Cancer Stem Cells: Potential Mediators of Therapeutic Resistance and Novel Targets of Anti-cancer Treatments

  • Hong Yan
  • Jichao Qin
  • Dean G. Tang

Over the last decade, anti-cancer therapies (chemotherapy and radiation, hormonal, neoadjuvant, and combinatorial therapies) have prolonged the lives of cancer patients. However, present cancer therapies fail in a high percentage of cases due to an incomplete elimination of the tumor cells, resulting in relapse and metastasis of the tumor. The vast majority of cancer-related deaths are due to metastatic tumor growth that impairs the function of vital organ(s). Thus, cancer relapse and metastasis are the major challenges in fighting cancer.


Cancer Stem Cell Side Population Mitochondrial Permeability Transition Pore Mitochondrial Permeability Transition Pore Side Population Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank all current and past Tang lab members for their support and helpful discussions. We apologize to those colleagues whose original work could not be cited in this chapter due to space constraint. This work was supported in part by grants from NIH (R01-AG023374, R01-ES015888, and R21-ES015893-01A1), American Cancer Society (RSG MGO-105961), Department of Defense (W81XWH-07-1-0616 & W81XWH-08-1-0472), Prostate Cancer Foundation, and Elsa Pardee Foundation (D.G.T) and by two Center Grants (CCSG-5 P30 CA166672 and ES07784). JQ was supported by a post-doctoral fellowship from DOD and HY was supported by a fellowship grant from the Chinese Ministry of Education.


  1. 1.
    Luzzi KJ, MacDonald IC, Schmidt EE et al. (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153: 865–873PubMedGoogle Scholar
  2. 2.
    Spillane JB, Henderson MA (2007) Cancer stem cells: a review. ANZ J Surg 77: 464–468PubMedGoogle Scholar
  3. 3.
    Li F, Tiede B, Massague J et al. (2007) Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res 17: 3–14PubMedGoogle Scholar
  4. 4.
    Vaidya JS (2007) An alternative model of cancer cell growth and metastasis. Int J Surg 5: 73–75PubMedGoogle Scholar
  5. 5.
    Kucia M, Ratajczak MZ (2006) Stem cells as a two edged sword – from regeneration to tumor formation. J Physiol Pharmacol 57(Suppl 7): 5–16Google Scholar
  6. 6.
    Allan AL, Vantyghem SA, Tuck AB et al. (2006) Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis. Breast Dis 26: 87–98PubMedGoogle Scholar
  7. 7.
    Holmgren L, O'Reilly MS, Folkman J (1995) Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med 1: 149–153PubMedGoogle Scholar
  8. 8.
    Chambers AF, Groom AC, MacDonald IC (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2: 563–572PubMedGoogle Scholar
  9. 9.
    Luzzi KJ, MacDonald I, Schmidt EE et al. (1998) Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153: 865–873PubMedGoogle Scholar
  10. 10.
    Raff M (2003) Adult stem cell plasticity: fact or artifact? Annu Rev Cell Dev Biol 19: 1–22PubMedGoogle Scholar
  11. 11.
    Passegue E, Wagers AJ (2006) Regulating quiescence: new insights into hematopoietic stem cell biology. Dev Cell 10: 415–417PubMedGoogle Scholar
  12. 12.
    Horsley V, Aliprantis AO, Polak L et al. (2008) NFATc1 balances quiescence and proliferation of skin stem cells. Cell 132: 299–310PubMedGoogle Scholar
  13. 13.
    Tumbar T, Guasch G, Greco V et al. (2004) Defining the epithelial stem cell niche in skin. Science 303: 359–363PubMedGoogle Scholar
  14. 14.
    Morrison SJ, Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132: 598–611PubMedGoogle Scholar
  15. 15.
    Bruce WR, Van Der Gaag H (1963) A quantitative assay for the number of murine lymphoma cells capable of proliferation in vivo. Nature 199: 79–80PubMedGoogle Scholar
  16. 16.
    Becker AJ, Mc CE, Till JE (1963) Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197: 452–454PubMedGoogle Scholar
  17. 17.
    Buick RN, Till JE, McCulloch EA (1977) Colony assay for proliferative blast cells circulating in myeloblastic leukaemia. Lancet 1: 862–863PubMedGoogle Scholar
  18. 18.
    Raftopoulou M (2006) Cancer stem cells: the needle in the haystack.
  19. 19.
    Lapidot T, Sirard C, Vormoor J et al. (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367: 645–648PubMedGoogle Scholar
  20. 20.
    Clarke MF, Dick JE, Dirks PB et al. (2006) Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 66: 9339–9344PubMedGoogle Scholar
  21. 21.
    Joseph NM, Mosher JT, Buchstaller J et al. (2008) The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells. Cancer Cell 13: 129–140PubMedGoogle Scholar
  22. 22.
    Zheng H, Chang L, Patel N et al. (2008) Induction of abnormal proliferation by nonmyelinating schwann cells triggers neurofibroma formation. Cancer Cell 13: 117–128PubMedGoogle Scholar
  23. 23.
    Kim CF, Dirks PB (2008) Cancer and stem cell biology: how tightly intertwined? Cell Stem Cell 3: 147–150PubMedGoogle Scholar
  24. 24.
    Tang DG, Patrawala L, Calhoun T et al. (2007) Prostate cancer stem/progenitor cells: identification, characterization, and implications. Mol Carcinog 46: 1–14PubMedGoogle Scholar
  25. 25.
    Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3: 895–902PubMedGoogle Scholar
  26. 26.
    Mazurier F, Gan OI, McKenzie JL et al. (2004) Lentivector-mediated clonal tracking reveals intrinsic heterogeneity in the human hematopoietic stem cell compartment and culture-induced stem cell impairment. Blood 103: 545–552PubMedGoogle Scholar
  27. 27.
    Barker N, van Es JH, Kuipers J et al. (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449: 1003–1007PubMedGoogle Scholar
  28. 28.
    Patrawala L, Calhoun T, Schneider-Broussard R et al. (2005) Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2– cancer cells are similarly tumorigenic. Cancer Res 65: 6207–6219PubMedGoogle Scholar
  29. 29.
    Clarke RB, Spence K, Anderson E et al. (2005) A putative human breast stem cell population is enriched for steroid receptor-positive cells. Dev Biol 277: 443–456PubMedGoogle Scholar
  30. 30.
    Kondo T, Setoguchi T, Taga T (2004) Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proc Natl Acad Sci USA 101: 781–786PubMedGoogle Scholar
  31. 31.
    Hadnagy A, Gaboury L, Beaulieu R et al. (2006) SP analysis may be used to identify cancer stem cell populations. Exp Cell Res 312: 3701–3710PubMedGoogle Scholar
  32. 32.
    Ho MM, Ng AV, Lam S et al. (2007) Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res 67: 4827–4833PubMedGoogle Scholar
  33. 33.
    Fang D, Nguyen TK, Leishear K et al. (2005) A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 65: 9328–9337PubMedGoogle Scholar
  34. 34.
    Singh SK, Hawkins C, Clarke ID et al. (2004) Identification of human brain tumour initiating cells. Nature 432: 396–401PubMedGoogle Scholar
  35. 35.
    Fuchs E, Tumbar T, Guasch G (2004) Socializing with the neighbors: stem cells and their niche. Cell 116: 769–778PubMedGoogle Scholar
  36. 36.
    Clarke RB, Anderson E, Howell A et al. (2003) Regulation of human breast epithelial stem cells. Cell Prolif 36(Suppl 1): 45–58PubMedGoogle Scholar
  37. 37.
    Patrawala L, Calhoun T, Schneider-Broussard R et al. (2006) Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25: 1696–1708PubMedGoogle Scholar
  38. 38.
    Yu F, Yao H, Zhu P et al. (2007) let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131: 1109–1123PubMedGoogle Scholar
  39. 39.
    Kiel MJ, He S, Ashkenazi R et al. (2007) Haematopoietic stem cells do not asymmetrically segregate chromosomes or retain BrdU. Nature 449: 238–242PubMedGoogle Scholar
  40. 40.
    Szotek PP, Chang HL, Brennand K et al. (2008) Normal ovarian surface epithelial label-retaining cells exhibit stem/progenitor cell characteristics. Proc Natl Acad Sci USA 105: 12469–12473PubMedGoogle Scholar
  41. 41.
    Barrandon Y, Green H (1985) Cell size as a determinant of the clone-forming ability of human keratinocytes. Proc Natl Acad Sci USA 82: 5390–5394PubMedGoogle Scholar
  42. 42.
    Barrandon Y, Green H (1987) Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci USA 84: 2302–2306PubMedGoogle Scholar
  43. 43.
    Locke M, Heywood M, Fawell S et al. (2005) Retention of intrinsic stem cell hierarchies in carcinoma-derived cell lines. Cancer Res 65: 8944–8950PubMedGoogle Scholar
  44. 44.
    Li H, Chen X, Calhoun-Davis T et al. (2008) PC3 human prostate carcinoma cell holoclones contain self-renewing tumor-initiating cells. Cancer Res 68: 1820–1825PubMedGoogle Scholar
  45. 45.
    Baguley BC (2006) Tumor stem cell niches: a new functional framework for the action of anticancer drugs. Recent Patents Anticancer Drug Discov 1: 121–127Google Scholar
  46. 46.
    Trumpp A, Wiestler OD (2008) Mechanisms of Disease: cancer stem cells – targeting the evil twin. Nat Clin Pract Oncol 5: 337–347PubMedGoogle Scholar
  47. 47.
    Arai F, Hirao A, Ohmura M et al. (2004) Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118: 149–161PubMedGoogle Scholar
  48. 48.
    Zhang J, Niu C, Ye L et al. (2003) Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425: 836–841PubMedGoogle Scholar
  49. 49.
    Kaplan RN, Psaila B, Lyden D (2007) Niche-to-niche migration of bone-marrow-derived cells. Trends Mol Med 13: 72–81PubMedGoogle Scholar
  50. 50.
    Li L, Xie T (2005) Stem cell niche: structure and function. Annu Rev Cell Dev Biol 21: 605–631PubMedGoogle Scholar
  51. 51.
    Sipkins DA, Wei X, Wu J et al. (2005) In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435: 969–973PubMedGoogle Scholar
  52. 52.
    Calabrese C, Poppleton H, Kocak M et al. (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11: 69–82PubMedGoogle Scholar
  53. 53.
    Bao S, Wu Q, Sathornsumetee S et al. (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66: 7843–7848PubMedGoogle Scholar
  54. 54.
    Croker AK, Allan AL (2008) Cancer stem cells: implications for the progression and treatment of metastatic disease. J Cell Mol Med 12: 374–390PubMedGoogle Scholar
  55. 55.
    Li L, Neaves WB (2006) Normal stem cells and cancer stem cells: the niche matters. Cancer Res 66: 4553–4557PubMedGoogle Scholar
  56. 56.
    Wicha MS, Liu S, Dontu G (2006) Cancer stem cells: an old idea – a paradigm shift. Cancer Res 66: 1883–1890; discussion 1895–1886PubMedGoogle Scholar
  57. 57.
    Raguz S, Yague E (2008) Resistance to chemotherapy: new treatments and novel insights into an old problem. Br J Cancer 99: 387–391PubMedGoogle Scholar
  58. 58.
    Sanchez-Garcia I, Vicente-Duenas C, Cobaleda C (2007) The theoretical basis of cancer-stem-cell-based therapeutics of cancer: can it be put into practice? Bioessays 29: 1269–1280PubMedGoogle Scholar
  59. 59.
    Szakacs G, Paterson JK, Ludwig JA et al. (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5: 219–234PubMedGoogle Scholar
  60. 60.
    Chapuy B, Koch R, Radunski U et al. (2008) Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. Leukemia 22: 1576–1586PubMedGoogle Scholar
  61. 61.
    Coelho AC, Messier N, Ouellette M et al. (2007) Role of the ABC transporter PRP1 (ABCC7) in pentamidine resistance in Leishmania amastigotes. Antimicrob Agents Chemother 51: 3030–3032PubMedGoogle Scholar
  62. 62.
    de Jonge-Peeters SD, Kuipers F, de Vries EG et al. (2007) ABC transporter expression in hematopoietic stem cells and the role in AML drug resistance. Crit Rev Oncol Hematol 62: 214–226PubMedGoogle Scholar
  63. 63.
    Engelman JA, Zejnullahu K, Mitsudomi T et al. (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316: 1039–1043PubMedGoogle Scholar
  64. 64.
    Weisberg E, Manley PW, Cowan-Jacob SW et al. (2007) Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer 7: 345–356PubMedGoogle Scholar
  65. 65.
    Ali S, Coombes RC (2002) Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2: 101–112PubMedGoogle Scholar
  66. 66.
    Hu C, Li H, Li J et al. (2008) Analysis of ABCG2 expression and side population identifies intrinsic drug efflux in the HCC cell line MHCC-97L and its modulation by Akt signaling. Carcinogenesis Sept. 26 Epub ahead of printGoogle Scholar
  67. 67.
    Loebinger MR, Giangreco A, Groot KR et al. (2008) Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade. Br J Cancer 98: 380–387PubMedGoogle Scholar
  68. 68.
    Zhou S, Schuetz JD, Bunting KD et al. (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7: 1028–1034PubMedGoogle Scholar
  69. 69.
    Gutova M, Najbauer J, Gevorgyan A et al. (2007) Identification of uPAR-positive chemoresistant cells in small cell lung cancer. PLoS ONE 2: e243PubMedGoogle Scholar
  70. 70.
    Frank NY, Margaryan A, Huang Y et al. (2005) ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res 65: 4320–4333PubMedGoogle Scholar
  71. 71.
    Wang S, Yang D, Lippman ME (2003) Targeting Bcl-2 and Bcl-XL with nonpeptidic small-molecule antagonists. Semin Oncol 30: 133–142PubMedGoogle Scholar
  72. 72.
    Todaro M, Alea MP, Di Stefano AB et al. (2007) Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1: 389–402PubMedGoogle Scholar
  73. 73.
    Cairns J (2002) Somatic stem cells and the kinetics of mutagenesis and carcinogenesis. Proc Natl Acad Sci USA 99: 10567–10570PubMedGoogle Scholar
  74. 74.
    Potten CS, Owen G, Booth D (2002) Intestinal stem cells protect their genome by selective segregation of template DNA strands. J Cell Sci 115: 2381–2388PubMedGoogle Scholar
  75. 75.
    Park Y, Gerson SL (2005) DNA repair defects in stem cell function and aging. Annu Rev Med 56: 495–508PubMedGoogle Scholar
  76. 76.
    Phillips TM, McBride WH, Pajonk F (2006) The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. J Natl Cancer Inst 98: 1777–1785PubMedGoogle Scholar
  77. 77.
    Bao S, Wu Q, McLendon RE et al. (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444: 756–760PubMedGoogle Scholar
  78. 78.
    Shafee N, Smith CR, Wei S et al. (2008) Cancer stem cells contribute to cisplatin resistance in Brca1/p53-mediated mouse mammary tumors. Cancer Res 68: 3243–3250PubMedGoogle Scholar
  79. 79.
    Liu G, Yuan X, Zeng Z et al. (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 5: 67PubMedGoogle Scholar
  80. 80.
    Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5: 275–284PubMedGoogle Scholar
  81. 81.
    Shipitsin M, Polyak K (2008) The cancer stem cell hypothesis: in search of definitions, markers, and relevance. Lab Invest 88: 459–463PubMedGoogle Scholar
  82. 82.
    Modok S, Mellor HR, Callaghan R (2006) Modulation of multidrug resistance efflux pump activity to overcome chemoresistance in cancer. Curr Opin Pharmacol 6: 350–354,PubMedGoogle Scholar
  83. 83.
    Pusztai L, Wagner P, Ibrahim N et al. (2005) Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer 104: 682–691PubMedGoogle Scholar
  84. 84.
    Wang J, Guo LP, Chen LZ et al. (2007) Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Res 67: 3716–3724PubMedGoogle Scholar
  85. 85.
    Chen JS, Pardo FS, Wang-Rodriguez J et al. (2006) EGFR regulates the side population in head and neck squamous cell carcinoma. Laryngoscope 116: 401–406PubMedGoogle Scholar
  86. 86.
    Karhadkar SS, Bova GS, Abdallah N et al. (2004) Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431: 707–712PubMedGoogle Scholar
  87. 87.
    Fan X, Matsui W, Khaki L et al. (2006) Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res 66: 7445–7452PubMedGoogle Scholar
  88. 88.
    Peacock CD, Wang Q, Gesell GS et al. (2007) Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA 104: 4048–4053PubMedGoogle Scholar
  89. 89.
    Sims-Mourtada J, Izzo JG, Ajani J et al. (2007) Sonic Hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene 26: 5674–5679PubMedGoogle Scholar
  90. 90.
    Clement V, Sanchez P, de Tribolet N et al. (2007) HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17: 165–172PubMedGoogle Scholar
  91. 91.
    Finkel E (2001) The mitochondrion: is it central to apoptosis? Science 292: 624–626PubMedGoogle Scholar
  92. 92.
    Papadopoulos V, Baraldi M, Guilarte TR et al. (2006) Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 27: 402–409PubMedGoogle Scholar
  93. 93.
    Papadopoulos K (2006) Targeting the Bcl-2 family in cancer therapy. Semin Oncol 33: 449–456PubMedGoogle Scholar
  94. 94.
    Chelli B, Lena A, Vanacore R et al. (2004) Peripheral benzodiazepine receptor ligands: mitochondrial transmembrane potential depolarization and apoptosis induction in rat C6 glioma cells. Biochem Pharmacol 68: 125–134PubMedGoogle Scholar
  95. 95.
    Chelli B, Rossi L, Da Pozzo E et al. (2005) PIGA (N,N-Di-n-butyl-5-chloro-2-(4-chlorophenyl)indol-3-ylglyoxylamide), a new mitochondrial benzodiazepine-receptor ligand, induces apoptosis in C6 glioma cells. Chembiochem 6: 1082–1088PubMedGoogle Scholar
  96. 96.
    Aguirre-Ghiso JA (2007) Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 7: 834–846PubMedGoogle Scholar
  97. 97.
    Jorgensen HG, Copland M, Allan EK et al. (2006) Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate. Clin Cancer Res 12: 626–633PubMedGoogle Scholar
  98. 98.
    Aguirre-Ghiso JA (2006) The problem of cancer dormancy: understanding the basic mechanisms and identifying therapeutic opportunities. Cell Cycle 5: 1740–1743PubMedGoogle Scholar
  99. 99.
    Ranganathan AC, Adam AP, Aguirre-Ghiso JA (2006) Opposing roles of mitogenic and stress signaling pathways in the induction of cancer dormancy. Cell Cycle 5: 1799–1807PubMedGoogle Scholar
  100. 100.
    Hope KJ, Jin L, Dick JE (2004) Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5: 738–743PubMedGoogle Scholar
  101. 101.
    Lo Coco F, Nervi C, Avvisati G et al. (1998) Acute promyelocytic leukemia: a curable disease. Leukemia 12: 1866–1880PubMedGoogle Scholar
  102. 102.
    Piccirillo SG, Reynolds BA, Zanetti N et al. (2006) Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444: 761–765PubMedGoogle Scholar
  103. 103.
    Leszczyniecka M, Roberts T, Dent P et al. (2001) Differentiation therapy of human cancer: basic science and clinical applications. Pharmacol Ther 90: 105–156PubMedGoogle Scholar
  104. 104.
    Sell S (2006) Cancer stem cells and differentiation therapy. Tumour Biol 27: 59–70PubMedGoogle Scholar
  105. 105.
    Ito K, Hirao A, Arai F et al. (2006) Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 12: 446–451PubMedGoogle Scholar
  106. 106.
    Liu Y, Liu R, Mao SC et al. (2008) Molecular-targeted antitumor agents. 19. Furospongolide from a marine Lendenfeldia sp. sponge inhibits hypoxia-inducible factor-1 activation in breast tumor cells. J Nat Prod Nov. 7 Epub ahead of printGoogle Scholar
  107. 107.
    Greenberger LM, Horak ID, Filpula D et al. (2008) A RNA antagonist of hypoxia-inducible factor-1{alpha}, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 7:3598–3608PubMedGoogle Scholar
  108. 108.
    Kiel MJ, Yilmaz OH, Iwashita T et al. (2005) SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121: 1109–1121PubMedGoogle Scholar
  109. 109.
    Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6: 273–286PubMedGoogle Scholar
  110. 110.
    Hurwitz H, Fehrenbacher L, Novotny W et al. (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335–2342PubMedGoogle Scholar
  111. 111.
    Vredenburgh JJ, Desjardins A, Herndon JE et al. (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13: 1253–1259PubMedGoogle Scholar
  112. 112.
    Kopp HG, Ramos CA, Rafii S (2006) Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue. Curr Opin Hematol 13: 175–181PubMedGoogle Scholar
  113. 113.
    Moreira IS, Fernandes PA, Ramos MJ (2007) Vascular endothelial growth factor (VEGF) inhibition – a critical review. Anticancer Agents Med Chem 7: 223–245PubMedGoogle Scholar
  114. 114.
    Lyden D, Hattori K, Dias S et al. (2001) Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med 7: 1194–1201PubMedGoogle Scholar
  115. 115.
    Davidoff AM, Ng CY, Brown P et al. (2001) Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice. Clin Cancer Res 7: 2870–2879PubMedGoogle Scholar
  116. 116.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307: 58–62PubMedGoogle Scholar
  117. 117.
    Wilson A, Trumpp A (2006) Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6: 93–106PubMedGoogle Scholar
  118. 118.
    Jin L, Hope KJ, Zhai Q et al. (2006) Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 12: 1167–1174,PubMedGoogle Scholar
  119. 119.
    Draffin JE, McFarlane S, Hill A et al. (2004) CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res 64: 5702–5711PubMedGoogle Scholar
  120. 120.
    Sneddon JB, Werb Z (2007) Location, location, location: the cancer stem cell niche. Cell Stem Cell 1: 607–611PubMedGoogle Scholar
  121. 121.
    Weijzen S, Rizzo P, Braid M et al. (2002) Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat Med 8: 979–986PubMedGoogle Scholar
  122. 122.
    Tozer GM, Kanthou C, Baguley BC (2005) Disrupting tumour blood vessels. Nat Rev Cancer, 5: 423–435PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of CarcinogenesisUniversity of Texas M.D Anderson Cancer Center, Science Park-Research Division, 1808 Park Rd. 1C, Smithville, TX 78957; Program in Molecular Carcinogenesis, Graduate School of Biomedical Sciences (GSBS), The University of Texas Health Science CenterHoustonUSA
  2. 2.Department of EpidemiologyWuhan University School of Public HealthWuhanChina
  3. 3.Program in Molecular Carcinogenesis, Graduate School of Biomedical Sciences (GSBS)The University of Texas Health Science CenterHoustonUSA

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