastases revisited. Nat Rev Clin Oncol 8(6):378–382

    CAS  PubMed  Google Scholar 

  66. Soslow RA et al (2012) Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma. Mod Pathol 25(4):625–636

    Article  CAS  PubMed  Google Scholar 

  67. Chen S et al (2012) Recent advances in morphological cell image analysis. Comput Math Methods Med 2012:101536

    PubMed  PubMed Central  Google Scholar 

  68. Gazdar AF et al (1985) Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res 45(6):2924–2930

    CAS  PubMed  Google Scholar 

  69. van de Stolpe A et al (2011) Circulating tumor cell isolation and diagnostics: toward routine clinical use. Cancer Res 71(18):5955–5960

    Article  PubMed  CAS  Google Scholar 

  70. Leversha MA et al (2009) Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin Cancer Res 15(6):2091–2097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Min JW et al (2015) Identification of distinct tumor subpopulations in lung adenocarcinoma via single-cell RNA-seq. PLoS One 10(8), e0135817

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Zhang L et al (2013) The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl Med 5(180):180ra48

    Google Scholar 

  73. Pantel K, Alix-Panabieres C (2013) Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res 73(21):6384–6388

    Article  CAS  PubMed  Google Scholar 

  74. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2(6):442–454

    Article  CAS  PubMed  Google Scholar 

  75. Ting DT et al (2014) Single-cell RNA sequencing identifies extracellular matrix gene expression by pancreatic circulating tumor cells. Cell Rep 8(6):1905–1918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Khoo BL et al (2016) Genesis of circulating tumor cells through epithelial–mesenchymal transition as a mechanism for distant dissemination. In: Circulating tumor cells. Springer, New York, pp 139–182

    Google Scholar 

  77. Marrinucci D et al (2007) Case study of the morphologic variation of circulating tumor cells. Hum Pathol 38(3):514–519

    Article  PubMed  Google Scholar 

  78. Goda K et al (2012) High-throughput single-microparticle imaging flow analyzer. Proc Natl Acad Sci U S A 109(29):11630–11635

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Goda K, Tsia KK, Jalali B (2009) Serial time-encoded amplified imaging for real-time observation of fast dynamic phenomena. Nature 458(7242):1145–1149

    Article  CAS  PubMed  Google Scholar 

  80. Navin N et al (2011) Tumour evolution inferred by single-cell sequencing. Nature 472:90–96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bissell MJ, Hines WC (2011) Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med 17(3):320–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Michor F, Weaver VM (2014) Understanding tissue context influences on intratumour heterogeneity. Nat Cell Biol 16(4):301–302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Network CGA (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337

    Article  CAS  Google Scholar 

  84. Brown JM, Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5(3):231–237

    CAS  PubMed  Google Scholar 

  85. Nagy P et al (1999) Activation-dependent clustering of the erbB2 receptor tyrosine kinase detected by scanning near-field optical microscopy. J Cell Sci 112(Pt 11):1733–1741

    CAS  PubMed  Google Scholar 

  86. Tan TZ et al (2014) Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med 6(10):1279–1293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4(6):448–456

    Article  CAS  PubMed  Google Scholar 

  88. Basik M et al (2013) Biopsies: next-generation biospecimens for tailoring therapy. Nat Rev Clin Oncol 10:437–450

    Article  CAS  PubMed  Google Scholar 

  89. Mimeault M, Batra SK (2014) Molecular biomarkers of cancer stem/progenitor cells associated with progression, metastases, and treatment resistance of aggressive cancers. Cancer Epidemiol Biomarkers Prev 23(2):234–254

    Article  CAS  PubMed  Google Scholar 

  90. Borgen E et al (1999) Standardization of the immunocytochemical detection of cancer cells in BM and blood: I. Establishment of objective criteria for the evaluation of immunostained cells. Cytotherapy 1(5):377–388

    Article  CAS  PubMed  Google Scholar 

  91. Gollapalli K et al (2012) Investigation of serum proteome alterations in human glioblastoma multiforme. Proteomics 12(14):2378–2390

    Article  CAS  PubMed  Google Scholar 

  92. Francis G, Stein S (2015) Circulating cell-free tumour DNA in the management of cancer. Int J Mol Sci 16(6):14122–14142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Diaz LA Jr et al (2012) The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature 486(7404):537–540

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Lebofsky R et al (2015) Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for tumor genotyping and personalized medicine in a prospective trial across all tumor types. Mol Oncol 9(4):783–790

    Article  CAS  PubMed  Google Scholar 

  95. Sonnenberg A et al (2013) Dielectrophoretic isolation and detection of cfc-DNA nanoparticulate biomarkers and virus from blood. Electrophoresis 34(7):1076–1084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. McCanna JP, Sonnenberg A, Heller MJ (2014) Low level epifluorescent detection of nanoparticles and DNA on dielectrophoretic microarrays. J Biophotonics 7(11–12):863–873

    Article  CAS  PubMed  Google Scholar 

  97. Bettegowda C et al (2014) Detection of circulating tumor DNA in early-and late-stage human malignancies. Sci Transl Med 6(224):224ra24

    Google Scholar 

  98. Diaz LA Jr et al (2013) Insights into therapeutic resistance from whole-genome analyses of circulating tumor DNA. Oncotarget 4(10):1856

    Article  PubMed  PubMed Central  Google Scholar 

  99. Chan M et al (2013) Identification of circulating microRNA signatures for breast cancer detection. Clin Cancer Res 19(16):4477–4487

    Article  CAS  PubMed  Google Scholar 

  100. Chen X et al (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18(10):997–1006

    Article  CAS  PubMed  Google Scholar 

  101. Dong L et al (2014) miRNA microarray reveals specific expression in the peripheral blood of glioblastoma patients. Int J Oncol 45(2):746–756

    CAS  PubMed  Google Scholar 

  102. Noerholm M et al (2012) RNA expression patterns in serum microvesicles from patients with glioblastoma multiforme and controls. BMC Cancer 12:22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Manterola L et al (2014) A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro Oncol 16(4):520–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Peinado H, Lavotshkin S, Lyden D (2011) The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol 21(2):139–146

    Article  CAS  PubMed  Google Scholar 

  105. Costa-Silva B et al (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol 17(6):816–826

    Article  CAS  PubMed  Google Scholar 

  106. Zhao L et al (2015) The role of exosomes and “exosomal shuttle microRNA” in tumorigenesis and drug resistance. Cancer Lett 356(2):339–346

    Article  CAS  PubMed  Google Scholar 

  107. Chen C et al (2010) Microfluidic isolation and transcriptome analysis of serum microvesicles. Lab Chip 10(4):505–511

    Article  CAS  PubMed  Google Scholar 

  108. Kanwar SS et al (2014) Microfluidic device (ExoChip) for on-chip isolation, quantification and characterization of circulating exosomes. Lab Chip 14(11):1891–1900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Davies RT et al (2012) Microfluidic filtration system to isolate extracellular vesicles from blood. Lab Chip 12(24):5202–5210

    Article  CAS  PubMed  Google Scholar 

  110. Im H et al (2014) Label-free detection and molecular profiling of exosomes with a nano-plasmonic sensor. Nat Biotechnol 32(5):490–495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Popescu ID et al (2014) Potential serum biomarkers for glioblastoma diagnostic assessed by proteomic approaches. Proc Natl Acad Sci U S A 12(1):47

    Google Scholar 

  112. Skog J et al (2008) Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol 10(12):1470–1476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zhang W et al (2012) miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression. Neuro Oncol 14(6):712–719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sozzi G et al (2014) Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. J Clin Oncol 32(8):768–773

    Article  PubMed  PubMed Central  Google Scholar 

  115. Belting M, Wittrup A (2008) Nanotubes, exosomes, and nucleic acid-binding peptides provide novel mechanisms of intercellular communication in eukaryotic cells: implications in health and disease. J Cell Biol 183(7):1187–1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Minciacchi VR, Freeman MR, Di Vizio D (2015) Extracellular vesicles in cancer: exosomes, microvesicles and the emerging role of large oncosomes. Semin Cell Dev Biol 40:41–51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Sun J et al (2010) A microfluidic platform for systems pathology: multiparameter single-cell signaling measurements of clinical brain tumor specimens. Cancer Res 70(15):6128–6138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Amir el-AD et al (2013) viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. Nat Biotechnol 31(6):545–552

    Google Scholar 

  119. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2(7):489–501

    Article  CAS  PubMed  Google Scholar 

  120. Khoo BL et al (2016b) Single‐cell profiling approaches to probing tumor heterogeneity. Int J Cancer 139(2):243–255

    Article  CAS  PubMed  Google Scholar 

  121. Dalerba P et al (2011) Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol 29(12):1120–1127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Jerome Marson V et al (2004) Expression of TTF-1 and cytokeratins in primary and secondary epithelial lung tumours: correlation with histological type and grade. Histopathology 45(2):125–134

    Article  CAS  PubMed  Google Scholar 

  123. Xu B et al (2010) Expression of thyroid transcription factor-1 in colorectal carcinoma. Appl Immunohistochem Mol Morphol 18(3):244–249

    Article  CAS  PubMed  Google Scholar 

  124. Ordonez NG (2012) Value of thyroid transcription factor-1 immunostaining in tumor diagnosis: a review and update. Appl Immunohistochem Mol Morphol 20(5):429–444

    Article  CAS  PubMed  Google Scholar 

  125. Lee JY et al (2015) Tumor evolution and intratumor heterogeneity of an epithelial ovarian cancer investigated using next-generation sequencing. BMC Cancer 15:85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Sottoriva A et al (2013) Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci U S A 110(10):4009–4014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hoadley KA et al (2014) Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin. Cell 158(4):929–944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Punnoose EA et al (2012) Evaluation of circulating tumor cells and circulating tumor DNA in non-small cell lung cancer: association with clinical endpoints in a phase II clinical trial of pertuzumab and erlotinib. Clin Cancer Res 18(8):2391–2401

    Article  CAS  PubMed  Google Scholar 

  129. Schiro PG et al (2012) Sensitive and high-throughput isolation of rare cells from peripheral blood with ensemble-decision aliquot ranking. Angew Chem Int Ed Engl 51(19):4618–4622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lohr JG et al (2014) Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat Biotechnol 32(5):479–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lacroix M (2007) Persistent use of “false” cell lines. Int J Cancer 122(1):1–4

    Article  CAS  Google Scholar 

  132. Cummings EB (2003) Streaming dielectrophoresis for continuous-flow microfluidic devices. IEEE Eng Med Biol Mag 22(6):75–84

    Article  PubMed  Google Scholar 

  133. Baldus SE et al (2010) Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding metastases. Clin Cancer Res 16:790

    Article  CAS  PubMed  Google Scholar 

  134. Kosmidou V et al (2014) Tumor heterogeneity revealed by KRAS, BRAF, and PIK3CA pyrosequencing: KRAS and PIK3CA intratumor mutation profile differences and their therapeutic implications. Hum Mutat 35(3):329–340

    Article  CAS  PubMed  Google Scholar 

  135. Deng G et al (2014) Single cell mutational analysis of PIK3CA in circulating tumor cells and metastases in breast cancer reveals heterogeneity, discordance, and mutation persistence in cultured disseminated tumor cells from bone marrow. BMC Cancer 14:456

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Cooper WA et al (2013) Molecular biology of lung cancer. J Thorac Dis 5(Suppl 5):S479–S490

    PubMed  PubMed Central  Google Scholar 

  137. Ide Y et al (2014) Single cell lipidomics of SKBR-3 breast cancer cells by using time-of-flight secondary-ion mass spectrometry. Surf Interface Anal. doi:10.1002/sia.5523

    Google Scholar 

  138. Denbigh JL, Lockyer NP (2014) ToF-SIMS as tool for profiling lipids in cancer and other diseases. Mater Sci Technol. doi:10.1179/1743284714Y.0000000648(0)

    Google Scholar 

  139. Joosse SA, Gorges TM, Pantel K (2015) Biology, detection, and clinical implications of circulating tumor cells. EMBO Mol Med 7(1):1–11

    Article  CAS  Google Scholar 

  140. Nemes P et al (2012) Single-cell metabolomics: changes in the metabolome of freshly isolated and cultured neurons. ACS Chem Neurosci 3:782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. O’Brien PJ et al (2013) Monitoring metabolic responses to chemotherapy in single cells and tumors using nanostructure-initiator mass spectrometry (NIMS) imaging. Cancer Metab 1(1):4

    Article  PubMed  PubMed Central  Google Scholar 

  142. Vishnoi M et al (2015) The isolation and characterization of CTC subsets related to breast cancer dormancy. Sci Rep 5:17533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Yu M et al (2014) Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 345(6193):216–220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Prince ME et al (2007) 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 104(3):973–978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Charafe-Jauffret E et al (2010) Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer. Clin Cancer Res 16(1):45–55

    Article  CAS  PubMed  Google Scholar 

  146. Ennen M et al (2014) Single-cell gene expression signatures reveal melanoma cell heterogeneity. Oncogene. doi:10.1038/onc.2014.262

    Google Scholar 

  147. Tinhofer I et al (2014) Cancer stem cell characteristics of circulating tumor cells. Int J Radiat Biol 90(8):622–627

    Article  CAS  PubMed  Google Scholar 

  148. Seymour T, Nowak A, Kakulas F (2015) Targeting aggressive cancer stem cells in glioblastoma. Front Oncol 5:159

    Article  PubMed  PubMed Central  Google Scholar 

  149. Whitesides GM (2006) The origins and the future of microfluidics. Nature 442(7101):368–373

    Article  CAS  PubMed  Google Scholar 

  150. Alix-Panabières C, Pantel K (2014) Challenges in circulating tumour cell research. Nat Rev Cancer 14(9):623–631

    Article  PubMed  CAS  Google Scholar 

  151. de Wit S et al (2015) The detection of EpCAM+ and EpCAM− circulating tumor cells. Sci Rep 5

    Google Scholar 

  152. Sun Y-F et al (2011) Circulating tumor cells: advances in detection methods, biological issues, and clinical relevance. J Cancer Res Clin Oncol 137(8):1151–1173

    Article  PubMed  Google Scholar 

  153. Brown P (2016) The Cobas(R) EGFR Mutation Test v2 assay. Future Oncol 12:451–452

    Article  CAS  PubMed  Google Scholar 

  154. Larsen JE, Minna JD (2011) Molecular biology of lung cancer: clinical implications. Clin Chest Med 32(4):703–740

    Article  PubMed  PubMed Central  Google Scholar 

  155. Krebs MG et al (2014) Molecular analysis of circulating tumour cells—biology and biomarkers. Nat Rev Clin Oncol 11(3):129–144

    Article  CAS  PubMed  Google Scholar 

  156. Plaks V, Koopman CD, Werb Z (2013) Cancer. Circulating tumor cells. Science 341(6151):1186–1188

    Article  CAS  PubMed  Google Scholar 

  157. Meng S et al (2004) Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 10(24):8152–8162

    Article  PubMed  Google Scholar 

  158. Kros JM et al (2015) Circulating glioma biomarkers. Neuro Oncol 17(3):343–360

    PubMed  Google Scholar 

  159. Khoo, BL et al (2016) Liquid biopsy and therapeutic response: Circulating tumor cell cultures for evaluation of anticancer treatment. Science Advances 2(e1600274).

    Google Scholar 

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Acknowledgments

B.L.K. acknowledges support from the National Research Foundation (NRF), Prime Minister’s Office, Singapore, under CREATE, Singapore-MIT Alliance for Research and Technology (SMART) BioSystems and Micromechanics (BioSyM) IRG and MBI. P.K.C. acknowledges the support from the Mechanobiology Institute (MBI) for the Graduate Scholarship. We thank Mr. Wong Chun Xi (MBInfo) for helping with the illustrations.

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Correspondence to Majid Ebrahimi Warkiani .

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Khoo, B.L., Chaudhuri, P.K., Lim, C.T., Warkiani, M.E. (2017). Advancing Techniques and Insights in Circulating Tumor Cell (CTC) Research. In: Aref, A., Barbie, D. (eds) Ex Vivo Engineering of the Tumor Microenvironment. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-45397-2_5

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