Circulating Tumor Cells pp 75-97

Part of the Current Cancer Research book series (CUCR) | Cite as

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

  • Ebrahim Azizi
  • Sunitha Nagrath
  • Molly Kozminsky
  • Max S. Wicha
Chapter

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.

Keywords

Cancer stem cells Circulating tumor cells Self-renewal Metastasis Tumor resistance Tumor recurrence CSC targeted therapy CTC isolation Microfluidics methods Liquid biopsy 

References

  1. 1.
    Sell S (2004) Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 51:1–28PubMedCrossRefGoogle Scholar
  2. 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 65:5506–5511PubMedCrossRefGoogle Scholar
  3. 3.
    Douville J, Beaulieu R, Balicki D (2009) ALDH1 as a functional marker of cancer stem and progenitor cells. Stem Cells Dev 18:17–25PubMedCrossRefGoogle Scholar
  4. 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):260–267PubMedCrossRefGoogle Scholar
  5. 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):4906–4913PubMedGoogle Scholar
  6. 6.
    Jaggupilli A, Elkord E (2012) Significance of CD44 and CD24 as cancer stem cell markers an enduring ambiguity. Clin Dev Immunol 2012:708036PubMedCentralPubMedCrossRefGoogle Scholar
  7. 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):3983–3988PubMedCentralPubMedCrossRefGoogle Scholar
  8. 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 64:937–946PubMedCrossRefGoogle Scholar
  9. 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):2807CrossRefGoogle Scholar
  10. 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):e6816PubMedCentralPubMedCrossRefGoogle Scholar
  11. 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):555–567PubMedCentralPubMedCrossRefGoogle Scholar
  12. 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):2587–2596PubMedCentralPubMedCrossRefGoogle Scholar
  13. 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 10:75–86PubMedCrossRefGoogle Scholar
  14. 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 12:468–476PubMedCrossRefGoogle Scholar
  15. 15.
    Benjamin CL, Melnikova VO, Ananthaswamy HN (2007) Models and mechanisms in malignant melanoma. Mol Carcinog 46:671–678PubMedCrossRefGoogle Scholar
  16. 16.
    Larue L, Beermann F (2007) Cutaneous melanoma in genetically modified animals. Pigment Cell Res 20:485–497PubMedCrossRefGoogle Scholar
  17. 17.
    Adams JM, Cory S (1991) Transgenic models of tumor development. Science 254:1161–1167PubMedCrossRefGoogle Scholar
  18. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  19. 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 PubMedCrossRefGoogle Scholar
  20. 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):730–735PubMedCrossRefGoogle Scholar
  21. 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):149ra118PubMedCentralPubMedCrossRefGoogle Scholar
  22. 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):R15PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Liu S, Dontu G, Wicha MS (2005) Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res 7:86–95PubMedCentralPubMedCrossRefGoogle Scholar
  24. 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 104:1730–1738PubMedCentralPubMedCrossRefGoogle Scholar
  25. 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 150:764–779PubMedCentralPubMedCrossRefGoogle Scholar
  26. 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 133:66–77PubMedCentralPubMedCrossRefGoogle Scholar
  27. 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):147–153PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Malik B, Nie D (2012) Cancer stem cells and resistance to chemo and radio therapy. Front Biosci (Elite Ed) 1(4):2142–2149CrossRefGoogle Scholar
  29. 29.
    Yu F, Yao H, Zhu P et al (2007) let-7 regulates self-renewal and tumorigenicity of breast cancer cells. Cell 131:1109–1123PubMedCrossRefGoogle Scholar
  30. 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):570–584PubMedCentralPubMedCrossRefGoogle Scholar
  31. 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 13:202PubMedCentralPubMedCrossRefGoogle Scholar
  32. 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) 00197–7PubMedCrossRefGoogle Scholar
  33. 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):704–715PubMedCentralPubMedCrossRefGoogle Scholar
  34. 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 PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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 PubMedGoogle Scholar
  36. 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):663–671PubMedCrossRefGoogle Scholar
  37. 37.
    Joosse SA, Pantel K (2013) Biologic challenges in the detection of circulating tumor cells. Cancer Res 73:8–11PubMedCrossRefGoogle Scholar
  38. 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):1420–1430PubMedCrossRefGoogle Scholar
  39. 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):366–377PubMedCentralPubMedCrossRefGoogle Scholar
  40. 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):1235–1239PubMedCentralPubMedCrossRefGoogle Scholar
  41. 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 107:18115–18120PubMedCentralPubMedCrossRefGoogle Scholar
  42. 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 PubMedCrossRefGoogle Scholar
  43. 43.
    Korkaya H, Paulson A, Iovino F, Wicha MS (2008) HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 27:6120–6130PubMedCentralPubMedCrossRefGoogle Scholar
  44. 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):1635–1646PubMedCentralPubMedCrossRefGoogle Scholar
  45. 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 16:2634–2645PubMedCrossRefGoogle Scholar
  46. 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 134:283–289PubMedCrossRefGoogle Scholar
  47. 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 339:580–584PubMedCentralPubMedCrossRefGoogle Scholar
  48. 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 129:451–458PubMedCrossRefGoogle Scholar
  49. 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):781–791PubMedCrossRefGoogle Scholar
  50. 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):1223–1229PubMedCrossRefGoogle Scholar
  51. 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):27–33PubMedCrossRefGoogle Scholar
  52. 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):6897–6904PubMedCrossRefGoogle Scholar
  53. 53.
    Whitesides GM (2006) The origins and the future of microfluidics. Nature 442(7101):368–373PubMedCrossRefGoogle Scholar
  54. 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):2995–3000PubMedCrossRefGoogle Scholar
  55. 55.
    Erickson D, Li D (2004) Integrated microfluidic devices. Anal Chim Acta 507(1):11–26CrossRefGoogle Scholar
  56. 56.
    Haeberle S, Zengerle R (2007) Microfluidic platforms for lab-on-a-chip applications. Lab Chip 7(9):1094–1110PubMedCrossRefGoogle Scholar
  57. 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):27–29PubMedCentralPubMedCrossRefGoogle Scholar
  58. 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):8633–8641PubMedCentralPubMedCrossRefGoogle Scholar
  59. 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):18392–18397PubMedCentralPubMedCrossRefGoogle Scholar
  60. 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):735–741PubMedCentralPubMedCrossRefGoogle Scholar
  61. 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):5011–5018PubMedCentralPubMedCrossRefGoogle Scholar
  62. 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):792–797PubMedCrossRefGoogle Scholar
  63. 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):154–161PubMedCrossRefGoogle Scholar
  64. 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):203–213PubMedCrossRefGoogle Scholar
  65. 65.
    Kuo JS, Zhao Y, Schiro PG, Ng L et al (2010) Deformability considerations in filtration of biological cells. Lab Chip 10(7):837–842PubMedCrossRefGoogle Scholar
  66. 66.
    Zhou J, Papautsky I (2013) Fundamentals of inertial focusing in microchannels. Lab Chip 13(6):1121–1132PubMedCrossRefGoogle Scholar
  67. 67.
    Bhagat AAS, Kuntaegowdanahalli SS, Papautsky I (2008) Continuous particle separation in spiral microchannels using dean flows and differential migration. Lab Chip 8(11):1906–1914PubMedCrossRefGoogle Scholar
  68. 68.
    Hou HW, Warkiani ME, Khoo BL, Li ZR et al (2013) Isolation and retrieval of circulating tumor cells using centrifugal forces. Sci Rep 3:1259PubMedCentralPubMedGoogle Scholar
  69. 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):179ra47PubMedCentralPubMedCrossRefGoogle Scholar
  70. 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):1118–1125PubMedCrossRefGoogle Scholar
  71. 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):121–126PubMedCrossRefGoogle Scholar
  72. 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):566–575PubMedCentralPubMedCrossRefGoogle Scholar
  73. 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):474–483PubMedCrossRefGoogle Scholar
  74. 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):61–66PubMedCentralPubMedCrossRefGoogle Scholar
  75. 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):18707–18712PubMedCentralPubMedCrossRefGoogle Scholar
  76. 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 47–51Google Scholar
  77. 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):1061–1067Google Scholar
  78. 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):3084–3088CrossRefGoogle Scholar
  79. 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):1547–1551PubMedCentralPubMedCrossRefGoogle Scholar
  80. 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):2756–2760PubMedCrossRefGoogle Scholar
  81. 81.
    Polyak K, Weinberg R (2009) Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9(4):265–273PubMedCrossRefGoogle Scholar
  82. 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):18–24PubMedCrossRefGoogle Scholar
  83. 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. 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 PubMedCentralPubMedGoogle Scholar
  85. 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):777–785PubMedCentralPubMedCrossRefGoogle Scholar
  86. 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):2580–2590PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Liu S, Wicha MS (2010) Targeting breast cancer stem cells. J Clin Oncol 28(25):4006–4012PubMedCrossRefGoogle Scholar
  88. 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):199–208PubMedCrossRefGoogle Scholar
  89. 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 106:209–215PubMedCrossRefGoogle Scholar
  90. 90.
    Schatton T, Frank NY, Frank MH (2009) Identification and targeting of cancer stem cells. Bioessays 31:1038–1049PubMedCentralPubMedCrossRefGoogle Scholar
  91. 91.
    Zhou BB, Zhang H, Damelin M et al (2009) Tumor-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 8:806–823PubMedCrossRefGoogle Scholar
  92. 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):318–324PubMedCrossRefGoogle Scholar
  93. 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):783–792PubMedCrossRefGoogle Scholar
  94. 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):672–679PubMedCrossRefGoogle Scholar
  95. 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):533–543PubMedCrossRefGoogle Scholar
  96. 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):616–627PubMedCrossRefGoogle Scholar
  97. 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):643–656PubMedCrossRefGoogle Scholar
  98. 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):485–497PubMedCentralPubMedCrossRefGoogle Scholar
  99. 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):937–941PubMedCrossRefGoogle Scholar
  100. 100.
    Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14(21):6735–6741PubMedCrossRefGoogle Scholar
  101. 101.
    Korkaya H, Wicha MS (2013) Breast cancer stem cells we’ve got them surrounded. Clin Cancer Res 19(3):511–513PubMedCrossRefGoogle Scholar
  102. 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):25–36PubMedGoogle Scholar
  103. 103.
    VanEs JH, Clevers H (2005) Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease. Trends Mol Med 11:496–502CrossRefGoogle Scholar
  104. 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/10.1016PubMedCentralPubMedCrossRefGoogle Scholar
  105. 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 30:2307–2313PubMedCrossRefGoogle Scholar
  106. 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 19:1512–1524PubMedCentralPubMedCrossRefGoogle Scholar
  107. 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):5008–5019PubMedCrossRefGoogle Scholar
  108. 108.
    Frank NY, Margaryan A, Huang Y, Schatton T et al (2005) ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 65:4320–4333PubMedCrossRefGoogle Scholar
  109. 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 15:762–772PubMedCrossRefGoogle Scholar
  110. 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 138:645–659PubMedCrossRefGoogle Scholar
  111. 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):275–280PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ebrahim Azizi
    • 1
  • Sunitha Nagrath
    • 3
  • Molly Kozminsky
    • 2
  • Max S. Wicha
    • 4
  1. 1.Cancer Stem Cells ResearchUniversity of MichiganAnn ArborUSA
  2. 2.Department of Chemical Engineering & Biomedical Engineering, Biointerfaces Institute, Translational Oncology ProgramUniversity of MichiganAnn ArborUSA
  3. 3.Department of Chemical Engineering, Biointerfaces Institute, Translational OncologyUniversity of MichiganAnn ArborUSA
  4. 4.Department of Internal MedicineUniversity of Michigan Comprehensive Cancer CenterAnn ArborUSA

Personalised recommendations