Targeting Cancer Stem Cells—A Renewed Therapeutic Paradigm

Oncology & Hematology Review, 2017;13(1):45–55 DOI: https://doi.org/10.17925/OHR.2017.13.01.45

Abstract:

Metastasis is often accompanied by radio- and chemotherapeutic resistance to anticancer treatments and is the major cause of death in cancer patients. Better understanding of how cancer cells circumvent therapeutic insults and how disseminated cancer clones generate life-threatening metastases would therefore be paramount to the development of effective therapeutic approaches for clinical management of malignant disease. Mounting reports over the past two decades have provided evidence for the existence of a minor population of highly malignant cells within liquid and solid tumors, which are capable of self-renewing and of regenerating secondary growths with the heterogeneity of the primary tumors from which they derive. These cells, called tumor-initiating cells or cancer stem cells (CSCs) exhibit increased resistance to standard radio- and chemotherapies and appear to have mechanisms that enable them to evade immune surveillance. CSCs are therefore considered to be responsible for systemic residual disease after cancer therapy, as well as for disease relapse. How CSCs develop, the nature of the interactions they establish with their microenvironment, their phenotypic and functional characteristics, as well as their molecular dependencies have all taken center stage in cancer therapy. Indeed, improved understanding of CSC biology is critical to the development of important CSC-based anti-neoplastic approaches that have the potential to radically improve cancer management. Here, we summarize some of the most pertinent elements regarding CSC development and properties, and highlight some of the clinical modalities in current development as anti-CSC therapeutics.
Keywords: Cancer biomarker, cancer stem cell, tumor-initiating cell, microenvironment, signaling pathway, targeted therapy, radioresistance, chemoresistance
Disclosure: Antoine E Karnoub has nothing to declare in relation to this article. Catherine L Amey is an employee of Touch Medical Media, Goring-On-Thames, UK.
Authorship:All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
Received: February 22, 2017 Accepted April 20, 2017
Correspondence: Antoine E Karnoub, Center for Life Science 0634, 3 Blackfan Circle, Boston, MA 02215, US. E: akarnoub@bidmc.harvard.edu
Support: The publication of this article was supported by Boston Biomedical, who was given the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the authors’ discretion.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.

Despite substantial advances in cancer diagnosis and treatment, the long-term survival rate for many cancer patients remains dismal.1 More than 90% of cancer-related mortality is ascribed to disease resurgence months or years after adjuvant therapy, either in the form of local recurrence or in the form of metastatic spread, which are typically refractory to existing treatment modalities (see Table 1).1,2 Novel anti-neoplastic therapeutic approaches aimed at eradicating residual relapsing disease are therefore sorely needed, but remain to be defined.

The cornerstone of current cancer management approaches relies on early detection and on chemotherapeutic and radiologic treatment of diagnosed neoplasms. Although detection methodologies have helped significantly in reducing the lethality associated with cancers such as prostate or breast neoplasms, they have had limited widespread efficacy in many others. Indeed, efforts to diagnose cancers early in their development are still hampered by serious limitations in technologies that cannot detect small tumorigenic growths or disseminated microscopic disease. Similarly, classical anti-neoplastic treatments, which target highly proliferating cancer cells, nondiscriminately target bystander normal cells, such as hair follicle cells or gut-regenerating cells, causing high degree of systemic toxicity. In addition, these systemic therapies, are, to a large extent, inefficient in eradicating disseminated disease, and often result in the emergence of resistance.

The discovery that unchallenged human primary tumors harbor subpopulations of cancer cells that are distinguished from bulk populations by exclusive abilities to self-renew and generate heterogeneous secondary growths refocused attention on understanding the fundamental biology of how these cells emerge, and on identifying means to kill them. Such tumor-initiating cells (TICs), dubbed cancer stem cells (CSCs), which pre-exist already in untreated tumors, were found to be amplified in recurrent disease, and were shown to be highly malignant and with augmented tolerance to existing radio- and chemotherapeutics.3 Indeed, it is widely accepted that CSCs represent the root cause for metastatic dissemination and disease relapse in cancer patients. As such, the identification of effective CSC-specific therapeutics has taken center stage in the development of anti-neoplastic therapies aimed at eradicating disease relapse.4 The molecular underpinnings of the CSC state have been extensively reviewed over the past several years, for example, by Bandhavkar,5 Kuhlman et al.,6 and others.7–17 The purpose of this article is to briefly summarize and highlight some of the most pertinent concepts surrounding CSC biology, as well as current and emerging therapies targeting CSCs. Bulleted format has been used to provide a more concise presentation of these broad topics to clinicians and researchers interested in an introduction to CSC research.

Revival of the cancer stem cell hypothesis
• In the 1860s, Rudolf Virchow observed microscopic similarities between cancer (in this case, teratocarcinoma) and developing embryonic tissues; this led him to postulate that cancers derive from embryonic-like cells.18
• The concept that cancers originate from cells with stem cell characteristics was re-formulated by Julius Cohnheim.19,20 His theory, termed “embryonal rest hypothesis”, stated that cancers initiate from tissue-resident stem cells left over from embryogenesis, which remain dormant in such tissues until reawakened later in life to give rise to cancer.
• Cancer’s potential origin from embryonic/germinal-like progenitor cells that are inadvertently stimulated to grow uncontrollably in adult tissues was again entertained by Durante,21 Beard,22 Rippert,23 and Rotter.24
• The idea that tumors contain cancer populations with special malignant properties was re-visited by many researchers, such as Hewitt in 1953, who noted that variations in tumor-initiating potential and transplantability exist among varying inocula of sarcoma suspensions,25 or by McCulloch et al. in 1971,26 who found that tumor colony-forming cells possessed different growth characteristics than their normal counterparts, and that the so-called tumor stem cells represented a very small percentage (0.01–1%) of the whole tumor population.
• In landmark studies published in 1989, 1994, and 1997,27–29 John Dick’s group used a model of acute myeloid leukemia (AML) to definitively show that AML was hierarchical in nature, that cells capable of serially initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease were rare, and that they possessed selfrenewal, proliferative, and differentiation capacities consistent with “true” leukemia stem cells.
• Chia-Cheng Chang and colleagues isolated two types (type I and II) of antigenically and phenotypically different normal epithelial cells from human breast tissue, and showed that only one type (type I, with luminal characteristics) is prone for transformation by SV40.30 Interestingly, type I could be stimulated to generate type II cells (with basal characteristics), prompting the hypothesis that cancers may originate from specialized progenitor-like cells pre-existing in solid tissues.
• Using a model in which human breast cancer cells were grown in immunocompromised mice, Al-Hajj and colleagues demonstrated that not all cancer cells within carcinomas are equally tumorigenic and that only a small subset of cells within such tumors is able to generate secondary tumors when transplanted.31
These observations suggested that solid cancers are, like liquid cancers,28 also hierarchical in nature, and harbor a small proportion of so-called tumor-initiating CSCs (also termed TICs).
• Cancer cells from several species were shown to exhibit stark activation patterns in molecular networks that otherwise function as critical regulators of embryonic, adult, and induced pluripotent stem cell homeostasis.32–35
• TICs/CSCs have now been identified in multiple malignancies, including multiple leukemias and various solid tumors36 such as lung,37 colon,38 prostate,39 ovarian,40 brain,41 and skin cancers.42
• Tumor transplantation studies in histocompatible mice suggested that CSCs can be more abundant than previously estimated, constituting as much as 10% in leukemias and lymphomas,43 and as much as 25% in melanomas.44
• The proportions of CSCs within tumors correlate positively with poor prognosis.45

Characteristics of cancer stem cells
• Normal self-renewing adult tissue stem cells give rise to progenitor cells that are often termed transit-amplifying cells which, in turn, divide and proliferate to engender more differentiated cells with restricted proliferating and clonogenic potentials. This hierarchical system calls upon stem cells (which sit at the top of the pyramid) to expand when more differentiated cells (laying at the bottom of the tissue pyramid) are depleted.
• The self-renewing ability of these stem cells ensures their continued presence within tissues and the balance between stem and differentiated cells ascertains tissue homeostasis.
• Normal stem cells are in constant interactions with their microenvironment, or niche, which tightly regulates stem cell state maintenance while controlling the expansion of the stem cell compartment.
• Tumors are formed of heterogeneous cancer cells that are organized in a hierarchy similar to that of normal tissues, and contain CSCs that share several characteristics with normal stem cells.
• The 2006 American Association for Cancer Research Workshop on Cancer Stem Cells defined a CSC as “a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor.”46
• In this model, each tumor contains a sub-population of cells (the CSCs) that are able to divide asymmetrically in order to self-renew and give rise to a phenotypically distinct daughter cell. CSCs are thus considered to be the source of all aggressive plastic cancer cells present in a malignant tumor.2

References:
1. Siegel R, Ma J, Zou Z, Jemal A, Cancer statistics, 2014, CA: a Cancer Journal for Clinicians, 2014;64:9–29.
2. Dawood S, Austin L, Cristofanilli M, Cancer stem cells: implications for cancer therapy, Oncology (Williston Park), 2014;28:1101–7, 10.
3. Creighton CJ, Li X, Landis M, et al., Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features, Proc Natl Acad Sci U S A, 2009;106:13820–5.
4. Vinogradov S, Wei X, Cancer stem cells and drug resistance: the potential of nanomedicine, Nanomedicine, 2012;7:597–615.
5. Bandhavkar S, Cancer stem cells: a metastasizing menace!, Cancer Med, 2016;5:649–55.
6. Kuhlmann JD, Hein L, Kurth I, et al., Targeting Cancer Stem Cells: Promises and Challenges, Anticancer Agents Med Chem, 2016;16:38–58.
7. Trosko JE, Review paper: cancer stem cells and cancer nonstem cells: from adult stem cells or from reprogramming of differentiated somatic cells, Vet Pathol, 2009;46:176–93.
8. de Sousa EMF, Vermeulen L, Wnt Signaling in Cancer Stem Cell Biology, Cancers (Basel). 2016;8.
9. Zanconato F, Cordenonsi M, Piccolo S, YAP/TAZ at the Roots of Cancer, Cancer Cell, 2016;29:783–803.
10. Semenza GL, Regulation of the breast cancer stem cell phenotype by hypoxia-inducible factors, Clin Sci (Lond), 2015;129:1037–45.
11. Plaks V, Kong N, Werb Z, The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?, Cell Stem Cell, 2015;16:225–38.
12. Korkaya H, Wicha MS, Selective targeting of cancer stem cells: a new concept in cancer therapeutics, BioDrugs, 2007;21:299–310.
13. Ward RJ, Dirks PB, Cancer stem cells: at the headwaters of tumor development, Ann Rev Pathol, 2007;2:175–89.
14. Park CY, Tseng D, Weissman IL, Cancer stem cell-directed therapies: recent data from the laboratory and clinic, Mol Ther, 2009;17:219–30.
15. Nguyen LV, Vanner R, Dirks P, Eaves CJ, Cancer stem cells: an evolving concept, Nature Reviews Cancer, 2012;12:133–43.
16. Visvader JE, Lindeman GJ, Cancer stem cells: current status and evolving complexities, Cell Stem Cell, 2012;10:717–28.
17. Meacham CE, Morrison SJ, Tumour heterogeneity and cancer cell plasticity, Nature, 2013;501:328–37.
18. Virchow R, Die krankhaften Geschwülste, Berlin, Germany: B.d. 1 Hirschwald 1863.
19. Cohnheim J, (1839-1884) experimental pathologist, JAMA, 1968;206:1561–2.
20. Cohnheim J, Ueber entzundung und eiterung, Path Anat Physiol Klin Med, 1867;40:1–79.
21. Durante F, Nesso fisio-pathologico tra la struttura dei nei materni e la genesi di alcuni tumori maligni, Arch Memor Observ Chir Pract, 1874;11:217–26.
22. Beard J, Embryological aspects and etiology of carcinoma, Lancet, 1902;1:1758–61.
23. Rippert H, Geschwulstelehre fur Aerzte und Studierende Bonn, 1904.
24. Rotter H, Histogenese der malignen Geschwülste, J Cancer Res Clin, 1922;18:171–208.
25. Hewitt HB, Studies of the quantitative transplantation of mouse sarcoma, Br J Cancer, 1953;7:367–83.
26. Park CH, Bergsagel DE, McCulloch EA, Mouse myeloma tumor stem cells: a primary cell culture assay, J Natl Cancer Inst, 1971;46:411–22.
27. Lapidot T, Sirard C, Vormoor J, et al., A cell initiating human acute myeloid leukaemia after transplantation into SCID mice, Nature, 1994;367:645–8.
28. Bonnet D, Dick JE, Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell, Nat Med, 1997;3:730–7.
29. Kamel-Reid S, Letarte M, Sirard C, et al., A model of human acute lymphoblastic leukemia in immune-deficient SCID mice, Science (New York, NY), 1989;246:1597–600.
30. Kao CY, Nomata K, Oakley CS, et al., Two types of normal human breast epithelial cells derived from reduction mammoplasty: phenotypic characterization and response to SV40 transfection, Carcinogenesis, 1995;16:531–8.
31. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al., Prospective identification of tumorigenic breast cancer cells, Proc Natl Acad Sci U S A, 2003;100:3983–8.
32. Tai MH, Chang CC, Kiupel M, et al., Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis, Carcinogenesis, 2005;26:495–502.
33. Webster JD, Yuzbasiyan-Gurkan V, Trosko JE, et al., Expression of the embryonic transcription factor Oct4 in canine neoplasms: a potential marker for stem cell subpopulations in neoplasia, Vet Pathol, 2007;44:893–900.
34. Ben-Porath I, Thomson MW, Carey VJ, et al., An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors, Nat Genet, 2008;40:499–507.
35. Guo W, Keckesova Z, Donaher JL, et al., Slug and Sox9 cooperatively determine the mammary stem cell state, Cell, 2012;148:1015–28.
36. Chen K, Huang YH, Chen JL, Understanding and targeting cancer stem cells: therapeutic implications and challenges, Acta Pharmacol Sin, 2013;34:732–40.
37. Kim CF, Jackson EL, Woolfenden AE, et al., Identification of bronchioalveolar stem cells in normal lung and lung cancer, Cell, 2005;121:823–35.
38. O'Brien CA, Pollett A, Gallinger S, Dick JE, A human colon cancer cell capable of initiating tumour growth in immunodeficient mice, Nature, 2007;445:106–10.
39. Collins AT, Berry PA, Hyde C, et al., Prospective identification of tumorigenic prostate cancer stem cells, Cancer Res, 2005;65:10946–51.
40. Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al., Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness, Proc Natl Acad Sci U S A, 2006;103:11154–9.
41. Piccirillo SG, Reynolds BA, Zanetti N, et al., Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumourinitiating cells, Nature, 2006;444:761–5.
42. Fang D, Nguyen TK, Leishear K, et al., A tumorigenic subpopulation with stem cell properties in melanomas, Cancer Res, 2005;65:9328–37.
43. Kelly PN, Dakic A, Adams JM, et al., Tumor growth need not be driven by rare cancer stem cells, Science (New York, NY), 2007;317:337.
44. Quintana E, Shackleton M, Sabel MS, et al., Efficient tumour formation by single human melanoma cells, Nature, 2008;456:593–8.
45. Charafe-Jauffret E, Ginestier C, Iovino F, et al., Aldehyde dehydrogenase 1-positive cancer stem cells mediate metastasis and poor clinical outcome in inflammatory breast cancer, Clin Cancer Res, 2010;16:45–55.
46. Clarke MF, Dick JE, Dirks PB, et al., Cancer stem cells-- perspectives on current status and future directions: AACR Workshop on cancer stem cells, Cancer Res, 2006;66:9339–44.
47. Hope KJ, Jin L, Dick JE, Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity, Nat Immunol, 2004;5:738–43.
48. Moore N, Lyle S, Quiescent, slow-cycling stem cell populations in cancer: a review of the evidence and discussion of significance, Journal of Oncology, 2011;2011.
49. Pajonk F, Vlashi E, Characterization of the stem cell niche and its importance in radiobiological response, Semin Radiat Oncol, 2013;23:237–41.
50. Castano Z, Fillmore CM, Kim CF, McAllister SS, The bed and the bugs: interactions between the tumor microenvironment and cancer stem cells, Semin Cancer Biol, 2012;22:462–70.
51. Jiang Y, He Y, Li H, et al., Expressions of putative cancer stem cell markers ABCB1, ABCG2, and CD133 are correlated with the degree of differentiation of gastric cancer, Gastric Cancer, 2012;15:440–50.
52. Xie ZY, Lv K, Xiong Y, Guo WH, ABCG2-meditated multidrug resistance and tumor-initiating capacity of side population cells from colon cancer, Oncology Research and Treatment, 2014;37:666–8, 70–2.
53. Fuchs E, Nowak JA, Building epithelial tissues from skin stem cells, Cold Spring Harb Symp Quant Biol, 2008;73:333–50.
54. Wilson A, Laurenti E, Oser G, et al., Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair, Cell, 2008;135:1118–29.
55. van der Flier LG, Clevers H, Stem cells, self-renewal, and differentiation in the intestinal epithelium, Annu Rev Physiol, 2009;71:241–60.
56. Seita J, Weissman IL, Hematopoietic stem cell: self-renewal versus differentiation, Wiley Interdiscip Rev Syst Biol Med, 2010;2:640–53.
57. Ajani JA, Song S, Hochster HS, Steinberg IB, Cancer stem cells: the promise and the potential, Semin Oncol, 2015;42(Suppl 1):S3–17.
58. Khong HT, Wang QJ, Rosenberg SA, Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression, J Immunother, 2004;27:184–90.
59. Tallerico R, Todaro M, Di Franco S, et al., Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules, J Immunol, 2013;190:2381–90.
60. Di Tomaso T, Mazzoleni S, Wang E, et al., Immunobiological characterization of cancer stem cells isolated from glioblastoma patients, Clin Cancer Res, 2010;16:800–13.
61. Wu A, Wiesner S, Xiao J, et al., Expression of MHC I and NK ligands on human CD133+ glioma cells: possible targets of immunotherapy, J Neurooncol, 2007;83:121–31.
62. Strand S, Hofmann WJ, Hug H, et al., Lymphocyte apoptosis induced by CD95 (APO-1/Fas) ligand-expressing tumor cells--a mechanism of immune evasion?, Nat Med, 1996;2:1361–6.
63. Peter ME, Hadji A, Murmann AE, et al., The role of CD95 and CD95 ligand in cancer, Cell Death Differ, 2015;22:549–59.
64. Zhang H, Lu H, Xiang L, et al., HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells, Proc Natl Acad Sci U S A, 2015;112:E6215–23.
65. McCracken MN, Cha AC, Weissman IL, Molecular Pathways: Activating T Cells after Cancer Cell Phagocytosis from Blockade of CD47 "Don't Eat Me" Signals, Clin Cancer Res, 2015;21:3597–601.
66. Yan Z, Zhuansun Y, Liu G, et al., Mesenchymal stem cells suppress T cells by inducing apoptosis and through PD-1/B7-H1 interactions, Immunol Lett, 2014;162(1 Pt A):248–55.
67. Luz-Crawford P, Noel D, Fernandez X, et al., Mesenchymal stem cells repress Th17 molecular program through the PD-1 pathway, PloS One, 2012;7:e45272.
68. Xu L, Wang X, Wang J, et al., Hypoxia-induced secretion of IL-10 from adipose-derived mesenchymal stem cell promotes growth and cancer stem cell properties of Burkitt lymphoma, Tumour Biol, 2016;37:7835–42.
69. Whiteside TL, Schuler P, Schilling B, Induced and natural regulatory T cells in human cancer, Expert Opin Biol Ther, 2012;12:1383–97.
70. Gilbert CA, Ross AH, Cancer stem cells: cell culture, markers, and targets for new therapies, J Cell Biochem, 2009;108:1031–8.
71. Jordan CT, Upchurch D, Szilvassy SJ, et al., The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells, Leukemia, 2000;14:1777–84.
72. Singh SK, Hawkins C, Clarke ID, et al., Identification of human brain tumour initiating cells, Nature, 2004;432:396–401.
73. Stemberger-Papic S, Vrdoljak-Mozetic D, Ostojic DV, et al., Expression of CD133 and CD117 in 64 Serous Ovarian Cancer Cases, Coll Antropol, 2015;39:745–53.
74. Williams SA, Anderson WC, Santaguida MT, Dylla SJ, Patientderived xenografts, the cancer stem cell paradigm, and cancer pathobiology in the 21st century, Lab Invest, 2013;93:970–82.
75. Eirew P, Stingl J, Raouf A, et al., A method for quantifying normal human mammary epithelial stem cells with in vivo regenerative ability, Nat Med, 2008;14:1384–9.
76. Junk DJ, Cipriano R, Bryson BL, et al., Tumor microenvironmental signaling elicits epithelial-mesenchymal plasticity through cooperation with transforming genetic events, Neoplasia, 2013;15:1100–9.
77. Conley SJ, Gheordunescu E, Kakarala P, et al., Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia, Proc Natl Acad Sci U S A, 2012;109:2784–9.
78. Trosko JE, Gap junctional intercellular communication as a biological "Rosetta stone" in understanding, in a systems biological manner, stem cell behavior, mechanisms of epigenetic toxicology, chemoprevention and chemotherapy, J Membr Biol, 2007;218:93–100.
79. Zhao Y, Feng F, Zhou YN, Stem cells in gastric cancer, World J Gastroenterol, 2015;21:112–23.
80. Tomasetti C, Vogelstein B, Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science, 2015;347:78–81.
81. Schepers AG, Snippert HJ, Stange DE, et al., Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas, Science, 2012;337:730–5.
82. Helczynska K, Kronblad A, Jogi A, et al., Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ, Cancer Res, 2003;63:1441–4.
83. Soltysova A, Altanerova V, Altaner C, Cancer stem cells, Neoplasma, 2005;52:435–40.
84. Loewenstein WR, Kanno Y, Intercellular communication and the control of tissue growth: lack of communication between cancer cells, Nature, 1966;209:1248–9.
85. Lu X, Kang Y, Cell fusion hypothesis of the cancer stem cell, Adv Exp Med Biol, 2011;714:129–40.
86. Li F, Tiede B, Massague J, Kang Y, Beyond tumorigenesis: cancer stem cells in metastasis, Cell Res, 2007;17:3–14.
87. Cammarota F, Laukkanen MO, Mesenchymal Stem/Stromal Cells in Stromal Evolution and Cancer Progression, Stem Cells Int, 2016;2016:4824573.
88. Santamaria-Martinez A, Barquinero J, Barbosa-Desongles A, et al., Identification of multipotent mesenchymal stromal cells in the reactive stroma of a prostate cancer xenograft by side population analysis, Exp Cell Res, 2009;315:3004–13.
89. Tamimi SO, Ahmed A, Stromal changes in invasive breast carcinoma: an ultrastructural study, J Pathol, 1987;153:163–70.
90. van der Horst G, Bos L, van der Pluijm G, Epithelial plasticity, cancer stem cells, and the tumor-supportive stroma in bladder carcinoma, Mol Cancer Res, 2012;10:995–1009.
91. Liu R, Wei S, Chen J, Xu S, Mesenchymal stem cells in lung cancer tumor microenvironment: their biological properties, influence on tumor growth and therapeutic implications, Cancer Lett, 2014;353:145–52.
92. Calon A, Lonardo E, Berenguer-Llergo A, et al., Stromal gene expression defines poor-prognosis subtypes in colorectal cancer, Nat Genet, 2015;47:320–9.
93. Isella C, Terrasi A, Bellomo SE, et al., Stromal contribution to the colorectal cancer transcriptome, Nat Genet, 2015;47:312–9.
94. Choi H, Sheng J, Gao D, et al., Transcriptome analysis of individual stromal cell populations identifies stroma-tumor crosstalk in mouse lung cancer model, Cell Reports, 2015;10:1187–201.
95. Margolin DA, Silinsky J, Grimes C, et al., Lymph node stromal cells enhance drug-resistant colon cancer cell tumor formation through SDF-1alpha/CXCR4 paracrine signaling, Neoplasia, 2011;13:874–86.
96. Li L, Yoon SO, Fu DD, et al., Novel follicular dendritic cell molecule, 8D6, collaborates with CD44 in supporting lymphomagenesis by a Burkitt lymphoma cell line, L3055, Blood, 2004;104:815–21.
97. Karnoub AE, Dash AB, Vo AP, et al., Mesenchymal stem cells within tumour stroma promote breast cancer metastasis, Nature, 2007;449:557–63.
98. Lin Q, Yun Z, Impact of the hypoxic tumor microenvironment on the regulation of cancer stem cell characteristics, Cancer Biol Ther, 2010;9:949–56.
99. Baccelli I, Trumpp A, The evolving concept of cancer and metastasis stem cells, J Cell Biol, 2012;198:281–93.
100. Malanchi I, Santamaria-Martinez A, Susanto E, et al., Interactions between cancer stem cells and their niche govern metastatic colonization, Nature, 2011;481:85–9.
101. Li Z, Rich JN, Hypoxia and hypoxia inducible factors in cancer stem cell maintenance, Curr Top Microbiol Immunol, 2010;345:21–30.
102. Trosko JE, Kang KS, Evolution of energy metabolism, stem cells and cancer stem cells: how the warburg and barker hypotheses might be linked, J Stem Cells, 2012;5:39–56.
103. Heddleston JM, Li Z, McLendon RE, et al., The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype, Cell Cycle, 2009;8:3274–84.
104. Graeber TG, Osmanian C, Jacks T, et al., Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours, Nature, 1996;379:88–91.
105. Subarsky P, Hill RP, The hypoxic tumour microenvironment and metastatic progression, Clin Exp Metastasis, 2003;20:237–50.
106. Wang KH, Kao AP, Lin TC, et al., Promotion of epithelialmesenchymal transition and tumor growth by 17beta-estradiol in an ER(+)/HER2(+) cell line derived from human breast epithelial stem cells, Biotechnol Appl Biochem, 2012;59:262–7.
107. Lim J, Thiery JP, Epithelial-mesenchymal transitions: insights from development, Development, 2012;139:3471–86.
108. Lamouille S, Xu J, Derynck R, Molecular mechanisms of epithelialmesenchymal transition, Nat Rev Mol Cell Biol, 2014;15:178–96.
109. Mani SA, Guo W, Liao MJ, et al., The epithelial-mesenchymal transition generates cells with properties of stem cells, Cell, 2008;133:704–15.
110. Puisieux A, Brabletz T, Caramel J, Oncogenic roles of EMT-inducing transcription factors, Nat Cell Biol, 2014;16:488–94.
111. Rofstad EK, Microenvironment-induced cancer metastasis, Int J Rad Biol, 2000;76:589–605.
112. Kong D, Li Y, Wang Z, Sarkar FH, Cancer Stem Cells and Epithelialto- Mesenchymal Transition (EMT)-Phenotypic Cells: Are They Cousins or Twins?, Cancers, 2011;3:716–29.
113. Wu K, Bonavida B, The activated NF-kappaB-Snail-RKIP circuitry in cancer regulates both the metastatic cascade and resistance to apoptosis by cytotoxic drugs, Crit Rev Immunol, 2009;29:241–54.
114. Liu C, Liu Y, Xu XX, et al., Potential effect of matrix stiffness on the enrichment of tumor initiating cells under three-dimensional culture conditions, Exp Cell Res, 2015;330:123–34.
115. Schrader J, Gordon-Walker TT, Aucott RL, et al., Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells, Hepatology, 2011;53:1192–205.
116. Porta C, Paglino C, Mosca A, Targeting PI3K/Akt/mTOR Signaling in Cancer, Front Oncol, 2014;4:64.
117. Xia P, Xu XY, PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application, Am J Cancer Res, 2015;5:1602–9.
118. Bromberg JF, Wrzeszczynska MH, Devgan G, et al., Stat3 as an oncogene, Cell, 1999;98:295–303.
119. Kroon P, Berry PA, Stower MJ, et al., JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stemlike cells, Cancer Res, 2013;73:5288–98.
120. Amiri KI, Richmond A, Role of nuclear factor-kappa B in melanoma, Cancer Metastasis Rev, 2005;24:301–13.
121. Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S, Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane, Cell, 1997;90:281–91.
122. Dunwoodie SL, Henrique D, Harrison SM, Beddington RS, Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo, Development, 1997;124:3065–76.
123. Lindsell CE, Shawber CJ, Boulter J, Weinmaster G, Jagged: a mammalian ligand that activates Notch1, Cell, 1995;80:909–17.
124. Shawber C, Boulter J, Lindsell CE, Weinmaster G, Jagged2: a serrate-like gene expressed during rat embryogenesis, Dev Biol, 1996;180:370–6.
125. Callahan R, Raafat A, Notch signaling in mammary gland tumorigenesis, J Mammary Gland Biol, 2001;6:23–36.
126. Espinoza I, Pochampally R, Xing F, et al., Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition, Onco Targets Ther, 2013;6:1249–59.
127. Gu JW, Rizzo P, Pannuti A, et al., Notch signals in the endothelium and cancer "stem-like" cells: opportunities for cancer therapy, Vascular Cell, 2012;4:7.
128. Pannuti A, Foreman K, Rizzo P, et al., Targeting Notch to target cancer stem cells, Clin Cancer Res, 2010;16:3141–52.
129. Justilien V, Fields AP, Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells, Clin Cancer Res, 2015;21:505–13.
130. Huang FT, Zhuan-Sun YX, Zhuang YY, et al., Inhibition of hedgehog signaling depresses self-renewal of pancreatic cancer stem cells and reverses chemoresistance, Int J Oncol, 2012;41:1707–14.
131. Olive KP, Jacobetz MA, Davidson CJ, et al., Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer, Science, 2009;324:1457–61.
132. Sims-Mourtada J, Izzo JG, Ajani J, Chao KS, Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport, Oncogene, 2007;26:5674–9.
133. Singh S, Chitkara D, Mehrazin R, et al., Chemoresistance in prostate cancer cells is regulated by miRNAs and Hedgehog pathway, PloS One, 2012;7:e40021.
134. Le PN, McDermott JD, Jimeno A, Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP- 54F28, Pharmacol Ther, 2015;146:1–11.
135. Clevers H, Loh KM, Nusse R, Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control, Science, 2014;346:1248012.
136. Moroishi T, Hansen CG, Guan KL, The emerging roles of YAP and TAZ in cancer, Nat Rev Cancer, 2015;15:73–9.
137. Mo JS, Park HW, Guan KL, The Hippo signaling pathway in stem cell biology and cancer, EMBO Reports, 2014;15:642–56.
138. Hayashi H, Higashi T, Yokoyama N, et al., An Imbalance in TAZ and YAP Expression in Hepatocellular Carcinoma Confers Cancer Stem Cell-like Behaviors Contributing to Disease Progression, Cancer Res, 2015;75:4985–97.
139. Chang C, Goel HL, Gao H, et al., A laminin 511 matrix is regulated by TAZ and functions as the ligand for the alpha6Bbeta1 integrin to sustain breast cancer stem cells, Genes Dev, 2015;29:1–6.
140. Song S, Ajani JA, Honjo S, et al., Hippo coactivator YAP1 upregulates SOX9 and endows esophageal cancer cells with stem-like properties, Cancer Res, 2014;74:4170–82.
141. Fisher ML, Kerr C, Adhikary G, et al., Transglutaminase Interaction with alpha6/beta4-Integrin Stimulates YAP1- Dependent DeltaNp63alpha Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation,Cancer Res, 2016;76:7265–76.
142. Wang Y, Liu J, Ying X, et al., Twist-mediated Epithelialmesenchymal Transition Promotes Breast Tumor Cell Invasion via Inhibition of Hippo Pathway, Sci Rep, 2016;6:24606.
143. Cordenonsi M, Zanconato F, Azzolin L, et al., The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells, Cell, 2011;147:759–72.
144. Peng X, Ueda H, Zhou H, Stokol T, Shen TL, Alcaraz A, et al., Overexpression of focal adhesion kinase in vascular endothelial cells promotes angiogenesis in transgenic mice, Cardiovasc Res, 2004;64:421–30.
145. Golubovskaya VM, Targeting FAK in human cancer: from finding to first clinical trials, Front Biosci, 2014;19:687–706.
146. Tabuse M, Ohta S, Ohashi Y, et al., Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells, Mol Cancer, 2011;10:60.
147. Sengupta A, Banerjee D, Chandra S, et al., Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression, Leukemia, 2007;21:949–55.
148. Hugo H, Ackland ML, Blick T, et al., Epithelial--mesenchymal and mesenchymal-epithelial transitions in carcinoma progression, J Cell Physio, 2007;213:374–83.
149. Fazilaty H, Gardaneh M, Akbari P, et al., SLUG and SOX9 Cooperatively Regulate Tumor Initiating Niche Factors in Breast Cancer, Cancer Microenviron, 2016;9:71–4.
150. Pardal R, Molofsky AV, He S, Morrison SJ, Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors, Cold Spring Harb Symp Quant Biol, 2005;70:177–85.
151. Liu S, Dontu G, Mantle ID, et al., Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells, Cancer Res, 2006;66:6063–71.
152. Hosen N, Yamane T, Muijtjens M, et al., Bmi-1-green fluorescent protein-knock-in mice reveal the dynamic regulation of bmi-1 expression in normal and leukemic hematopoietic cells, Stem Cells, 2007;25:1635–44.
153. Hurt EM, Kawasaki BT, Klarmann GJ, et al., CD44+ CD24(-) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis, Br J Cancer, 2008;98:756–65.
154. Lee CJ, Dosch J, Simeone DM, Pancreatic cancer stem cells, J Clin Oncol, 2008;26:2806–12.
155. Lee CY, Robinson KJ, Doe CQ, Lgl, Pins and aPKC regulate neuroblast self-renewal versus differentiation, Nature, 2006;439:594–8.
156. Wang Y, Hill KS, Fields AP, PKCiota maintains a tumor-initiating cell phenotype that is required for ovarian tumorigenesis, Mol Cancer Res, 2013;11:1624–35.
157. Zhang K, Zhao H, Ji Z, et al., Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition, Oncogene, 2016;35:1271–82.
158. Newton AC, Protein kinase C: structure, function, and regulation, J Biol Chem, 1995;270:28495–8.
159. Shiozawa Y, Nie B, Pienta KJ, et al., Cancer stem cells and their role in metastasis, Pharmacol Ther, 2013;138:285–93.
160. Oskarsson T, Batlle E, Massague J, Metastatic stem cells: sources, niches, and vital pathways, Cell Stem Cell, 2014;14:306–21.
161. Liu H, Patel MR, Prescher JA, et al., Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models, Proc Natl Acad Sci U S A, 2010;107:18115–20.
162. Hermann PC, Huber SL, Herrler T, et al., Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer, Cell Stem Cell, 2007;1:313–23.
163. Phay JE, Ringel MD, Metastatic mechanisms in follicular cellderived thyroid cancer, Endocr Relat Cancer, 2013;20:R307–19.
164. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG, Cancer drug resistance: an evolving paradigm, Nat Rev Cancer, 2013;13:714–26.
165. Engelman JA, Settleman J, Acquired resistance to tyrosine kinase inhibitors during cancer therapy, Curr Opin Genetics Dev, 2008;18:73–9.
166. Obenauf AC, Zou Y, Ji AL, et al., Therapy-induced tumour secretomes promote resistance and tumour progression, Nature, 2015;520:368–72.
167. Doherty MR, Smigiel JM, Junk DJ, Jackson MW, Cancer Stem Cell Plasticity Drives Therapeutic Resistance, Cancers, 2016;8.
168. Phillips TM, McBride WH, Pajonk F, The response of CD24(-/low)/ CD44+ breast cancer-initiating cells to radiation, J Natl Cancer Inst, 2006;98:1777–85.
169. Woodward WA, Chen MS, Behbod F, et al., WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells, Proc Natl Acad Sci U S A, 2007;104:618–23.
170. Bao S, Wu Q, McLendon RE, et al., Glioma stem cells promote radioresistance by preferential activation of the DNA damage response, Nature, 2006;444:756–60.
171. Eramo A, Ricci-Vitiani L, Zeuner A, et al., Chemotherapy resistance of glioblastoma stem cells, Cell Death Differ, 2006;13:1238–41.
172. Chiou SH, Kao CL, Chen YW, et al., Identification of CD133-positive radioresistant cells in atypical teratoid/rhabdoid tumor, PloS One, 2008;3:e2090.
173. Blazek ER, Foutch JL, Maki G, Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia, Int J Radiat Oncol Biol Phys, 2007;67:1–5.
174. Chang CJ, Hsu CC, Yung MC, et al., Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression, Biochem Biophys Res Commun, 2009;380:236–42.
175. Holtz MS, Forman SJ, Bhatia R, Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli, Leukemia, 2005;19:1034–41.
176. Lomonaco SL, Finniss S, Xiang C, et al., The induction of autophagy by gamma-radiation contributes to the radioresistance of glioma stem cells, Int J Cancer, 2009;125:717–22.
177. Fillmore CM, Kuperwasser C, Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy, Breast Cancer Res, 2008;10:R25.
178. Diehn M, Cho RW, Lobo NA, et al., Association of reactive oxygen species levels and radioresistance in cancer stem cells, Nature, 2009;458:780–3.
179. Vlashi E, Kim K, Lagadec C, et al., In vivo imaging, tracking, and targeting of cancer stem cells, J Natl Cancer Inst, 2009;101:350–9.
180. Gong X, Schwartz PH, Linskey ME, Bota DA, Neural stem/ progenitors and glioma stem-like cells have differential sensitivity to chemotherapy, Neurology, 2011;76:1126–34.
181. Schatton T, Murphy GF, Frank NY, et al., Identification of cells initiating human melanomas, Nature, 2008;451:345–9.
182. Skvortsova I, Debbage P, Kumar V, Skvortsov S, Radiation resistance: Cancer stem cells (CSCs) and their enigmatic prosurvival signaling, Semin Cancer Biol, 2015;35:39–44.
183. Chang L, Graham PH, Hao J, et al., Acquisition of epithelialmesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance, Cell Death Dis, 2013;4:e875.
184. Dahan P, Martinez Gala J, Delmas C, et al., Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance, Cell Death Dis, 2014;5:e1543.
185. Ventela S, Sittig E, Mannermaa L, et al., CIP2A is an Oct4 target gene involved in head and neck squamous cell cancer oncogenicity and radioresistance, Oncotarget, 2015;6:144–58.
186. Trosko JE, Human adult stem cells as the target cells for the initiation of carcinogenesis and for the generation of "cancer stem cells", Int J Stem Cells, 2008;1:8–26.
187. Kang KS, Trosko JE, Stem cells in toxicology: fundamental biology and practical considerations, Toxicol Sci, 2011;120(Suppl 1):S269–89.
188. Trosko JE, Induction of iPS cells and of cancer stem cells: the stem cell or reprogramming hypothesis of cancer?, Anat Rec, 2014;297:161–73.
189. Bao S, Wu Q, Li Z, et al., Targeting cancer stem cells through L1CAM suppresses glioma growth, Cancer Res, 2008;68:6043–8.
190. Sole RV, Rodriguez-Caso C, Deisboeck TS, Saldana J, Cancer stem cells as the engine of unstable tumor progression, J Theor Biol, 2008;253:629–37.
191. Dragu DL, Necula LG, Bleotu C, et al., Therapies targeting cancer stem cells: Current trends and future challenges, World J Stem Cells, 2015;7:1185–201.
192. Vermeulen L, Todaro M, de Sousa Mello F, et al., Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity, Proc Natl Acad Sci U S A, 2008;105:13427–32.
193. Beier D, Wischhusen J, Dietmaier W, et al., CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors, Brain Pathol, 2008;18:370–7.
194. Beier D, Rohrl S, Pillai DR, et al., Temozolomide preferentially depletes cancer stem cells in glioblastoma, Cancer Res, 2008;68:5706–15.
195. Sarvi S, Mackinnon AC, Avlonitis N, et al., CD133+ cancer stemlike cells in small cell lung cancer are highly tumorigenic and chemoresistant but sensitive to a novel neuropeptide antagonist, Cancer Res, 2014;74:1554–65.
196. Stratford EW, Bostad M, Castro R, et al., Photochemical internalization of CD133-targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity, Biochim Biophys Acta, 2013;1830:4235–43.
197. Haraguchi N, Utsunomiya T, Inoue H, et al., Characterization of a side population of cancer cells from human gastrointestinal system, Stem Cells, 2006;24:506–13.
198. Kotasek D, Hughes B, Markman B, et al., A Phase 1b Study of the Anti-Cancer Stem Cell Agent Demcizumab, Pemetrexed and Carboplatin in Patients with 1st line Non-Squamous Non-Small Cell Lung Cancer (NSCLC), J Clin Oncol, 2015;33(suppl; abstract 8045).
199. Jimeno A, Gordon MS, Chugh R, et al., A first-in-human phase 1 study of anticancer stem cell agent OMP-54F28 (FZD8-Fc), decoy receptor for WNT ligands, in patients with advanced solid tumors, J Clin Oncol, 2014;32(5s):(suppl; abstract 2505).
200. Laurie SA, Jonker DJ, Edenfield WJ, et al., A phase 1 doseescalation study of BBI503, a first-in-class cancer stemness kinase inhibitor in adult patients with advanced solid tumors. Presented at 2014 American Society of Clinical Oncology (ASCO) Annual Meeting; Chicago, IL, USA, 2014.
201. Li Y, Rogoff HA, Keates S, et al., Suppression of cancer relapse and metastasis by inhibiting cancer stemness, Proc Natl Acad Sci U S A, 2015;112:1839–44.
202. Tan FH, Putoczki TL, Stylli SS, Luwor RB, The role of STAT3 signaling in mediating tumor resistance to cancer therapy, Curr Drug Targets, 2014;15:1341–53.
203. Shahda S, El-Rayes BF, O'Neil BH, et al., A phase Ib study of cancer stem cell (CSC) pathway inhibitor BBI-608 in combination with gemcitabine and nab-paclitaxel (nab-PTX) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC), J Clin Oncol, 2016;34(suppl 4S; abstr 284).
204. Bekaii-Saab TS, Mikhail S, Langleben A, et al., A phase Ib/II study of BBI608 combined with weekly paclitaxel in advanced pancreatic cancer, J Clin Oncol, 2016;34(suppl 4S; abstr 196).
205. Hubbard JM, O'Neil BH, Jonker DJ, et al., Phase Ib study of cancer stem cell (CSC) pathway inhibitor BBI-608 administered in combination with FOLFIRI with and without bevacizumab (Bev) in patients (pts) with advanced colorectal cancer (CRC), J Clin Oncol, 2016;34(suppl 4S; abstr 569).
206. Cochrane CR, Szczepny A, Watkins DN, Cain JE, Hedgehog Signaling in the Maintenance of Cancer Stem Cells, Cancers, 2015;7:1554–85.
207. Panneerselvam J, Jin J, Shanker M, et al., IL-24 inhibits lung cancer cell migration and invasion by disrupting the SDF-1/C XCR4 signaling axis, PloS One, 2015;10:e0122439.
208. Graham NA, Graeber TG, Complexity of metastasis-associated SDF-1 ligand signaling in breast cancer stem cells, Proc Natl Acad Sci U S A, 2014;111:7503–4.
209. Gatti M, Pattarozzi A, Bajetto A, et al., Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity, Toxicology, 2013;314:209–20.
210. Li L, Cole J, Margolin DA, Cancer stem cell and stromal microenvironment, The Ochsner Journal, 2013;13:109–18.
211. Kong F, Gao F, Li H, et al., CD47: a potential immunotherapy target for eliminating cancer cells, Clin Transl Oncol, 2016;18:1051–5.
212. Kaur S, Elkahloun AG, Singh SP, et al., A function-blocking CD47 antibody suppresses stem cell and EGF signaling in triplenegative breast cancer, Oncotarget, 2016;7:10133–52.
213. Theocharides AP, Jin L, Cheng PY, et al., Disruption of SIRPalpha signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts, J Exp Med, 2012;209:1883–99.
214. Krampitz GW, George BM, Willingham SB, et al., Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors, Proc Natl Acad Sci U S A, 2016;113:4464–9.
215. Todaro M, Perez Alea M, Scopelliti A, et al., IL-4-mediated drug resistance in colon cancer stem cells, Cell Cycle, 2008;7:309–13.
216. Yoo YD, Lee DH, Cha-Molstad H, et al., Glioma-derived cancer stem cells are hypersensitive to proteasomal inhibition, EMBO Reports, 2017;18:150–68.
217. Jachetti E, Caputo S, Mazzoleni S, et al., Tenascin-C Protects Cancer Stem-like Cells from Immune Surveillance by Arresting T-cell Activation, Cancer Res, 2015;75:2095–108.
218. Kakarala M, Wicha MS, Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy, J Clin Oncol, 2008;26:2813–20.
219. Marjanovic ND, Weinberg RA, Chaffer CL, Cell plasticity and heterogeneity in cancer, Clin Chem, 2013;59:168–79.
220. Singh SK, Clarke ID, Terasaki M, et al., Identification of a cancer stem cell in human brain tumors,Cancer Res, 2003;63:5821–8.
221. He J, Liu Y, Zhu T, et al., CD90 is identified as a candidate marker for cancer stem cells in primary high-grade gliomas using tissue microarrays, Mol Cell Proteomics, 2012;11:M111.010744.
222. Ginestier C, Hur MH, Charafe-Jauffret E, et al., ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome, Cell Stem Cell, 2007;1:555–67.
223. Vaiopoulos AG, Kostakis ID, Koutsilieris M, Papavassiliou AG, Colorectal cancer stem cells, Stem Cells, 2012;30:363–71.
224. Cherciu I, Barbalan A, Pirici D, et al., Stem cells, colorectal cancer and cancer stem cell markers correlations, Curr Health Sci J, 2014;40:153–61.
225. Dalerba P, Dylla SJ, Park IK, et al., Phenotypic characterization of human colorectal cancer stem cells, Proc Natl Acad Sci U S A, 2007;104:10158–63.
226. Huang EH, Hynes MJ, Zhang T, et al., Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis, Cancer Res, 2009;69:3382–9.
227. Rutella S, Bonanno G, Procoli A, et al., Cells with characteristics of cancer stem/progenitor cells express the CD133 antigen in human endometrial tumors, Clin Cancer Res, 2009;15:4299–311.
228. Takaishi S, Okumura T, Tu S, et al., Identification of gastric cancer stem cells using the cell surface marker CD44, Stem Cells, 2009;27:1006–20.
229. Han J, Fujisawa T, Husain SR, Puri RK, Identification and characterization of cancer stem cells in human head and neck squamous cell carcinoma, BMC Cancer, 2014;14:173.
230. Majeti R, Chao MP, Alizadeh AA, et al., CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells, Cell, 2009;138:286–99.
231. van Rhenen A, van Dongen GA, Kelder A, et al., The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells, Blood, 2007;110:2659–66.
232. Hosen N, Park CY, Tatsumi N, et al., CD96 is a leukemic stem cellspecific marker in human acute myeloid leukemia, Proc Natl Acad Sci U S A, 2007;104:11008–13.
233. Jan M, Chao MP, Cha AC, et al., Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker, Proc Natl Acad Sci U S A, 2011;108:5009–14.
234. Saito Y, Kitamura H, Hijikata A, et al., Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells,Sci Transl Med, 2010;2:17ra9.
235. Yamashita T, Wang XW, Cancer stem cells in the development of liver cancer, J Clin Invest, 2013;123:1911–8.
236. Ma S, Chan KW, Lee TK, et al., Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations, Mol Cancer Res, 2008;6:1146–53.
237. Alamgeer M, Peacock CD, Matsui W, et al., Cancer stem cells in lung cancer: Evidence and controversies, Respirology, 2013;18:757–64.
238. Donnenberg VS, Landreneau RJ, Donnenberg AD, Tumorigenic stem and progenitor cells: implications for the therapeutic index of anti-cancer agents, J Control Release, 2007;122:385–91.
239. Bertolini G, Roz L, Perego P, et al., Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment, Proc Natl Acad Sci U S A, 2009;106:16281–6.
240. Boonyaratanakornkit JB, Yue L, Strachan LR, et al., Selection of tumorigenic melanoma cells using ALDH, J Invest Dermatol, 2010;130:2799–808.
241. Zhang S, Balch C, Chan MW, et al., Identification and characterization of ovarian cancer-initiating cells from primary human tumors, Cancer Res, 2008;68:4311–20.
242. Li L, Hao X, Qin J, et al., Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice, Gastroenterology, 2014;146:1108–18.
Keywords: Cancer biomarker, cancer stem cell, tumor-initiating cell, microenvironment, signaling pathway, targeted therapy, radioresistance, chemoresistance