Skip to main content
SpringerLink
Log in

Cancer Stem Cells and Circulating Tumor Cells: Molecular Markers, Isolation Techniques, and Clinical Implications

  • Chapter
  • First Online:
Circulating Tumor Cells

Part of the book series: Current Cancer Research ((CUCR))

  • 1764 Accesses

Abstract

There is now a considerable body of evidence that many cancers are hierarchically organized and driven by a cellular component termed “cancer stem cells” (CSCs). These cells have the ability to self-renew and to generate heterogeneous populations that constitute the tumor bulk. Preclinical studies have demonstrated that CSCs mediate tumor metastasis and resistance to chemotherapy and radiation therapy. CSC biomarkers have been identified and both in vitro and mouse models have been developed to facilitate the isolation of these cells as well as the elucidation of CSC regulatory pathways. Agents targeting CSCs have now entered early phase clinical trials. The development of these clinical trials highlights the important need to develop technologies to monitor CSCs in patients. Unlike hematologic malignancies, where tumor specimens are readily obtainable, in solid tumors obtaining serial biopsies to assess CSCs is difficult. Studies suggest that circulating tumor cells (CTCs) contain a highly enriched proportion of CSCs and thus monitoring these cells in blood may provide a liquid biopsy for CSC assessment in solid tumors. In parallel with developments of efficient CTC isolation technologies, assays to molecularly characterize these cells at single cell resolution are also being developed. In this chapter we will review the current status of CSC therapeutic technologies as well as microfluidic techniques for isolation and molecular characterization of CTCs in cancer patients. If CSCs are responsible for tumor metastasis, resistance, and recurrence, development of effective CSC therapies has the potential to significantly improve the efficacy of cancer treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Sell S (2004) Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 51:1–28

    Article  PubMed  Google Scholar 

  2. Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G et al (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65:5506–5511

    Article  CAS  PubMed  Google Scholar 

  3. Douville J, Beaulieu R, Balicki D (2009) ALDH1 as a functional marker of cancer stem and progenitor cells. Stem Cells Dev 18:17–25

    Article  CAS  PubMed  Google Scholar 

  4. Naor D, Wallach-Dayan SB, Zahalka MA, Sionov RV (2008) Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin Cancer Biol 18(4):260–267

    Article  CAS  PubMed  Google Scholar 

  5. Kristiansen G, Winzer KJ, Mayordomo E, Bellach J et al (2003) CD24 expression is a new prognostic marker in breast cancer. Clin Cancer Res 9(13):4906–4913

    CAS  PubMed  Google Scholar 

  6. Jaggupilli A, Elkord E (2012) Significance of CD44 and CD24 as cancer stem cell markers an enduring ambiguity. Clin Dev Immunol 2012:708036

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  7. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100(7):3983–3988

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Ricardo S, Vieira AF, Gerhard R, Leitão D et al (2011) Breast cancer stem cell markers CD44, CD24 and ALDH1 expression distribution within intrinsic molecular subtype. J Clin Pathol 64:937–946

    Article  PubMed  Google Scholar 

  9. Swaminathan SK, Roger E, Toti U, Niu L et al (2013) CD133-targeted paclitaxel delivery inhibits local tumor recurrence in a mouse model of breast cancer. J Control Release 171(3):2807

    Article  CAS  Google Scholar 

  10. Ji Q, Hao X, Zhang M, Tang W et al (2009) MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One 4(8):e6816

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. Ginestier C, HeeHur M, Charafe-Jauffret E, Monville F et al (2007) ALDH1 is a marker of normal and malignant breast stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1(5):555–567

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Suman S, Das TP, Damodaran C (2013) Silencing NOTCH signaling causes growth arrest in both breast cancer stem cells and breast cancer cells. Br J Cancer 109(10):2587–2596

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Dontu G, Wicha MS (2005) Survival of mammary stem cells in suspension culture: implications for stem cell biology and neoplasia. J Mammary Gland Biol Neoplasia 10:75–86

    Article  PubMed  Google Scholar 

  14. Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K et al (2010) Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12:468–476

    Article  CAS  PubMed  Google Scholar 

  15. Benjamin CL, Melnikova VO, Ananthaswamy HN (2007) Models and mechanisms in malignant melanoma. Mol Carcinog 46:671–678

    Article  CAS  PubMed  Google Scholar 

  16. Larue L, Beermann F (2007) Cutaneous melanoma in genetically modified animals. Pigment Cell Res 20:485–497

    Article  CAS  PubMed  Google Scholar 

  17. Adams JM, Cory S (1991) Transgenic models of tumor development. Science 254:1161–1167

    Article  CAS  PubMed  Google Scholar 

  18. Chen J, Li Y, Yu T-S, McKay RM et al (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:522–526. doi:10.1038/nature11287

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C (2012) Defining the mode of tumor growth by clonal analysis. Nature 488:527–530. doi:10.1038/nature11344

    Article  CAS  PubMed  Google Scholar 

  20. Schepers AG, Snippert HJ, Stange DE, van den Born M et al (2012) Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337(6095):730–735

    Article  CAS  PubMed  Google Scholar 

  21. Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P et al (2012) Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 4(149):149ra118

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Chavey C, Bibeau F, Gourgou-Bourgade S, Burlinchon S et al (2007) Oestrogen receptor negative breast cancers exhibit high cytokine content. Breast Cancer Res 9(1):R15

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Liu S, Dontu G, Wicha MS (2005) Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res 7:86–95

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Lee HE, Kim JH, Kim YJ, Choi SY et al (2011) An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer. Br J Cancer 104:1730–1738

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Gao H, Chakraborty G, Lee-Lim AP, Mo Q et al (2012) The BMP inhibitor coco reactivates breast cancer cells at lung metastatic sites. Cell 150:764–779

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Padua D, Zhang XH, Wang Q, Nadal C et al (2008) TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133:66–77

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Tu LC, Foltz G, Lin E, Hood L, Tian Q (2009) Targeting stem cells clinical implications for cancer therapy. Curr Stem Cell Res Ther 4(2):147–153

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Malik B, Nie D (2012) Cancer stem cells and resistance to chemo and radio therapy. Front Biosci (Elite Ed) 1(4):2142–2149

    Article  Google Scholar 

  29. Yu F, Yao H, Zhu P et al (2007) let-7 regulates self-renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123

    Article  CAS  PubMed  Google Scholar 

  30. Korkaya H, Kim GI, Davis A, Malik F et al (2012) Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell 47(4):570–584

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. May CD, Sphyris N, Evans KW, Werden SJ et al (2011) Epithelial–mesenchymal transition and cancer stem cells a dangerously dynamic duo in breast cancer progression. Breast Cancer Res 13:202

    Article  PubMed Central  PubMed  Google Scholar 

  32. Mallini P, Lennard T, Kirby J, Meeson A (2014) Epithelial-to-mesenchymal transition: what is the impact on breast cancer stem cells and drug resistance. Cancer Treat Rev 40:341–348, pii S0305-7372 (13) 00197–7

    Article  CAS  PubMed  Google Scholar 

  33. Mani SA, Guo W, Liao MJ, Eaton EN et al (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133(4):704–715

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Liu S, Cong Y, Wang D, Sun Y et al (2013) Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2:78–91. doi:10.1016/j.stemcr.2013.11.009

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Murray NP, Reyes E, Tapia P, Badinez L et al (2012) Redefining micrometastasis in prostate cancer—a comparison of circulating prostate cells, bone marrow disseminated tumor cells and micrometastasis: implications in determining local or systemic treatment for biochemical failure after radical prostatectomy. Int J Mol Med 30:896–904. doi:10.3892/ijmm.2012.1071

    CAS  PubMed  Google Scholar 

  36. Lianidou ES, Markou A, Strati A (2012) Molecular characterization of circulating tumor cells in breast cancer challenges and promises for individualized cancer treatment. Cancer Metastasis Rev 31(3–4):663–671

    Article  CAS  PubMed  Google Scholar 

  37. Joosse SA, Pantel K (2013) Biologic challenges in the detection of circulating tumor cells. Cancer Res 73:8–11

    Article  CAS  PubMed  Google Scholar 

  38. Cristofanilli M, Hayes DF, Budd GT, Ellis MJ 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 

  39. Maheswaran S, Sequist LV, Nagrath S, Ulkus L et al (2008) Detection of mutations in EGFR in circulating lung-cancer cells. N Engl J Med 359(4):366–377

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Nagrath S, Sequist LV, Maheswaran S, Bell DW et al (2007) Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450(7173):1235–1239

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Liu H, Patel MR, Prescher JA, Patsialou A et al (2010) Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci U S A 107:18115–18120

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A 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 31:539–544. doi:10.1038/nbt.2576

    Article  CAS  PubMed  Google Scholar 

  43. Korkaya H, Paulson A, Iovino F, Wicha MS (2008) HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 27:6120–6130

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Ithimakin S, Day KC, Malik F, Zen Q et al (2013) HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification implications for efficacy of adjuvant trastuzumab. Cancer Res 73(5):1635–1646

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Riethdorf S, Müller V, Zhang L, Rau T et al (2010) Detection and HER2 expression of circulating tumor cells prospective monitoring in breast cancer patients treated in the neoadjuvant Gepar Quattro trial. Clin Cancer Res 16:2634–2645

    Article  CAS  PubMed  Google Scholar 

  46. Pestrin M, Bessi S, Puglisi F, Minisini AM et al (2012) 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 134:283–289

    Article  CAS  PubMed  Google Scholar 

  47. Yu M, Bardia A, Wittner BS, Stott SL et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339:580–584

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Giordano A, Giuliano M, De Laurentiis M et al (2011) Artificial neural network analysis of circulating tumor cells in metastatic breast cancer patients. Breast Cancer Res Treat 129:451–458

    Article  PubMed  Google Scholar 

  49. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A 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 

  50. Cohen S, Punt C, Iannotti N, Saidman B et al (2009) Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer. Ann Oncol 20(7):1223–1229

    Article  CAS  PubMed  Google Scholar 

  51. Olmos D, Arkenau H, Ang J, Ledaki I et al (2009) Circulating tumor cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience. Ann Oncol 20(1):27–33

    Article  CAS  PubMed  Google Scholar 

  52. Allard WJ, Matera J, Miller MC, Repollet M 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 

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

    Article  CAS  PubMed  Google Scholar 

  54. Khandurina J, McKnight TE, Jacobson SC, Waters LC, Foote RS, Ramsey JM (2000) Integrated system for rapid PCR-based DNA analysis in microfluidic devices. Anal Chem 72(13):2995–3000

    Article  CAS  PubMed  Google Scholar 

  55. Erickson D, Li D (2004) Integrated microfluidic devices. Anal Chim Acta 507(1):11–26

    Article  CAS  Google Scholar 

  56. Haeberle S, Zengerle R (2007) Microfluidic platforms for lab-on-a-chip applications. Lab Chip 7(9):1094–1110

    Article  CAS  PubMed  Google Scholar 

  57. Gleghorn JP, Pratt ED, Denning D, Liu H et al (2010) Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody. Lab Chip 10(1):27–29

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Adams AA, Okagbare PI, Feng J, Hupert ML et al (2008) Highly efficient circulating tumor cell isolation from whole blood and label-free enumeration using polymer-based microfluidics with an integrated conductivity sensor. J Am Chem Soc 130(27):8633–8641

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Stott SL, Hsu C, Tsukrov DI, Yu M et al (2010) Isolation of circulating tumor cells using a microvortex-generating herringbone-chip. Proc Natl Acad Sci 107(43):18392–18397

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Yoon HJ, Kim TH, Zhang Z, Azizi E et al (2013) Sensitive capture of circulating tumour cells by functionalized graphene oxide nanosheets. Nat Nanotechnol 8(10):735–741

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Lin HK, Zheng S, Williams AJ, Balic M et al (2010) Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin Cancer Res 16(20):5011–5018

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Vona G, Estepa L, Béroud C, Damotte D et al (2004) Impact of cytomorphological detection of circulating tumor cells in patients with liver cancer. Hepatology 39(3):792–797

    Article  PubMed  Google Scholar 

  63. Zheng S, Lin H, Liu J, Balic M et al (2007) Membrane microfilter device for selective capture, electrolysis and genomic analysis of human circulating tumor cells. J Chromatogr A 1162(2):154–161

    Article  CAS  PubMed  Google Scholar 

  64. Zheng S, Lin HK, Lu B, Williams A 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 

  65. Kuo JS, Zhao Y, Schiro PG, Ng L et al (2010) Deformability considerations in filtration of biological cells. Lab Chip 10(7):837–842

    Article  CAS  PubMed  Google Scholar 

  66. Zhou J, Papautsky I (2013) Fundamentals of inertial focusing in microchannels. Lab Chip 13(6):1121–1132

    Article  CAS  PubMed  Google Scholar 

  67. Bhagat AAS, Kuntaegowdanahalli SS, Papautsky I (2008) Continuous particle separation in spiral microchannels using dean flows and differential migration. Lab Chip 8(11):1906–1914

    Article  CAS  PubMed  Google Scholar 

  68. Hou HW, Warkiani ME, Khoo BL, Li ZR et al (2013) Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci Rep 3:1259

    PubMed Central  PubMed  Google Scholar 

  69. Ozkumur E, Shah AM, Ciciliano JC, Emmink BL et al (2013) Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells. Sci Transl Med 5(179):179ra47

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  70. Moon H, Kwon K, Kim S, Han H et al (2011) Continuous separation of breast cancer cells from blood samples using multi-orifice flow fractionation (MOFF) and dielectrophoresis (DEP). Lab Chip 11(6):1118–1125

    Article  CAS  PubMed  Google Scholar 

  71. Fuchs AB, Romani A, Freida D, Medoro G et al (2006) Electronic sorting and recovery of single live cells from microlitre sized samples. Lab Chip 6(1):121–126

    Article  CAS  PubMed  Google Scholar 

  72. Chen W, Weng S, Zhang F, Allen S et al (2012) Nanoroughened surfaces for efficient capture of circulating tumor cells without using capture antibodies. ACS Nano 7(1):566–575

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  73. Chen C, Chen K, Pan Y, Lee T et al (2011) Separation and detection of rare cells in a microfluidic disk via negative selection. Lab Chip 11(3):474–483

    Article  CAS  PubMed  Google Scholar 

  74. Sieuwerts AM, Kraan J, Bolt J, van der Spoel P et al (2009) Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst 101(1):61–66

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Zhang W, Kai K, Choi DS, Iwamoto T et al (2012) Microfluidics separation reveals the stem-cell-like deformability of tumor-initiating cells. Proc Natl Acad Sci U S A 109(46):18707–18712

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Fachin F, Wardle B, Chen G, Toner M (2010) Integration of vertically-aligned carbon nanotube forests in microfluidic devices for multiscale isolation of bioparticles. IEEE SENSORS 47–51

    Google Scholar 

  77. Chen GD, Fachin F, Fernandez-Suarez M, Wardle BL, Toner M (2011) Nanoporous elements in microfluidics for multiscale manipulation of bioparticles. Small 7(8):1061–1067

    Google Scholar 

  78. Wang S, Liu K, Liu J, Yu ZT, Xu X et al (2011) Highly efficient capture of circulating tumor cells by using nanostructured silicon substrates with integrated chaotic micromixers. Angew Chem Int Ed 50(13):3084–3088

    Article  CAS  Google Scholar 

  79. Hou S, Zhao H, Zhao L, Shen Q et al (2013) Capture and stimulated release of circulating tumor cells on Polymer‐Grafted silicon nanostructures. Adv Mater 25(11):1547–1551

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Zhang N, Deng Y, Tai Q, Cheng B et al (2012) Electrospun TiO2 nanofiber‐based cell capture assay for detecting circulating tumor cells from colorectal and gastric cancer patients. Adv Mater 24(20):2756–2760

    Article  CAS  PubMed  Google Scholar 

  81. Polyak K, Weinberg R (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273

    Article  CAS  PubMed  Google Scholar 

  82. Galizia G, Gemei M, Del Vecchio L, Zamboli A et al (2012) Combined CD133/CD44 expression as a prognostic indicator of disease-free survival in patients with colorectal cancer. Arch Surg 147(1):18–24

    Article  CAS  PubMed  Google Scholar 

  83. Saigusa S, Inoue Y, Tanaka K, Toiyama Y et al (2012) Clinical significance of LGR5 and CD44 expression in locally advanced rectal cancer after preoperative chemoradiotherapy. Int J Oncol. doi:10.3892/ijo.2012.1598

    Google Scholar 

  84. Song CW, Lee H, Dings RP, Williams B et al (2012) Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep 2:362. doi:10.1038/srep00362

    PubMed Central  PubMed  Google Scholar 

  85. Kakarala M, Brenner DE, Khorkaya H, Cheng C et al (2010) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122(3):777–785

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Li Y, Zhang T, Korkaya H, Liu S et al (2010) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 16(9):2580–2590

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  87. Liu S, Wicha MS (2010) Targeting breast cancer stem cells. J Clin Oncol 28(25):4006–4012

    Article  CAS  PubMed  Google Scholar 

  88. Tokunaga E, Oki E, Nishida K, Koga T et al (2006) Trastuzumab and breast cancer developments and current status. Int J Clin Oncol 11(3):199–208

    Article  CAS  PubMed  Google Scholar 

  89. Grotenhuis BA, Wijnhoven BP, van Lanschot JJ (2012) Cancer stem cells and their potential implications for the treatment of solid tumors. J Surg Oncol 106:209–215

    Article  CAS  PubMed  Google Scholar 

  90. Schatton T, Frank NY, Frank MH (2009) Identification and targeting of cancer stem cells. Bioessays 31:1038–1049

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Zhou BB, Zhang H, Damelin M et al (2009) Tumor-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 8:806–823

    Article  CAS  PubMed  Google Scholar 

  92. Montemurro F, Donadio M, Clavarezza M, Redana S et al (2006) Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab based therapy. Oncologist 11(4):318–324

    Article  CAS  PubMed  Google Scholar 

  93. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792

    Article  CAS  PubMed  Google Scholar 

  94. Li X, Lewis MT, Huang J, Gutierrez C et al (2008) Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 100(9):672–679

    Article  CAS  PubMed  Google Scholar 

  95. Cameron D, Casey M, Press M, Lindquist D et al (2008) A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab updated efficacy and biomarker analyses. Breast Cancer Res Treat 112(3):533–543

    Article  CAS  PubMed  Google Scholar 

  96. Farnie G, Clarke RB, Spence K, Pinnock N et al (2007) Novel cell culture technique for primary ductal carcinoma in situ role of Notch and epidermal growth factor receptor signaling pathways. J Natl Cancer Inst 99(8):616–627

    Article  CAS  PubMed  Google Scholar 

  97. Singh JK, Farnie G, Bundred NJ, Simoes BM et al (2013) Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clin Cancer Res 19(3):643–656

    Article  CAS  PubMed  Google Scholar 

  98. Ginestier C, Liu S, Diebel ME, Korkaya H et al (2010) CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 120(2):485–497

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Green AR, Green VL, White MC, Speirs V (1997) Expression of cytokine messenger RNA in normal and neoplastic human breast tissue identification of interleukin-8 as a potential regulatory factor in breast tumors. Int J Cancer 72(6):937–941

    Article  CAS  PubMed  Google Scholar 

  100. Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14(21):6735–6741

    Article  CAS  PubMed  Google Scholar 

  101. Korkaya H, Wicha MS (2013) Breast cancer stem cells we’ve got them surrounded. Clin Cancer Res 19(3):511–513

    Article  CAS  PubMed  Google Scholar 

  102. Leitner JM, Mayr FB, Firbas C, Spiel AO et al (2007) Reparixin, a specific interleukin-8 inhibitor, has no effects on inflammation during endotoxemia. Int J Immunopathol Pharmacol 20(1):25–36

    CAS  PubMed  Google Scholar 

  103. VanEs JH, Clevers H (2005) Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol Med 11:496–502

    Article  CAS  Google Scholar 

  104. Takebe N, Nguyen D, Yang SX (2014) Targeting Notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther 141:140–149, doi.org/10.1016

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Krop I, Demuth T, Guthrie T, Wen PY et al (2012) Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol 30:2307–2313

    Article  CAS  PubMed  Google Scholar 

  106. Schott AF, Landis MD, Dontu G, Griffith KA et al (2013) Preclinical and clinical studies of gamma secretase inhibitors with docetaxel onhuman breast tumors. Clin Cancer Res 19:1512–1524

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Zhang CC, Pavlicek A, Zhang Q, Lira ME et al (2012) Biomarker and pharmacologic evaluation of the γ-secretase inhibitor PF-03084014 in breast cancer models. Clin Cancer Res 18(18):5008–5019

    Article  CAS  PubMed  Google Scholar 

  108. Frank NY, Margaryan A, Huang Y, Schatton T et al (2005) ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 65:4320–4333

    Article  CAS  PubMed  Google Scholar 

  109. Todaro M, Lombardo Y, Francipane MG, Alea MP et al (2008) Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ 15:762–772

    Article  CAS  PubMed  Google Scholar 

  110. Gupta PB, Onder TT, Jiang G, Tao K et al (2009) Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138:645–659

    Article  CAS  PubMed  Google Scholar 

  111. Saito Y, Uchida N, Tanaka S, Suzuki N et al (2010) Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 28(3):275–280

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cancer Stem Cells Research, University of Michigan, Ann Arbor, MI, USA

    Ebrahim Azizi Pharm.D, Ph.D.

  2. Department of Chemical Engineering & Biomedical Engineering, Biointerfaces Institute, Translational Oncology Program, University of Michigan, Ann Arbor, MI, USA

    Molly Kozminsky M.S.E.

  3. Department of Chemical Engineering, Biointerfaces Institute, Translational Oncology, University of Michigan, Ann Arbor, MI, USA

    Sunitha Nagrath Ph.D.

  4. Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, NCRC 26-335S, SPC 2800, 2800 Plymouth Road, Ann Arbor, MI, USA

    Max S. Wicha M.D.

Authors
  1. Ebrahim Azizi Pharm.D, Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sunitha Nagrath Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Molly Kozminsky M.S.E.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Max S. Wicha M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Max S. Wicha M.D. .

Editor information

Editors and Affiliations

  1. Jackson Memorial Hospital, University of Miami, Miami, Florida, USA

    Richard J. Cote

  2. University of Miami, Miami, Florida, USA

    Ram H. Datar

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Science+Business Media New York

About this chapter

Cite this chapter

Azizi, E., Nagrath, S., Kozminsky, M., Wicha, M.S. (2016). Cancer Stem Cells and Circulating Tumor Cells: Molecular Markers, Isolation Techniques, and Clinical Implications. In: Cote, R., Datar, R. (eds) Circulating Tumor Cells. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3363-1_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-3363-1_5

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-3361-7

  • Online ISBN: 978-1-4939-3363-1

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation