Cancer Stem Cells: Novel Target Using Dietary Components for Prevention and Treatment

  • Animesh Dhar
  • Laura Fogt
  • Dharmalingam Subramaniam
  • Shrikant Anant


Cancer is the second leading cause of mortality in the United States and no significant treatment is currently available. Although an increasing number of therapeutic options exist for patients with advanced disease, their efficacy is time limited and non-curative. Presently approximately close to 60% of cancer patients in the United States are believed to utilize therapies derived from plants, herbs, flowers, or nutrients either exclusively or concurrently with traditional chemotherapy or radiation therapy. A growing body of evidence suggests that cancer stem cells within a solid tumor initiate and sustain tumor growth and could be quiescent even after therapeutic intervention by common anti-cancer drugs. Identification of important signaling pathways that regulate cancer stem cells could lead to novel targets for drug intervention. Dietary compounds have been shown to interfere in cancer stem cell related pathways and therefore offer a promising approach for prevention.


Acute Myeloid Leukemia Cancer Stem Cell Adenomatous Polyposis Coli Sonic Hedgehog Adenomatous Polyposis Coli Gene 
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.



Work cited from our laboratory was supported by the US PHS grant CA109269 and CA135559, awarded by the National Cancer Institute. Contributions of the present and past members of the TOSA and CA151727 to AD Anant laboratory are greatly appreciated.


  1. Aggarwal BB, Bhardwaj A, Aggarwal RS et al (2004) Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 24:2783–2840PubMedGoogle Scholar
  2. Aggarwal BB, Sethi G, Baladandayuthapani V (2007) Targeting cell signaling pathways for drug discovery: an old lock needs a new key. J Cell Biochem 102:580–592PubMedCrossRefGoogle Scholar
  3. Al-Hajj M, Wicha MS, Benito-Hernandez A et al (2003) Prospective Identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988PubMedCrossRefGoogle Scholar
  4. Androutsellis-Theotokis A, Leker RR, Soldner F et al (2006) Notch signaling regulates stem cell numbers in vitro and in vivo. Nature 442:823–826PubMedCrossRefGoogle Scholar
  5. Bapat SA, Mali AM, Koppikar CB et al (2005) Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Res 65:3025–3029PubMedGoogle Scholar
  6. Barker N, Ridgway RA, van Es JH et al (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457:608–612PubMedCrossRefGoogle Scholar
  7. Barnes S (1995) Effect of genistein on in vitro and in vivo models of cancer. J Nutr 125:777S–783SPubMedGoogle Scholar
  8. Bednar F, Simeone DM (2009) Pancreatic cancer stem cells and relevance to cancer treatments. J Cell Biochem 107:40–45PubMedCrossRefGoogle Scholar
  9. Bettuzzi S, Brausi M, Rizzi F (2006) Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of principle study. Cancer Res 66:1234–1240PubMedCrossRefGoogle Scholar
  10. Bishayee A (2009) Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev Res 2:409–418CrossRefGoogle Scholar
  11. Blank U, Karlsson G, Karlsson S (2008) Signaling pathways governing stem-cell fate. Blood 111:492–503PubMedCrossRefGoogle Scholar
  12. Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737PubMedCrossRefGoogle Scholar
  13. Booth C, Potten CS (2000) Gut instincts: thoughts on intestinal epithelial stem cells. J Clin Invest 105:1493–1499PubMedCrossRefGoogle Scholar
  14. Borggrefe T, Oswald F (2009) The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell Mol Life Sci 66:1631–1646PubMedCrossRefGoogle Scholar
  15. Bose M, Hao X, Ju J et al (2007) Inhibition of tumorigenesis in ApcMin/+ mice by a combination of (-)-epigallocatechin-3-gallate and fish oil. J. Agric. Food Chem 55:7695–7700PubMedCrossRefGoogle Scholar
  16. Byers S, Shah S (2007) Vitamin D and the regulation of Wnt/beta-catenin signaling and innate immunity in colorectal cancer. Nutr Rev 65:S118–S120PubMedCrossRefGoogle Scholar
  17. Cecchinato V, Chiaramonte R, Nizzardo M et al (2007) Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells. Biochem Pharmacol 74:1568–1574PubMedCrossRefGoogle Scholar
  18. Charafe-Jauffret E, Monville F, Ginestier C et al (2008) Cancer stem cells in breast: current opinion and future challenges. Pathobiology 75:75–84PubMedCrossRefGoogle Scholar
  19. Chaudhuri D, Orsulic S, Ashok BT (2007) Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells. Mol Cancer Ther 6:334–345PubMedCrossRefGoogle Scholar
  20. Chen CC, Sun YT, Chen JJ et al (2000) TNF-alpha-induced cyclooxygenase-2 expression in human lung epithelial cells: involvement of the phospholipase C-gamma 2, protein kinase C-alpha, tyrosine kinase, NF-kappa B-inducing kinase, and I-kappa B kinase 1/2 pathway. J Immunol 165:2719–2728PubMedGoogle Scholar
  21. Chen Y, Shu W, Chen W et al (2007) Curcumin, both histone deacetylase and p300/CBP-specific inhibitor, represses the activity of nuclear factor kappa B and Notch 1 in Raji cells. Basic Clin Pharmacol Toxicol 101:427–433PubMedCrossRefGoogle Scholar
  22. Cheng P, Zlobin A, Volgina V et al (2001) Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells. J Immunol 167:4458–4467PubMedGoogle Scholar
  23. Choi S, Lew KL, Xiao H et al (2007) D,L-Sulforaphane-induced cell death in human prostate cancer cells is regulated by inhibitor of apoptosis family proteins and Apaf-1. Carcinogenesis 28:151–162PubMedCrossRefGoogle Scholar
  24. Choudhuri T, Pal S, Agwarwal ML, Das T et al (2002) Curcumin induces apoptosis in human breast cancer cells through p53-dependent Bax induction. FEBS Lett 512:334–340PubMedCrossRefGoogle Scholar
  25. Christensen JG, LeBlanc GA (1996) Reversal of multidrug resistance in vivo by dietary administration of the phytochemical indole-3-carbinol. Cancer Res 56:574–581PubMedGoogle Scholar
  26. Chung FL, Conaway CC, Rao CV et al (2000) Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate Carcinogenesis 21:2287–2291PubMedCrossRefGoogle Scholar
  27. Clarke MF, Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 125:1111–1115CrossRefGoogle Scholar
  28. Clarke JD, Dashwood RH, Ho E (2008) Multi-targeted prevention of cancer by sulforaphane. Cancer Lett 269:291–304PubMedCrossRefGoogle Scholar
  29. 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 17:165–77PubMedCrossRefGoogle Scholar
  30. Cohen Jr MM (2003) The hedgehog signaling network. Am J Med Genet 123A:5–28PubMedCrossRefGoogle Scholar
  31. Corbeil D, Roper K, Hellwig A et al (2000) The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 275:5512–5520PubMedCrossRefGoogle Scholar
  32. Corbeil D, Roper K, Fargeas CA et al (2001) Prominin: a story of cholesterol, plasma membrane protrusions and human pathology. Traffic 2:82–91PubMedCrossRefGoogle Scholar
  33. Dalerba P, Clarke MF (2007) Cancer stem cells and tumor metastasis: first steps into uncharted territory. Cell Stem Cell 1:241–242PubMedCrossRefGoogle Scholar
  34. Dalerba P, Dylla SJ, Park IK et al (2007a) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 104:10158–10163PubMedCrossRefGoogle Scholar
  35. Dalerba P, Cho RW, Clarke MF (2007b) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284PubMedCrossRefGoogle Scholar
  36. Danilenko M, Studzinski GP (2004) Enhancement by other compounds of the anticancer activity of vitamin D(3) and its analogs. Exp Cell Res 298:339–358PubMedCrossRefGoogle Scholar
  37. Davis JN, Kucuk O, Sarkar FH (1999) Genistein inhibits NF-kappa B activation in prostate cancer cells. Nutr Cancer 35:167–174PubMedCrossRefGoogle Scholar
  38. Dean M, Fojo T, Bates S (2005) Tumor stem cells and drug resistance. Nat Rev Cancer 5:275–284PubMedCrossRefGoogle Scholar
  39. Dontu G, Abdallah WM, Foley JM et al (2003) In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 17:1253–1270PubMedCrossRefGoogle Scholar
  40. Dick JE (2003) Breast cancer stem cells revealed. Proc Natl Acad Sci USA 100:3547–3549PubMedCrossRefGoogle Scholar
  41. Fahey JW, Zhang Y, Talalay P (1997) Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci USA 94:10367–10372PubMedCrossRefGoogle Scholar
  42. Fahey JW, Haristoy X, Dolan PM et al (2002) Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci USA 99:7610–7615PubMedCrossRefGoogle Scholar
  43. Fan X, Eberhart CG (2008) Medulloblastoma stem cells. J Clin Oncol 26:2821–2827PubMedCrossRefGoogle Scholar
  44. Fang D, Nguyen TK, Leishear K et al (2005) A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 65:9328–9337PubMedCrossRefGoogle Scholar
  45. Farnie G, Clarke RB (2007) Mammary stem cells and breast cancer – role of Notch signalling. Stem Cell Rev 3:169–175PubMedCrossRefGoogle Scholar
  46. Fodde R, Brabletz T (2007) Wnt/beta-catenin signaling in cancer stemness and malignant behavior. Curr Opin Cell Biol 19:150–158PubMedCrossRefGoogle Scholar
  47. Fornelli F, Leone A, Verdesca I et al (2007) The influence of lycopene on the proliferation of human breast cell line (MCF-7). Toxicol In Vitro 21:217–223PubMedCrossRefGoogle Scholar
  48. Gao Z, Xu Z, Hung MS et al (2009). Promoter demethylation of WIF-1 by epigallocatechin-3-gallate in lung cancer cells 15. Anticancer Res 29:2025–2030PubMedGoogle Scholar
  49. Giannakis M, Chen SL, Karam SM et al (2008) Helicobacter pylori evolution during progression from chronic atrophic gastritis to gastric cancer and its impact on gastric stem cells. Proc Natl Acad Sci USA 105:4358–4363PubMedCrossRefGoogle Scholar
  50. Ginestier C, Hur MH, Charafe-Jauffret E et al (2007) ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 1:555–5566PubMedCrossRefGoogle Scholar
  51. Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627PubMedCrossRefGoogle Scholar
  52. Grant WB, Garland CF (2002) Evidence supporting the role of vitamin D in reducing the risk of cancer. J Intern Med 252:178–179PubMedCrossRefGoogle Scholar
  53. Gunasekera RS, Sewgobind K, Desai S et al (2007) Lycopene and lutein inhibit proliferation in rat prostate carcinoma cells. Nutr Cancer 58:171–177PubMedCrossRefGoogle Scholar
  54. Gupta S, Hussain T, Mukhtar H (2003) Molecular pathway for (−)-epigallocatechin-3-gallate-induced cell cycle arrest and apoptosis of human prostate carcinoma cells. Arch Biochem Biophys 410:177–185PubMedCrossRefGoogle Scholar
  55. Guyton KZ, Kensler TW, Posner GH (2003) Vitamin D and vitamin D analogs as cancer chemopreventive agents. Nutr Rev 61:227–238PubMedCrossRefGoogle Scholar
  56. Haegebarth A, Clevers H (2009) Wnt signaling, Lgr5, and stem cells in the intestine and the skin. Am J Pathol 174:715–721PubMedCrossRefGoogle Scholar
  57. Hammerschmidt M, Brook A, McMahon AP (1997) The world according to hedgehog. Trends Genet 13:14–21PubMedCrossRefGoogle Scholar
  58. Hantz HL, Young LF, Martin KR (2005) Physiologically attainable concentrations of lycopene induce mitochondrial apoptosis in LNCaP human prostate cancer cells. Exp Biol Med 230:171–179Google Scholar
  59. Haraguchi N, Utsunomiya T, Inoue H et al (2006) Characterization of a side population of cancer cells from human gastrointestinal system. Stem Cells 24:506–513PubMedCrossRefGoogle Scholar
  60. Harikumar KB, Aggarwal BB (2008) Resveratrol, a multitargeted agent for age associated chronic diseases. Cell Cycle 7:1020–1035PubMedCrossRefGoogle Scholar
  61. Hemmati HD, Nakano I, Lazareff JA et al (2003) Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci USA 100:15178–15183PubMedCrossRefGoogle Scholar
  62. Hermann PC, Huber SL, Herrler T et al (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1:313–323PubMedCrossRefGoogle Scholar
  63. Hirsch HA, Iliopoulos D, Tsichlis PN et al (2009) Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 69:7507–7511PubMedCrossRefGoogle Scholar
  64. Hope C, Planutis K, Planutiene M et al (2008) Low concentrations of resveratrol inhibit Wnt signal throughput in colon-derived cells: implications for colon cancer prevention. Mol Nutr Food Res 52(Suppl 1):S52–S61PubMedGoogle Scholar
  65. Huang EH, Hynes MJ, Zhang T et al (2009) Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res 69:3382–3389PubMedCrossRefGoogle Scholar
  66. Huntley BJ, Gilliland DJ (2005) Leukemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 5:311–321CrossRefGoogle Scholar
  67. Ichikawa H, Nakamura Y, Kashiwada Y et al (2007) Anticancer drugs designed by mother nature: Ancient drugs but modern targets. Curr Pharm Des 13:3400–3416PubMedCrossRefGoogle Scholar
  68. Immervoll H, Hoem D, Sakariassen PO et al (2008) Expression of the “stem cell marker” CD133 in pancreas and pancreatic ductal adenocarcinomas. BMC Cancer 8:48–62PubMedCrossRefGoogle Scholar
  69. Ischenko I, Seeliger H, Schaffer M et al (2008) Cancer stem cells: how can we target them? Curr Med Chem 15:3171–3184PubMedCrossRefGoogle Scholar
  70. Iwasaki M, InoueM, Otani T et al (2008) Plasma isoflavone level and subsequent risk of breast cancer among Japanese women: a nested case-control study from the Japan Public Health Center-based prospective study group. J Clin Oncol 26:1677–1683PubMedCrossRefGoogle Scholar
  71. Jackson SJ, Singletary KW (2004) Sulforaphane inhibits human MCF-7 mammary cancer mitotic progression and tubulin polymerization. J Nutr 134:2229–2236PubMedGoogle Scholar
  72. Jaiswal AS, Marlow BP, Gupta N et al (2002) Beta-catenin-mediated transactivation and cell–cell adhesion pathways are important in curcumin (diferuylmethane)- induced growth arrest and apoptosis in colon cancer cells. Oncogene 21:8414–8427PubMedCrossRefGoogle Scholar
  73. Jang MS, Miao H, Carlesso N et al (2004) Notch-1 regulates cell death independently of differentiation in murine erythroleukemia cells through multiple apoptosis and cell cycle pathways. J Cell Physiol 199:418–433PubMedCrossRefGoogle Scholar
  74. Jeong WS, Kim IW, Hu R et al (2004) Modulatory properties of various natural chemopreventive agents on the activation of NF-kappaB signaling pathway. Pharm Res 21:661–670PubMedCrossRefGoogle Scholar
  75. Jodoin J, Demeule M, Beliveau R (2002) Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta 1542:149–159PubMedCrossRefGoogle Scholar
  76. Kakarala M, Wicha MS (2008) Implications of the cancer stem-cell hypothesis for breast cancer prevention and therapy. J Clin Oncol 26:2813–2820PubMedCrossRefGoogle Scholar
  77. Kakarala M, Brenner DE, Korkaya H et al (2010) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122:777–785PubMedCrossRefGoogle Scholar
  78. Kallifatidis G, Rausch V, Baumann B et al (2009) Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Gut 58:949–963PubMedCrossRefGoogle Scholar
  79. Kaneko Y, Sakakibara S, Imai T et al (2000) Musashi1: an evolutionally conserved marker for CNS progenitor cells including neural stem cells. Dev Neurosci 22:139–153PubMedCrossRefGoogle Scholar
  80. Karmakar S, Banik NL, Ray SK (2007) Molecular mechanism of inositol hexaphosphate-mediated apoptosis in human malignant glioblastoma T98G cells. Neurochem Res 32:2094–2102PubMedCrossRefGoogle Scholar
  81. Kasperczyk H, Baumann B, Debatin KM (2009) Characterization of sonic hedgehog as a novel NF-kappaB target gene that promotes NF-kappaB-mediated apoptosis resistance and tumor growth in vivo. FASEB J 23:21–33PubMedCrossRefGoogle Scholar
  82. Kawasaki BT, Hurt EM, Mistree T et al (2008) Targeting cancer stem cells with phytochemicals. Mol Interven 8:174–183CrossRefGoogle Scholar
  83. Keshet GI, Goldstein I, Itzhaki O et al (2008) MDR1 expression identifies human melanoma stem cells. Biochem Biophys Res Commun 368:930–936PubMedCrossRefGoogle Scholar
  84. Khor TO, Hu R, Shen G et al (2006) Pharmacogenomics of cancer chemopreventive isothiocyanate compound sulforaphane in the intestinal polyps of ApcMin/+mice. Biopharm Drug Dispos 27:407–420PubMedCrossRefGoogle Scholar
  85. Kim J, Zhang X, Rieger-Christ KM et al (2006) Suppression of Wnt signaling by the green tea compound (-)-epigallocatechin 3-gallate (EGCG) in invasive breast cancer cells. Requirement of the transcriptional repressor HBP1. J Biol Chem 281:10865–10875PubMedCrossRefGoogle Scholar
  86. Korkaya H, Paulson A, Charafe-Jauffret E et al (2009) Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. PLoS Biol e1000121:7Google Scholar
  87. Lapidot T, Sirard C, Vormoor J et al (1994) A cell initiating human acute myeloid leukemia after transplantation into SCID mice. Nature 367:645–648PubMedCrossRefGoogle Scholar
  88. Lev-Ari S, Vexler A, Starr A (2007) Curcumin augments gemcitabine cytotoxic effect on pancreatic adenocarcinoma cell lines. Cancer Invest 25:411–418PubMedCrossRefGoogle Scholar
  89. Lewis MT, Veltmaat JM (2004) Next stop, the twilight zone: hedgehog network regulation of mammary gland development. J Mammary Gland Biol Neoplasia 9:165–181PubMedCrossRefGoogle Scholar
  90. Li C, Heidt DG, Dalerba P et al (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037PubMedCrossRefGoogle Scholar
  91. Li Y, Wang Z, Kong D, Li R et al (2008) Regulation of Akt/FOXO3a/GSK- 3beta/AR signaling network by isoflavone in prostate cancer cells. J Biol Chem 283:27707–27716PubMedCrossRefGoogle Scholar
  92. Li Y, Zhang T, Korkaya H et al (2010) Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 16:2580–2590PubMedCrossRefGoogle Scholar
  93. Li Y, Wicha MS, Schwartz SJ et al (2011) Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Chem (Epub ahead of print)Google Scholar
  94. Lian F, Smith DE, Ernst H et al (2007) Apo-19′-lycopenoic acid inhibits lung cancer cell growth in vitro, and suppresses lung tumorigenesis in the A/J mouse model in vivo. Carcinogenesis 28:1567–1574PubMedCrossRefGoogle Scholar
  95. Liang D, Shi, Y (2011) Aldehyde dehydrogenase-1 is a specific marker for stem cells in human lung adenocarcinoma. Med Oncol (Epub ahead of print)Google Scholar
  96. Liu S, Dontu G, Wicha MS (2005) Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res 7:86–95PubMedCrossRefGoogle Scholar
  97. Liu S, Dontu G, Mantle ID et al (2006) Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 66:6063–6071PubMedCrossRefGoogle Scholar
  98. Marshall II, GP, Reynolds BA, Laywell ED (2007) Using the neurosphere assay to quantify neural stem cells in vivo. Curr Pharm Biotechnol 8:141–145PubMedCrossRefGoogle Scholar
  99. Maund SL, Barclay WW, Hover LD et al (2011) Interleukin alpha mediates the anti-proliferative effects of 1, 25dihydroxyvitamin D3 in prostate progenitor/stem cells. Cancer Res (Epub ahead of print)Google Scholar
  100. May R, Riehl TE, Hunt C (2008) Identification of a novel putative gastrointestinal stem cell and adenoma stem cell marker, doublecortin and CaM kinase-like-1, following radiation injury and in adenomatous polyposis coli/multiple intestinal neoplasia mice. Stem Cells 26:630–637PubMedCrossRefGoogle Scholar
  101. May R, Sureban SM, Lightfoot SA et al (2010) Identification of a novel putative/pancreatic stem cell marker DCAMKL-1 in normal mouse pancreas. Am J Physiol Gastrointest Liver Physiol 299:G303–G310PubMedCrossRefGoogle Scholar
  102. Mei Y, Wei D, Liu J (2003) Reversal of cancer multidrug resistance by tea polyphenol in KB cells. J. Chemother 15:260–265Google Scholar
  103. Miquel J, Bernd A, Sempere JM et al (2002) The curcuma antioxidants: pharmacological effects and prospects for future clinical use. A review. Arch Gerontolal Geriatr 34:37–46CrossRefGoogle Scholar
  104. Morimoto K, kim SJ, Tanei T et al (2009) Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression. Cancer Sci 100:1062–1068PubMedCrossRefGoogle Scholar
  105. Mumm JS, Kopan R (2000) Notch signaling: from the outside in. Dev Biol 228:151–65PubMedCrossRefGoogle Scholar
  106. Mwangi SM, Srinivasan S (2010) DCAMKL-1: a new horizon for pancreatic progenitor identification (Comment). Am J Physiol Gastrointest Liver Physiol 299:G303–G310CrossRefGoogle Scholar
  107. Nagasawa H, Mitamura T, Sakamoto S et al (1995) Effects of lycopene on spontaneous mammary tumour development in SHN virgin mice. Anticancer Res 15:1173–1178PubMedGoogle Scholar
  108. Nahum A, Hirsch K, Danilenko M et al (2001) Lycopene inhibition of cell cycle progression in breast and endometrial cancer cells is associated with reduction in cyclin D levels and retention of p27(Kip1) in the cyclin E–cdk2 complexes. Oncogene 20:3428–3436PubMedCrossRefGoogle Scholar
  109. Nahum A, Zeller L, Danilenko M et al (2006) Lycopene inhibition of IGF-induced cancer cell growth depends on the level of cyclin D1. Eur J Nutr 45:275–282PubMedCrossRefGoogle Scholar
  110. Nakashima H, Nakamura M, Yamaguchi H et al (2006) Nuclear factor-kappaB contributes to hedgehog signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res 66:7041–7049PubMedCrossRefGoogle Scholar
  111. Nickoloff BJ, Qin JZ, Chaturvedi V et al (2002) Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPAR gamma. Cell Death Differ 9:842–855PubMedCrossRefGoogle Scholar
  112. Nishimura S, Wakabayashi N, Toyoda K et al (2003) Expression of Musashi-1 in human normal colon crypt cells: a possible stem cell marker of human colon epithelium. Dig Dis Sci 8:1523–1529CrossRefGoogle Scholar
  113. O’Brian CA, Pollen A, Galinger S et al (2007) A human colon cancer cell capable of initiating tumor growth in immunodeficient mice. Nature 445:106–110CrossRefGoogle Scholar
  114. Oswald F, Liptay S, Adler G, Schmid RM (1998) NF-kappaB2 is a putative target gene of activated Notch-1 via RBP-Jkappa. Mol Cell Biol 18:2077–2088PubMedGoogle Scholar
  115. Palomero T, Lim WK, Odom DT et al (2006) NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 103:18261–18266PubMedCrossRefGoogle Scholar
  116. Papailiou J, Bramis KJ, Gazouli M et al (2011) Stem cells ion colon cancer: a new era in cancer theory begins. Int J Colorectal Dis 26:1–11PubMedCrossRefGoogle Scholar
  117. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902PubMedCrossRefGoogle Scholar
  118. Park CH, Hahm ER, Park S et al (2005)The inhibitory mechanism of curcumin and its derivative against beta-catenin/Tcf signaling. FEBS Lett 579:2965–2971PubMedCrossRefGoogle Scholar
  119. Park SY, Kim GY, Bae SJ et al (2007) Induction of apoptosis by isothiocyanate sulforaphane in human cervical carcinoma HeLa and hepatocarcinoma HepG2 cells through activation of caspase-3. Oncol Rep 18:181–187PubMedGoogle Scholar
  120. Pasca, DM, Hebrok, M (2003) Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 3:903–911CrossRefGoogle Scholar
  121. Patel BB, Sengupta R, Qazi S et al (2008) Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF-1R. Int J Cancer 122:267–273PubMedCrossRefGoogle Scholar
  122. Peacock CD, Watkins DN (2008) Cancer stem cells and the ontogeny of lung cancer. J Clin Oncol 26:2883–2889PubMedCrossRefGoogle Scholar
  123. Prince ME, Sivanandan R, Kaczorowski A et al (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104:973–978PubMedCrossRefGoogle Scholar
  124. Rangarajan A, Talora C, Okuyama R et al (2001) Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J 20:3427–3436PubMedCrossRefGoogle Scholar
  125. Rao CV, Cooma I, Rodriguez JG et al (2000) Chemoprevention of familial adenomatous polyposis development in the APC(min) mouse model by 1,4-phenylene bis(methylene) selenocyanate. Carcinogenesis 21:617–621PubMedCrossRefGoogle Scholar
  126. Reguart N, He B, Taron MR (2005) The role of Wnt signaling in cancer and stem cells. Future Oncol 1:787–797PubMedCrossRefGoogle Scholar
  127. Ricci-Vitiani L, Lombardi DG, Pilozzi E et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–1115PubMedCrossRefGoogle Scholar
  128. Roccaro AM, Leleu X, Sacco A et al (2008) Resveratrol exerts antiproliferative activity and induces apoptosis in Waldenstrom’s macroglobulinemia. Clin Cancer Res 14:1849–1858PubMedCrossRefGoogle Scholar
  129. Ronchini C, Capobianco AJ (2001) Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch (ic). Mol Cell Biol 21:5925–5934PubMedCrossRefGoogle Scholar
  130. Ryu MJ, Cho M, Song JY et al (2008) Natural derivatives of curcumin attenuate the Wnt/beta-catenin pathway through down-regulation of the transcriptional coactivator p300. Biochem Biophys Res Commun 377:1304–1308PubMedCrossRefGoogle Scholar
  131. Sadzuka Y, Sugiyama T, Sonobe T (2000) Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance. Toxicol. Lett 114:155–162Google Scholar
  132. Saigusa S, Tanaka K, Toiyama Y et al (2009) Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol 6:3488–3498CrossRefGoogle Scholar
  133. Salman H, Bergman M, Djaldetti M et al (2007) Lycopene affects proliferation and apoptosis of four malignant cell lines. Biomed Pharmacother 61:366–369PubMedCrossRefGoogle Scholar
  134. Sarkar FH, Li Y, Wang Z et al (2009) Cellular signaling perturbation by natural products. Cell Signal 21:1541–1547PubMedCrossRefGoogle Scholar
  135. Sarkar FH, LI Y, Wang Z et al (2010) The role of nutriceuticals in the regulation of Wnt and Hedgehog signaling in cancer. Cancer Metasta Rev 29:383–394Google Scholar
  136. Sato T, Vries RG, Snippert HJ et al (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–265PubMedCrossRefGoogle Scholar
  137. Satoh Y, Matsumura I, Tanaka H et al (2004) Roles for c-Myc in self-renewal of hematopoietic stem cells. J Biol Chem 279:24986–24993PubMedCrossRefGoogle Scholar
  138. Satoskar RR, Shah SJ, Shenoy SG (1986) Evaluation of anti-inflammatory property of curcumin (diferuloyl methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol 24:651–6544PubMedGoogle Scholar
  139. Schatton T, Murphy GF, Frank NY et al (2008) Identification of cells initiating human melanomas. Nature 451:345–349PubMedCrossRefGoogle Scholar
  140. Scoville DH, Sato T, He XC et al (2008) Current view: intestinal stem cells and signaling. Gastroenterology 134:849–864PubMedCrossRefGoogle Scholar
  141. Shao ZM, Shen ZZ, Liu CH et al (2002) Curcumin exerts multiple suppressive effects on human breast carcinoma cells. Int J Cancer 98:234–240PubMedCrossRefGoogle Scholar
  142. Sharoni Y, Giron E, Rise M (1997) Effects of lycopene-enriched tomato oleoresin on 7,12-dimethyl-benz[a]anthracene-induced rat mammary tumors. Cancer Detect Prev 21:118–123PubMedGoogle Scholar
  143. Shen G, Khor TO, Hu R et al (2007) Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in ApcMin/+ mouse. Cancer Res 67:9937–9944PubMedCrossRefGoogle Scholar
  144. Shervington A, Lu C (2008) Expression of multidrug resistance genes in normal and cancer stem cells. Cancer Invest 26:535–542PubMedCrossRefGoogle Scholar
  145. Shin MH, Holmes MD, Hankinson SE et al (2002) Intake of dairy products, calcium, and vitamin D and risk of breast cancer. J Natl Cancer Inst 94:1301–1311PubMedCrossRefGoogle Scholar
  146. Shin HM, Minter LM, Cho OH et al (2006) Notch1 augments NF-kappaB activity by facilitating its nuclear retention. EMBO J 25:129–138PubMedCrossRefGoogle Scholar
  147. Singh SK, Clarke ID, Teraski M et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63:5821–5828PubMedGoogle Scholar
  148. Singh SK, Hawkins C, Clarke ID et al (2004a) Identification of human brain tumour initiating cells. Nature 432:396–401PubMedCrossRefGoogle Scholar
  149. Singh AV, Xiao D, Lew KL et al (2004b) Sulforaphane induces caspasemediated apoptosis in cultured PC-3 human prostate cancer cells and retards growth of PC-3 xenografts in vivo. Carcinogenesis 25:83–90PubMedCrossRefGoogle Scholar
  150. Slusarz A, Shenouda NS, Sakla MS et al (2010) Common botanical compounds inhibit the hedgehog signaling pathway in prostate cancer. Cancer Res70:3382–3390PubMedCrossRefGoogle Scholar
  151. So JY, Lee HJ, Smolarek AK et al (2011) A novel Gemini vitamin D analog represses the expression of a stem cell marker CD44 in breast cancer. Mol Pharmacol 79:360–367PubMedCrossRefGoogle Scholar
  152. Son MJ, Woolard K, Nam DH et al (2009) SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 4:440–452PubMedCrossRefGoogle Scholar
  153. Stockler M, Wilcken NR, Ghersi D et al (2000) Systematic reviews of chemotherapy and endocrine therapy in metastatic breast cancer. Cancer Treat Rev 26:151–168PubMedCrossRefGoogle Scholar
  154. Su Y, Simmen RC (2009) Soy isoflavone genistein upregulates epithelial adhesion molecule E-cadherin expression and attenuates beta-catenin signaling in mammary epithelial cells. Carcinogenesis 30:331–339PubMedCrossRefGoogle Scholar
  155. Su LK, Kinzler KW, Vogelstein B et al (1992) Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256:668–670PubMedCrossRefGoogle Scholar
  156. Su Y, Simmen FA, Xiao R, Simmen RC (2007) Expression profiling of rat mammary epithelial cells reveals candidate signaling pathways in dietary protection from mammary tumors. Physiol Genomics 30:8–16PubMedCrossRefGoogle Scholar
  157. Subramaniam D, Ramalingam S, Houchen CW et al (2010) Cancer stem cells: a novel paradigm for cancer prevention and treatment. Mini Rev Med Chem 10:359–371PubMedCrossRefGoogle Scholar
  158. Sureban S, May R, Lightfoot et al (2011) DCAMKL-1 regulates epithililial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism. Cancer Res 71:2328–2338PubMedCrossRefGoogle Scholar
  159. Taipale J, Beachy PA (2011) The Hedgehog and Wnt signalling pathways in cancer. Nature 411:349–354CrossRefGoogle Scholar
  160. Tang L, Jin T, Zeng X, Wang JS (2005) Lycopene inhibits the growth of human androgenindependent prostate cancer cells in vitro and in BALB/c nude mice. J Nutr 135:287–290PubMedGoogle Scholar
  161. Tang FY, Shih CJ, Cheng LH et al (2008) Lycopene inhibits growth of human colon cancer cells via suppression of the Akt signaling pathway. Mol Nutr Food Res 52:646–654PubMedCrossRefGoogle Scholar
  162. Tang GQ, Yan TQ, Guo W et al (2010) (−)- Epigallocatechin-3-gallate induces apoptosis and suppresses proliferation by inhibiting the human Indian Hedgehog pathway in human chondrosarcoma cells. J Cancer Res Clin Oncology 136:1179–1185CrossRefGoogle Scholar
  163. van Breemen RB, Pajkovic N (2008) Multitargeted therapy of cancer by lycopene. Cancer Lett 269:339–351PubMedCrossRefGoogle Scholar
  164. Verheus M, van Gils CH, Keinan-Boker L et al (2007) Plasma phytoestrogens and subsequent breast cancer risk. J Clin Oncol 25:648–655PubMedCrossRefGoogle Scholar
  165. Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768PubMedCrossRefGoogle Scholar
  166. Wang J, Shelly L, Miele L (2001) Human Notch-1 inhibits NF-kappa B activity in the nucleus through a direct interaction involving a novel domain. J Immunol167:289–295Google Scholar
  167. Wang Z, Banerjee S, Li Y (2006a) Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res 66:2778–2784PubMedCrossRefGoogle Scholar
  168. Wang Z, Zhang Y, Li Y et al (2006b) Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther 5:483–493PubMedCrossRefGoogle Scholar
  169. Wang Z, Zhang Y, Banerjee S et al (2006c) Inhibition of nuclear factor kappab activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells. Int J Cancer 118:1930–1936PubMedCrossRefGoogle Scholar
  170. Wang Z, Li Y, Banerjee S, Sarkar FH (2009) Emerging role of Notch in stem cells and cancer. Cancer Lett 279:8–12PubMedCrossRefGoogle Scholar
  171. Weng AP, Millholland JM, Yashiro-Ohtani Y et al (2006) c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20:2096–2109PubMedCrossRefGoogle Scholar
  172. Wilson A, Radtke F (2006) Multiple functions of Notch signaling in self-renewing organs and cancer. FEBS Lett 580:2860–2568Google Scholar
  173. Woodward WA, Chen MS, Behbod F et al (2007) WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc Natl Acad Sci USA 4:618–623CrossRefGoogle Scholar
  174. Wu JY, Rao Y (1999) Fringe: defining borders by regulating the notch pathway. Curr Opin Neurobiol 9:537–543PubMedCrossRefGoogle Scholar
  175. Wu CP, Calcagno AM, Hladky SB et al (2005) Modulatory effects of plant phenols on human multidrug-resistance proteins 1, 4 and 5 (ABCC1, 4 and 5). FEBS J 272:4725–4740PubMedCrossRefGoogle Scholar
  176. Xu C, Shen G, Chen C et al (2005) Suppression of NF-kappaB and NFkappaB- regulated gene expression by sulforaphane and PEITC through Ikappa-B alpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene 24:4486–4495PubMedCrossRefGoogle Scholar
  177. Yan C, Jamaluddin MS, Aggarwal B et al (2005) Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin. Mol Cancer Ther 4:233–241PubMedGoogle Scholar
  178. Yang ZF, Ho DW, Ng MN et al (2008a) Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13:153–66PubMedCrossRefGoogle Scholar
  179. Yang W, Yan HX, Chen L et al (2008b) Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 68:4287–4295PubMedCrossRefGoogle Scholar
  180. Yu Y, Kanwar SS, Patel BB et al (2009) Elimination of colon cancer stem-like cells by the combination of curcumin and FOLFOX. Transl Oncol 2:321–328PubMedGoogle Scholar
  181. Zhang Y, Tang L (2007) Discovery and development of sulforaphane as a cancer chemopreventive phytochemical. Acta Pharmacol Sin 28:1343–1354PubMedCrossRefGoogle Scholar
  182. Zhang Y, Talalay P, Cho CG et al (1992) A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci USA 89:2399–2403PubMedCrossRefGoogle Scholar
  183. Zhang Y, Kensler TW, Cho CG et al (1994) Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 91:3147–3150PubMedCrossRefGoogle Scholar
  184. Zhou, J, Zhang, H, Gu, P et al (2007) NF-kappa B pathway inhibitors preferentially inhibit breast cancer stemlike cells. Breast Cancer Res Treat 111:419–427PubMedCrossRefGoogle Scholar
  185. Zhou J, Wang CY, Liu T et al (2008) Persistence of side population cells with high drug efflux capacity in pancreatic cancer. World J. Gastroenterol 14:925–930Google Scholar
  186. Zhou BB, Zhang H, Damelin M et al (2009) Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 8:806–823PubMedCrossRefGoogle Scholar
  187. Zhu A, Wang X, Guo Z (2001) Study of tea polyphenol as a reversal agent for carcinoma cell lines’ multidrug resistance (study of TP as a MDR reversal agent). Nucl Med Biol 28:735–740PubMedCrossRefGoogle Scholar
  188. Zhu L, Gibson P, Currle DS et al (2009) Promini1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457:603–607PubMedCrossRefGoogle Scholar
  189. Ziegler RG, Hoover RN, Pike MC et al (1993) Migration patterns and breast cancer risk in Asian-American women. J Natl Cancer Inst 85:1819–1827PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Animesh Dhar
    • 1
  • Laura Fogt
    • 2
  • Dharmalingam Subramaniam
    • 3
  • Shrikant Anant
    • 3
  1. 1.Department of Cancer Biology, Cancer CenterUniversity of Kansas Medical CenterKansas CityUSA
  2. 2.Department of Molecular and Integrative PhysiologyUniversity of Kansas Medical CenterKansas CityUSA
  3. 3.Department of Molecular and Integrative Physiology, Cancer CenterUniversity of Kansas Medical CenterKansas CityUSA

Personalised recommendations