Onkopipeline

, Volume 1, Issue 3, pp 91–100

Tumorstammzellen: Grundlagen, klinische Implikationen und Kontroversen

  • Joachim Wahl
  • Klaus-Michael Debatin
  • Christian Beltinger
REVIEW

Zusammenfassung

Bisher galten alle Tumorzellen innerhalb eines Tumors als grundsätzlich gleich maligne. Es mehren sich nun Hinweise, dass Tumoren auch hierarchisch gegliedert sein können. Danach befinden sich im Tumor einige wenige, sich selbst erneuernde und dadurch tumorbildende Tumorstammzellen (TSZ), welche die Quelle von differenzierteren Tumorzellen sind. TSZ können ihren Ursprung zum einen in Gewebestammzellen, zum anderen aber auch in schon differenzierten Gewebezellen haben.

Der Nachweis von TSZ in einer Tumorart kann zu einer Änderung in der klinischen Vorgehensweise führen. Es werden nicht mehr die zahlenmäßig überwiegenden differenzierten Tumorzellen für die Prognose, die Patientenstratifizierung und die Beurteilung des Therapieansprechens, einer minimalen Resterkrankung oder eines Rezidivs als ausschlaggebend betrachtet, sondern die Zahl, die Funktionsfähigkeit und das Genexpressionsmuster der wenigen TSZ in Primärtumor und Metastasen. Ein Tumor mit TSZ wird nach dem TSZ-Modell nur dann erfolgreich therapiert werden können, wenn auch die vergleichsweise therapieresistenten TSZ abgetötet oder differenziert werden.

Trotz Kontroversen, die sich an der Definition von TSZ und deren Nachweismethoden entzündet haben, könnte das TSZ-Konzept zu verbesserten prognostischen und therapeutischen Verfahren in der Onkologie führen.

Schlüsselwörter:

Tumorstammzellen Tumorinitiierende Zellen Solide Tumoren Selbsterneuerung Differenzierung 

Cancer Stem Cells: Basics, Clinical Implications, and Controversies

Abstract

All tumor cells within a tumor are widely considered to be of equal malignancy. However, there is increasing evidence of a hierarchy within tumors. According to this view, rare self-renewing cancer stem cells (CSCs) on the top of the tumor’s hierarchy initiate tumor growth and are the source of more differentiated tumor cells. CSCs can originate from tissue stem cells or from more differentiated tissue progenitors.

The detection of CSCs within a tumor entity can lead to a change in the clinical management of cancer. Not the prevalent differentiated cancer cells within a primary tumor or metastases would be considered to be pivotal for prognosis, patient stratification and assessment of therapeutic response, but the number, functionality and gene expression of the rare CSCs. This would implicate that the – relatively resistant – CSCs have to be eliminated if a tumor were to be eradicated.

Despite recent controversies about the definition of CSCs and methods to assess them, the CSC model may lead to improved prognostic and therapeutic approaches in oncology.

Key Words:

Cancer stem cells Tumor-initiating cells Self-renewal Solid tumors Differentiation 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Adams JM, Strasser A. Is tumor growth sustained by rare cancer stem cells or dominant clones? Cancer Res 2008;68:4018–21.PubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    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.PubMedCrossRefGoogle Scholar
  4. 4.
    Bao S, Wu Q, Sathornsumetee S, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 2006;66:7843–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Bapat SA, Mali AM, Koppikar CB, et al. Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res 2005;65:3025–9.PubMedGoogle Scholar
  6. 6.
    Bar EE, Chaudhry A, Lin A, et al. Cyclopamine-mediated hedgehog pathway inhibition depletes stem-like cancer cells in glioblastoma. Stem Cells 2007;25:2524–33.PubMedCrossRefGoogle Scholar
  7. 7.
    Barabe F, Kennedy JA, Hope KJ, et al. Modeling the initiation and progression of human acute leukemia in mice. Science 2007;316:600–4.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    Braun S, Pantel K, Muller P, et al. Cytokeratin-positive cells in the bone marrow and survival of patients with stage I, II, or III breast cancer. N Engl J Med 2000;342:525–33.PubMedCrossRefGoogle Scholar
  10. 10.
    Brunschwig A, Southam CM, Levin AG. Host resistance to cancer. Clinical experiments by homotransplants, autotransplants and admixture of autologous leucocytes. Ann Surg 1965;162:416–25.PubMedCrossRefGoogle Scholar
  11. 11.
    Bussolati B, Bruno S, Grange C, et al. Identification of a tumor-initiating stem cell population in human renal carcinomas. FASEB J 2008;22:3696–705.PubMedCrossRefGoogle Scholar
  12. 12.
    Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007;11:69–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Castor A, Nilsson L, Astrand-Grundstrom I, et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med 2005;11:630–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Chan EF, Gat U, McNiff JM, et al. A common human skin tumour is caused by activating mutations in beta-catenin. Nat Genet 1999;21:410–3.PubMedCrossRefGoogle Scholar
  15. 15.
    Chen YC, Hsu HS, Chen YW, et al. Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS ONE 2008;3:e2637.PubMedCrossRefGoogle Scholar
  16. 16.
    Chiba T, Kita K, Zheng YW, et al. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 2006;44:240–51.PubMedCrossRefGoogle Scholar
  17. 17.
    Chung EJ, Hwang SG, Nguyen P, et al. Regulation of leukemic cell adhesion, proliferation, and survival by beta-catenin. Blood 2002;100:982–90.PubMedCrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    Clarke MF, Fuller M. Stem cells and cancer: two faces of Eve. Cell 2006;124:1111–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Cobaleda C, Gutierrez-Cianca N, Perez-Losada J, et al. A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia-positive acute lymphoblastic leukemia. Blood 2000;95:1007–13.PubMedGoogle Scholar
  21. 21.
    Collins AT, Berry PA, Hyde C, et al. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005;65:10946–51.PubMedCrossRefGoogle Scholar
  22. 22.
    Costello RT, Mallet F, Gaugler B, et al. Human acute myeloid leukemia CD34+/CD38− progenitor cells have decreased sensitivity to chemotherapy and Fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res 2000;60:4403–11.PubMedGoogle Scholar
  23. 23.
    Coustan-Smith E, Sancho J, Hancock ML, et al. Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood 2000;96:2691–6.PubMedGoogle Scholar
  24. 24.
    Cox CV, Evely RS, Oakhill A, et al. Characterization of acute lymphoblastic leukemia progenitor cells. Blood 2004;104:2919–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Cox CV, Martin HM, Kearns PR, et al. Characterization of a progenitor cell population in childhood T-cell acute lymphoblastic leukemia. Blood 2007;109:674–82.PubMedCrossRefGoogle Scholar
  26. 26.
    Cozzio A, Passegue E, Ayton PM, et al. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003;17:3029–35.PubMedCrossRefGoogle Scholar
  27. 27.
    Cui H, Hu B, Li T, et al. Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol 2007;170:1370–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Cui H, Ma J, Ding J, et al. Bmi-1 regulates the differentiation and clonogenic self-renewal of I-type neuroblastoma cells in a concentration-dependent manner. J Biol Chem 2006;281:34696–704.PubMedCrossRefGoogle Scholar
  29. 29.
    Dahmane N, Lee J, Robins P, et al. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours. Nature 1997;389:876–81.PubMedCrossRefGoogle Scholar
  30. 30.
    Dahmen RP, Koch A, Denkhaus D, et al. Deletions of AXIN1, a component of the WNT/wingless pathway, in sporadic medulloblastomas. Cancer Res 2001;61:7039–43.PubMedGoogle Scholar
  31. 31.
    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.PubMedCrossRefGoogle Scholar
  32. 32.
    Duerr EM, Rollbrocker B, Hayashi Y, et al. PTEN mutations in gliomas and glioneuronal tumors. Oncogene 1998;16:2259–64.PubMedCrossRefGoogle Scholar
  33. 33.
    Dylla SJ, Beviglia L, Park IK, et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE 2008;3:e2428.PubMedCrossRefGoogle Scholar
  34. 34.
    Eramo A, Lotti F, Sette G, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 2008;15:504–14.PubMedCrossRefGoogle Scholar
  35. 35.
    Eyler CE, Foo WC, Lafiura KM, et al. Brain cancer stem cells display preferential sensitivity to Akt inhibition. Stem Cells 2008: in press (Epub 2008 Sep 18).Google Scholar
  36. 36.
    Fan X, Matsui W, Khaki L, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 2006;66:7445–52.PubMedCrossRefGoogle Scholar
  37. 37.
    Fang D, Nguyen TK, Leishear K, et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 2005;65:9328–37.PubMedCrossRefGoogle Scholar
  38. 38.
    Francipane MG, Alea MP, Lombardo Y, et al. Crucial role of interleukin-4 in the survival of colon cancer stem cells. Cancer Res 2008;68:4022–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004;64:7011–21.PubMedCrossRefGoogle Scholar
  40. 40.
    George AA, Franklin J, Kerkof K, et al. Detection of leukemic cells in the CD34(+)CD38(−) bone marrow progenitor population in children with acute lymphoblastic leukemia. Blood 2001;97:3925–30.PubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedCrossRefGoogle Scholar
  42. 42.
    Groszer M, Erickson R, Scripture-Adams DD, et al. PTEN negatively regulates neural stem cell self-renewal by modulating G0-G1 cell cycle entry. Proc Natl Acad Sci U S A 2006;103:111–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 2001;98:2301–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A 2002;99:16220–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Hansford LM, McKee AE, Zhang L, et al. Neuroblastoma cells isolated from bone marrow metastases contain a naturally enriched tumor-initiating cell. Cancer Res 2007;67:11234–43.PubMedCrossRefGoogle Scholar
  46. 46.
    Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A 2003;100:15178–83.PubMedCrossRefGoogle Scholar
  47. 47.
    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.PubMedCrossRefGoogle Scholar
  48. 48.
    Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci U S A 2004;101:14228–33.PubMedCrossRefGoogle Scholar
  49. 49.
    Hong D, Gupta R, Ancliff P, et al. Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia. Science 2008;319:336–9.PubMedCrossRefGoogle Scholar
  50. 50.
    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.PubMedCrossRefGoogle Scholar
  51. 51.
    Huang D, Gao Q, Guo L, et al. Isolation and identification of cancer stem-like cells in esophageal carcinoma cell lines. Stem Cells Dev 2008: in press (Epub 2008 Aug 04).Google Scholar
  52. 52.
    Huss WJ, Gray DR, Greenberg NM, et al. Breast cancer resistance protein-mediated efflux of androgen in putative benign and malignant prostate stem cells. Cancer Res 2005;65:6640–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Jamieson CH, Ailles LE, Dylla SJ, et al. Granulocyte- macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med 2004;351:657–67.PubMedCrossRefGoogle Scholar
  54. 54.
    Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006;12:1167–74.PubMedCrossRefGoogle Scholar
  55. 55.
    Johnson RL, Rothman AL, Xie J, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 1996;272:1668–71.PubMedCrossRefGoogle Scholar
  56. 56.
    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.PubMedCrossRefGoogle Scholar
  57. 57.
    Kelly PN, Dakic A, Adams JM, et al. Tumor growth need not be driven by rare cancer stem cells. Science 2007;317:337.PubMedCrossRefGoogle Scholar
  58. 58.
    Kennedy JA, Barabe F, Poeppl AG, et al. Comment on “Tumor growth need not be driven by rare cancer stem cells”. Science 2007;318:1722, author reply 1722.PubMedCrossRefGoogle Scholar
  59. 59.
    Koch A, Waha A, Tonn JC, et al. Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer 2001;93:445–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Korkaya H, Paulson A, Iovino F, et al. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 2008;27:6120–30.PubMedCrossRefGoogle Scholar
  61. 61.
    Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006;442:818–22.PubMedCrossRefGoogle Scholar
  62. 62.
    Kruger JA, Kaplan CD, Luo Y, et al. Characterization of stem cell-like cancer cells in immune-competent mice. Blood 2006;108:3906–12.PubMedCrossRefGoogle Scholar
  63. 63.
    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.PubMedCrossRefGoogle Scholar
  64. 64.
    Lee J, Kotliarova S, Kotliarov Y, et al. Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 2006;9:391–403.PubMedCrossRefGoogle Scholar
  65. 65.
    Lee J, Son MJ, Woolard K, et al. Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell 2008;13:69–80.PubMedCrossRefGoogle Scholar
  66. 66.
    Lessard J, Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 2003;423:255–60.PubMedCrossRefGoogle Scholar
  67. 67.
    Le Viseur C, Hotfilder M, Bomken S, et al. In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell 2008;14:47–58.PubMedCrossRefGoogle Scholar
  68. 68.
    Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030–7.PubMedCrossRefGoogle Scholar
  69. 69.
    Li G, Wong AJ. EGF receptor variant III as a target antigen for tumor immunotherapy. Expert Rev Vaccines 2008;7:977–85.PubMedCrossRefGoogle Scholar
  70. 70.
    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.PubMedCrossRefGoogle Scholar
  71. 71.
    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.PubMedCrossRefGoogle Scholar
  72. 72.
    Mahlknecht U, Schonbein C. Histone deacetylase inhibitor treatment downregulates VLA-4 adhesion in hematopoietic stem cells and acute myeloid leukemia blast cells. Haematologica 2008;93:443–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Malanchi I, Peinado H, Kassen D, et al. Cutaneous cancer stem cell maintenance is dependent on betacatenin signalling. Nature 2008;452:650–3.PubMedCrossRefGoogle Scholar
  74. 74.
    Marzi I, D’Amico M, Biagiotti T, et al. Purging of the neuroblastoma stem cell compartment and tumor regression on exposure to hypoxia or cytotoxic treatment. Cancer Res 2007;67:2402–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Matsui W, Huff CA, Wang Q, et al. Characterization of clonogenic multiple myeloma cells. Blood 2004;103:2332–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Matsui W, Wang Q, Barber JP, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 2008;68:190–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Moore KA, Lemischka IR. Stem cells and their niches. Science 2006;311:1880–5.PubMedCrossRefGoogle Scholar
  78. 78.
    Park IK, Qian D, Kiel M, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 2003;423:302–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Patrawala L, Calhoun T, Schneider-Broussard R, et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 2006;25:1696–708.PubMedCrossRefGoogle Scholar
  80. 80.
    Pear WS, Aster JC, Scott ML, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996;183:2283–91.PubMedCrossRefGoogle Scholar
  81. 81.
    Pezzolo A, Parodi F, Corrias MV, et al. Tumor origin of endothelial cells in human neuroblastoma. J Clin Oncol 2007;25:376–83.PubMedCrossRefGoogle Scholar
  82. 82.
    Phillips TM, Kim K, Vlashi E, et al. Effects of recombinant erythropoietin on breast cancer-initiating cells. Neoplasia 2007;9:1122–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Piccirillo SG, Reynolds BA, Zanetti N, et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006;444:761–5.PubMedCrossRefGoogle Scholar
  84. 84.
    Pretlow TG, Delmoro CM, Dilley GG, et al. Transplantation of human prostatic carcinoma into nude mice in Matrigel. Cancer Res 1991;51:3814–7.PubMedGoogle Scholar
  85. 85.
    Prince ME, Sivanandan R, Kaczorowski A, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 2007;104:973–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Proia DA, Kuperwasser C. Reconstruction of human mammary tissues in a mouse model. Nat Protoc 2006;1:206–14.PubMedCrossRefGoogle Scholar
  87. 87.
    Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007;445:111–5.PubMedCrossRefGoogle Scholar
  88. 88.
    Richardson GD, Robson CN, Lang SH, et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 2004;117:3539–45.PubMedCrossRefGoogle Scholar
  89. 89.
    Schatton T, Murphy GF, Frank NY, et al. Identification of cells initiating human melanomas. Nature 2008;451:345–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Shipitsin M, Polyak K. The cancer stem cell hypothesis: in search of definitions, markers, and relevance. Lab Invest 2008;88:459–63.PubMedCrossRefGoogle Scholar
  91. 91.
    Shmelkov SV, Butler JM, Hooper AT, et al. CD133 expression is not restricted to stem cells, and both CD133+ and CD133- metastatic colon cancer cells initiate tumors. J Clin Invest 2008;118:2111–20.PubMedGoogle Scholar
  92. 92.
    Sievers EL, Appelbaum FR, Spielberger RT, et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 1999;93:3678–84.PubMedGoogle Scholar
  93. 93.
    Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821–8.PubMedGoogle Scholar
  94. 94.
    Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004;432:396–401.PubMedCrossRefGoogle Scholar
  95. 95.
    Taussig DC, Miraki-Moud F, Anjos-Afonso F, et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood 2008;112:568–75.PubMedCrossRefGoogle Scholar
  96. 96.
    Van de Wetering M, Sancho E, Verweij C, et al. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 2002;111:241–50.PubMedCrossRefGoogle Scholar
  97. 97.
    Virchow R. Die krankhaften Geschwülste. Berlin: Hirschwald, 1863.Google Scholar
  98. 98.
    Wang J, Guo LP, Chen LZ, et al. Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res 2007;67:3716–24.PubMedCrossRefGoogle Scholar
  99. 99.
    Wang S, Garcia AJ, Wu M, et al. Pten deletion leads to the expansion of a prostatic stem/progenitor cell subpopulation and tumor initiation. Proc Natl Acad Sci U S A 2006;103:1480–5.PubMedCrossRefGoogle Scholar
  100. 100.
    Wu C, Wei Q, Utomo V, et al. Side population cells isolated from mesenchymal neoplasms have tumor initiating potential. Cancer Res 2007;67:8216–22.PubMedCrossRefGoogle Scholar
  101. 101.
    Wulf GG, Wang RY, Kuehnle I, et al. A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia. Blood 2001;98:1166–73.PubMedCrossRefGoogle Scholar
  102. 102.
    Xin L, Lawson DA, Witte ON. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci U S A 2005;102:6942–7.PubMedCrossRefGoogle Scholar
  103. 103.
    Xu Q, Yuan X, Liu G, et al. Hedgehog signaling regulates brain tumor initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. Stem Cells 2008: in press (Epub 2008 Sep 11).Google Scholar
  104. 104.
    Yang W, Yan HX, Chen L, et al. Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 2008;68:4287–95.PubMedCrossRefGoogle Scholar
  105. 105.
    Yang ZF, Ho DW, Ng MN, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 2008;13:153–66.PubMedCrossRefGoogle Scholar
  106. 106.
    Yang ZF, Ngai P, Ho DW, et al. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 2008;47:919–28.PubMedCrossRefGoogle Scholar
  107. 107.
    Yang ZJ, Ellis T, Markant SL, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 2008;14:135–45.PubMedCrossRefGoogle Scholar
  108. 108.
    Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006;441:475–82.PubMedCrossRefGoogle Scholar
  109. 109.
    Yin S, Li J, Hu C, et al. CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. Int J Cancer 2007;120:1444–50.PubMedCrossRefGoogle Scholar
  110. 110.
    Yuan X, Curtin J, Xiong Y, et al. Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 2004;23:9392–400.PubMedCrossRefGoogle Scholar
  111. 111.
    Zeilstra J, Joosten SP, Dokter M, et al. Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res 2008;68:3655–61.PubMedCrossRefGoogle Scholar
  112. 112.
    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.PubMedCrossRefGoogle Scholar
  113. 113.
    Zhang X, Komaki R, Wang L, et al. Treatment of radioresistant stem-like esophageal cancer cells by an apoptotic gene-armed, telomerase-specific oncolytic adenovirus. Clin Cancer Res 2008;14:2813–23.PubMedCrossRefGoogle Scholar
  114. 114.
    Zhou J, Wulfkuhle J, Zhang H, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A 2007;104:16158–63.PubMedCrossRefGoogle Scholar
  115. 115.
    Zurawel RH, Chiappa SA, Allen C, et al. Sporadic medulloblastomas contain oncogenic beta-catenin mutations. Cancer Res 1998;58:896–9.PubMedGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Joachim Wahl
  • Klaus-Michael Debatin
  • Christian Beltinger
    • 1
    • 2
  1. 1.Universitätsklinik für Kinder- und JugendmedizinUlmGermany
  2. 2.Universitätsklinik für Kinder- und JugendmedizinUlmGermany

Personalised recommendations