Document Type : Review Article

Authors

1 Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran

2 Ph.D. in Biochemistry, Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran

3 Assistant Professor of Medical Physiology, Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran

Abstract

The presence of stem cells in leukemia and solid tumors has been demonstrated in recent decades. Cancer stem cells have the potency of tumorigenesis; furthermore, they have the ability of self-renewing and differentiation like other stem cells. They also play important role in the process of tumor invasion and metastasis. Several studies have been performed to discover the specific markers and different phenotypes of these cells that can be very important in their identification. It seems that the characteristic of cancer stem cells, like tumor genesis, is greatly related to the specific signaling pathways such as Wnt, β catenin and hedgehog. In addition, the tumor microenvironment and its controlling agents are the important factors involving in the regulation of cancer stem cell function. The present review aimed to investigate the biology of cancer stem cells, specific signaling pathways, factors controlling the microenvironment as well as the role of microRNAs in controlling the function of these cells to provide new therapeutic methods.

Keywords

  1. Lawson JC, Blatch GL, Edkins AL. Cancer stem cells in breast cancer and metastasis. Breast Cancer Res Treat 2009; 118(2): 241-54.
  2. Morrison SJ, Kimble J. Review article Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 2006; 441: 1068-74.
  3. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y, Abramova N, et al. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 2004; 304(5675): 1338-40.
  4. Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science 2009; 324(5935): 1670-3.
  5. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645-8.
  6. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003; 100(7): 3983-8.
  7. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63(18): 5821-8.
  8. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci U S A 2007; 104(24): 10158-63.
  9. Rasheed ZA, Yang J, Wang Q, Kowalski J, Freed I, Murter C, et al. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst 2010; 102(5): 340-51.
  10. Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005; 121(6): 823-35.
  11. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005; 65(23): 10946-51.
  12. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M, et al. Identification of cells initiating human melanomas. Nature 2008; 451(7176): 345-9.
  13. Son MJ, Woolard K, Nam DH, Lee J, Fine HA. SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. Cell Stem Cell 2009; 4(5): 440-52.
  14. Roukos DH. Breast-cancer stromal cells with TP53 mutations. N Engl J Med 2008; 358(15): 1636.
  15. Kelly PN, Dakic A, Adams JM, Nutt SL, Strasser A. Tumor growth need not be driven by rare cancer stem cells. Science 2007; 317(5836): 337.
  16. Alizadeh AM, Shiri S, Farsinejad S. Metastasis review: from bench to bedside. Tumour Biol 2014; 35(9): 8483-523.
  17. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133(4): 704-15.
  18. Mohsenikia M, Alizadeh AM, Khodayari S, Khodayari H, Kouhpayeh SA, Karimi A, et al. The protective and therapeutic effects of alpha-solanine on mice breast cancer. Eur J Pharmacol 2013; 718(1-3): 1-9.
  19. Khodayari S, Alizadeh A, Kouhpayeh S, Mohsenikia M, Karimi A, Khodayari H, et al. The Acute and Chronic Toxicity Effects of Alpha-Solanine in Mice. J Babol Univ Med Sci 2013; 15(5): 24-31. [In Persian].
  20. Schatton T, Frank NY, Frank MH. Identification and targeting of cancer stem cells. Bioessays 2009; 31(10): 1038-49.
  21. Lim SC. CD24 and human carcinoma: tumor biological aspects. Biomed Pharmacother 2005; 59(Suppl 2): S351-S354.
  22. Wright MH, Calcagno AM, Salcido CD, Carlson MD, Ambudkar SV, Varticovski L. Brca1 breast tumors contain ‎distinct CD44+/. Breast Cancer Res 2008; 10(1): R10.‎
  23. Hwang-Verslues WW, Kuo WH, Chang PH, Pan CC, Wang HH, Tsai ST, et al. Multiple lineages of human breast ‎cancer stem/progenitor cells identified by profiling with stem cell markers. PLoS One 2009; 4(12): e8377.‎
  24. Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, et al. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell 2010; 140(1): 62-73.
  25. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature 2004; 432(7015): 396-401.
  26. Fang D, Nguyen TK, Leishear K, Finko R, Kulp AN, Hotz S, et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 2005; 65(20): 9328-37.
  27. Rybak AP, He L, Kapoor A, Cutz JC, Tang D. Characterization of sphere-propagating cells with stem-like properties from DU145 prostate cancer cells. Biochim Biophys Acta 2011; 1813(5): 683-94.
  28. Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009; 27(5): 1006-20.
  29. Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, et al. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 2007; 132(7): 2542-56.
  30. Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 2008; 13(2): 153-66.
  31. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di VA, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 2008; 15(3): 504-14.
  32. Tirino V, Camerlingo R, Franco R, Malanga D, La RA, Viglietto G, et al. The role of CD133 in the identification and characterisation of tumour-initiating cells in non-small-cell lung cancer. Eur J Cardiothorac Surg 2009; 36(3): 446-53.
  33. Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, 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(38): 16281-6.
  34. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007; 67(3): 1030-7.
  35. Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007; 1(3): 313-23.
  36. 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(7123): 106-10.
  37. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445(7123): 111-5.
  38. Albers AE, Chen C, Koberle B, Qian X, Klussmann JP, Wollenberg B, et al. Stem cells in squamous head and neck cancer. Critical Reviews in Oncology/Hematology 2012; 81(3): 224-40.
  39. Tirino V, Desiderio V, Paino F, de Rosa A, Papaccio F, Fazioli F, et al. Human primary bone sarcomas contain CD133+ cancer stem cells displaying high tumorigenicity in vivo. FASEB J 2011; 25(6): 2022-30.
  40. Tirino V, Desiderio V, Papaccio G, Aquino R. Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS One 2008; 3(10): e3469.
  41. Terry J, Nielsen T. Expression of CD133 in synovial sarcoma. Appl Immunohistochem Mol Morphol 2010; 18(2): 159-65.
  42. Suva ML, Riggi N, Stehle JC, Baumer K, Tercier S, Joseph JM, et al. Identification of cancer stem cells in Ewing's sarcoma. Cancer Res 2009; 69(5): 1776-81.
  43. Walter D, Satheesha S, Albrecht P, Bornhauser BC, D'Alessandro V, Oesch SM, et al. CD133 positive embryonal rhabdomyosarcoma stem-like cell population is enriched in rhabdospheres. PLoS One 2011; 6(5): e19506.
  44. Borghaei H, Robinson M, Weiner LM. Monoclonal antibody therapy of cancer. In: Disis ML, Editor. Immunotherapy of cancer. New York, NY: Humana Press; 2006. p. 487-502.
  45. Pierce BL, Ballard-Barbash R, Bernstein L, Baumgartner RN, Neuhouser ML, Wener MH, et al. Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients. J Clin Oncol 2009; 27(21): 3437-44.
  46. Vries RG, Huch M, Clevers H. Stem cells and cancer of the stomach and intestine. Mol Oncol 2010; 4(5): 373-84.
  47. Almhanna K, Philip PA. Defining new paradigms for the treatment of pancreatic cancer. Curr Treat Options Oncol 2011; 12(2): 111-25.
  48. Corbeil D, Marzesco AM, Wilsch-Brauninger M, Huttner WB. The intriguing links between prominin-1 (CD133), cholesterol-based membrane microdomains, remodeling of apical plasma membrane protrusions, extracellular membrane particles, and (neuro) epithelial cell differentiation. FEBS Lett 2010; 584(9): 1659-64.
  49. Sano A, Kato H, Sakurai S, Sakai M, Tanaka N, Inose T, et al. CD24 expression is a novel prognostic factor in esophageal squamous cell carcinoma. Ann Surg Oncol 2009; 16(2): 506-14.
  50. Aigner S, Sthoeger ZM, Fogel M, Weber E, Zarn J, Ruppert M, et al. CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood 1997; 89(9): 3385-95.
  51. Pirruccello SJ, LeBien TW. The human B cell-associated antigen CD24 is a single chain sialoglycoprotein. J Immunol 1986; 136(10): 3779-84.
  52. Baumann P, Cremers N, Kroese F, Orend G, Chiquet-Ehrismann R, Uede T, et al. CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res 2005; 65(23): 10783-93.
  53. Hurt EM, Kawasaki BT, Klarmann GJ, Thomas SB, Farrar WL. CD44+CD24- prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. British Journal of Cancer 2008; 98: 756-65.
  54. Lo HW, Zhu H, Cao X, Aldrich A, Ali-Osman F. A novel splice variant of GLI1 that promotes glioblastoma cell migration and invasion. Cancer Res 2009; 69(17): 6790-8.
  55. Hess DA, Wirthlin L, Craft TP, Herrbrich PE, Hohm SA, Lahey R, et al. Selection based on CD133 and high aldehyde dehydrogenase activity isolates long-term reconstituting human hematopoietic stem cells. Blood 2006; 107(5): 2162-9.
  56. Ma S, Chan KW, Lee TK, Tang KH, Wo JY, Zheng BJ, et al. Aldehyde dehydrogenase discriminates the CD133 liver cancer stem cell populations. Mol Cancer Res 2008; 6(7): 1146-53.
  57. Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res 2009; 15(12): 4234-41.
  58. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, 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(5): 555-67.
  59. Visus C, Ito D, Amoscato A, Maciejewska-Franczak M, Abdelsalem A, Dhir R, et al. Identification of human aldehyde dehydrogenase 1 family member A1 as a novel CD8+ T-cell-defined tumor antigen in squamous cell carcinoma of the head and neck. Cancer Res 2007; 67(21): 10538-45.
  60. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and A. Cancer Res 2005; 65(14): 6207-19.
  61. Jones PM, George AM. The ABC transporter structure and mechanism: perspectives on recent research. Cell Mol Life Sci 2004; 61(6): 682-99.
  62. Loebinger MR, Giangreco A, Groot KR, Prichard L, Allen K, Simpson C, et al. Squamous cell cancers contain a side population of stem-like cells that are made chemosensitive by ABC transporter blockade. Br J Cancer 2008; 98(2): 380-7.
  63. Chan EF, Gat U, McNiff JM, Fuchs E. A common human skin tumour is caused by activating mutations in beta-catenin. Nat Genet 1999; 21(4): 410-3.
  64. Takigawa Y, Brown AM. Wnt signaling in liver cancer. Curr Drug Targets 2008; 9(11): 1013-24.
  65. Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982; 31(1): 99-109.
  66. Sandberg CJ, Altschuler G, Jeong J, Stromme KK, Stangeland B, Murrell W, et al. Comparison of glioma stem cells to neural stem cells from the adult human brain identifies dysregulated Wnt- signaling and a fingerprint associated with clinical outcome. Exp Cell Res 2013; 319(14): 2230-43.
  67. Barker N, van Es JH, Kuiper J, Kujala P, van den Born M, Cozijnsen M, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449: 1003-7.
  68. Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R, et al. Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol 1999; 154(2): 515-23.
  69. Katoh Y, Katoh M. Comparative genomics on PROM1 gene encoding stem cell marker CD133. Int J Mol Med 2007; 19(6): 967-70.
  70. Correa S, Binato R, du Rocher B, Castelo-Branco MT, Pizzatti L, Abdelhay E. Wnt/beta-catenin pathway regulates ABCB1 transcription in chronic myeloid leukemia. BMC Cancer 2012; 12: 303.
  71. Munz M, Baeuerle PA, Gires O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res 2009; 69(14): 5627-9.
  72. Wang Y, Krivtsov AV, Sinha AU, North TE, Goessling W, Feng Z, et al. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science 2010; 327(5973): 1650-3.
  73. di Meo TA, Anderson K, Phadke P, Fan C, Perou CM, Naber S, et al. A novel lung metastasis signature links Wnt signaling with cancer cell self-renewal and epithelial-mesenchymal transition in basal-like breast cancer. Cancer Res 2009; 69(13): 5364-73.
  74. Zhang Y, Toy KA, Kleer CG. Metaplastic breast carcinomas are enriched in markers of tumor-initiating cells and epithelial to mesenchymal transition. Mod Pathol 2012; 25(2): 178-84.
  75. Conacci-Sorrell M, Simcha I, Ben-Yedidia T, Blechman J, Savagner P, Ben-Ze'ev A. Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of beta-catenin signaling, Slug, and MAPK. J Cell Biol 2003; 163(4): 847-57.
  76. Alizadeh AM, Khaniki M, Azizian S, Mohaghgheghi MA, Sadeghizadeh M, Najafi F. Chemoprevention of azoxymethane-initiated colon cancer in rat by using a novel polymeric nanocarrier--curcumin. Eur J Pharmacol 2012; 689(1-3): 226-32.
  77. Brabletz T, Hlubek F, Spaderna S, Schmalhofer O, Hiendlmeyer E, Jung A, et al. Invasion and metastasis in colorectal cancer: epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta-catenin. Cells Tissues Organs 2005; 179(1-2): 56-65.
  78. Bhat-Nakshatri P, Appaiah H, Ballas C, Pick-Franke P, Goulet R, Badve S, et al. SLUG/SNAI2 and tumor necrosis factor generate breast cells with CD44+/CD24- phenotype. BMC Cancer 2010; 10: 411.
  79. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287: 795-801.
  80. Cheng WT, Xu K, Tian DY, Zhang ZG, Liu LJ, Chen Y. Role of Hedgehog signaling pathway in proliferation and invasiveness of hepatocellular carcinoma cells. Int J Oncol 2009; 34(3): 829-36.
  81. Athar M, Tang X, Lee JL, Kopelovich L, Kim AL. Hedgehog signalling in skin development and cancer. Exp Dermatol 2006; 15(9): 667-77.
  82. Amakye D, Jagani Z, Dorsch M. Unraveling the therapeutic potential of the Hedgehog pathway in cancer. Nature Medicine 2013; 19: 1410-22.
  83. Lai EC. Notch signaling: control of cell communication and cell fate. Development 2004; 131(5): 965-73.
  84. Rulifson EJ, Blair SS. Notch regulates wingless expression and is not required for reception of the paracrine wingless signal during wing margin neurogenesis in Drosophila. Development 1995; 121(9): 2813-24.
  85. Yin L, Velazquez OC, Liu ZJ. Notch signaling: emerging molecular targets for cancer therapy. Biochem Pharmacol 2010; 80(5): 690-701.
  86. Wu WK, Cho CH, Lee CW, Fan D, Wu K, Yu J, et al. Dysregulation of cellular signaling in gastric cancer. Cancer Lett 2010; 295(2): 144-53.
  87. Arora PS, Ansari AZ. Chemical biology: A Notch above other inhibitors. Nature 2009; 462: 171-3.
  88. Sikandar SS, Pate KT, Anderson S, Dizon D, Edwards RA, Waterman ML, et al. NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res 2010; 70(4): 1469-78.
  89. Harrison H, Farnie G, Howell SJ, Rock RE, Stylianou S, Brennan KR, et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 2010; 70(2): 709-18.
  90. Farnie G, Clarke RB. Mammary stem cells and breast cancer--role of Notch signalling. Stem Cell Rev 2007; 3(2): 169-75.
  91. Wang C, Qi R, Li N, Wang Z, An H, Zhang Q, et al. Notch1 signaling sensitizes tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human hepatocellular carcinoma cells by inhibiting Akt/Hdm2-mediated p53 degradation and up-regulating p53-dependent DR5 expression. J Biol Chem 2009; 284(24): 16183-90.
  92. Gramantieri L, Giovannini C, Lanzi A, Chieco P, Ravaioli M, Venturi A, et al. Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma. Liver Int 2007; 27(7): 997-1007.
  93. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008; 100(9): 672-9.
  94. Liu H, Patel MR, Prescher JA, Patsialou A, Qian D, Lin J, 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(42): 18115-20.
  95. Kardeh S, Ashkani-Esfahani S, Alizadeh AM. Paradoxical action of reactive oxygen species in creation and therapy of cancer. Eur J Pharmacol 2014; 735: 150-68.
  96. Vera-Ramirez L, Sanchez-Rovira P, Ramirez-Tortosa CL, Quiles JL, Ramirez-Tortosa MC, Alvarez JC, et al. Gene-expression profiles, tumor microenvironment, and cancer stem cells in breast cancer: latest advances towards an integrated approach. Cancer Treat Rev 2010; 36(6): 477-84.
  97. Liu S, Ginestier C, Ou SJ, Clouthier SG, Patel SH, Monville F, et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 2011; 71(2): 614-24.
  98. Imanieh MH, Bagheri F, Alizadeh AM, Ashkani-Esfahani S. Oxytocin has therapeutic effects on cancer, a hypothesis. Eur J Pharmacol 2014; 741: 112-23.
  99. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143-7.

100. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33(Suppl): 245-54.

101. Patocs A, Zhang L, Xu Y, Weber F, Caldes T, Mutter GL, et al. Breast-cancer stromal cells with TP53 mutations and nodal metastases. N Engl J Med 2007; 357(25): 2543-51.

102. Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet 2009; 25(1): 30-8.

103. Farhanji B, Latifpour M, Alizadeh AM, Khodayari H, Khodayari S, Khaniki M, et al. Tumor suppression effects of myoepithelial cells on mice breast cancer. Eur J Pharmacol 2015; 765: 171-8.

104. Ghalandarlaki N, Alizadeh A, Ashkani-Esfahani S. Nanotechnology-applied curcumin for different diseases therapy. Bio Med Research International 2014; 2014: 23.

105. Farsinejad S, Gheisary Z, Ebrahimi SS, Alizadeh AM. Mitochondrial targeted peptides for cancer therapy. Tumour Biol 2015; 36(8): 5715-25.

106. Scheller J, Rose-John S. Interleukin-6 and its receptor: from bench to bedside. Med Microbiol Immunol 2006; 195(4): 173-83.

107. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 2007; 117(12): 3988-4002.

108. Waugh DJ, Wilson C. The interleukin-8 pathway in cancer. Clin Cancer Res 2008; 14(21): 6735-41.

109. Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer 2010; 46(7): 1223-31.

110. Benoy IH, Salgado R, van Dam P, Geboers K, van Marck E, Scharpe S, et al. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clin Cancer Res 2004; 10(21): 7157-62.

111. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 2009; 139(4): 693-706.

112. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001; 357(9255): 539-45.

113. Hassane DC, Sen S, Minhajuddin M, Rossi RM, Corbett CA, Balys M, et al. Chemical genomic screening reveals synergism between parthenolide and inhibitors of the PI-3 kinase and mTOR pathways. Blood 2010; 116(26): 5983-90.

114. Hu M, Yao J, Cai L, Bachman KE, van den Brule F, Velculescu V, et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 2005; 37(8): 899-905.

115. Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 2009; 15(1): 68-74.

116. Bhati R, Patterson C, Livasy CA, Fan C, Ketelsen D, Hu Z, et al. Molecular characterization of human breast tumor vascular cells. Am J Pathol 2008; 172(5): 1381-90.

117. Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 2009; 15(3): 220-31.

118. Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest 2007; 117(12): 3846-56.

119. Sethi N, Dai X, Winter CG, Kang Y. Tumor-derived jagged1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 2011; 19(2): 192-205.

120. Farhangi B, Alizadeh AM, Khodayari H, Khodayari S, Dehghan MJ, Khori V, et al. Protective effects of dendrosomal curcumin on an animal metastatic breast tumor. Eur J Pharmacol 2015; 758: 188-96.

121. Shiri S, Alizadeh AM, Baradaran B, Farhanghi B, Shanehbandi D, Khodayari S, et al. Dendrosomal curcumin suppresses metastatic breast cancer in mice by changing m1/m2 macrophage balance in the tumor microenvironment. Asian Pacific Journal of Cancer Prevention 2014; 16(9): 3917-22.

122. Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, et al. The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res 2010; 70(24): 10464-73.

123. Joshi PA, Jackson HW, Beristain AG, di Grappa MA, Mote PA, Clarke CL, et al. Progesterone induces adult mammary stem cell expansion. Nature 2010; 465(7299): 803-7.

124. Asselin-Labat ML, Vaillant F, Sheridan JM, Pal B, Wu D, Simpson ER, et al. Control of mammary stem cell function by steroid hormone signalling. Nature 2010; 465(7299): 798-802.

125. Martinez NJ, Gregory RI. MicroRNA gene regulatory pathways in the establishment and maintenance of ESC identity. Cell Stem Cell 2010; 7(1): 31-5.

126. Kohlhapp FJ, Mitra AK, Lengyel E, Peter ME. MicroRNAs as mediators and communicators between cancer cells and the tumor microenvironment. Oncogene 2015; 34(48): 5857-68.

127. Khori V, Amani SS, Isanejad A, Alizadeh AM, Alizadeh S, Khodayari S, et al. Effects of exercise training together with tamoxifen in reducing mammary tumor burden in mice: Possible underlying pathway of miR-21. Eur J Pharmacol 2015; 765: 179-87.

128. Card DA, Hebbar PB, Li L, Trotter KW, Komatsu Y, Mishina Y, et al. Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Mol Cell Biol 2008; 28(20): 6426-38.

129. Lin CH, Jackson AL, Guo J, Linsley PS, Eisenman RN. Myc-regulated microRNAs attenuate embryonic stem cell differentiation. EMBO J 2009; 28(20): 3157-70.

130. Li X, Zhang J, Gao L, McClellan S, Finan MA, Butler TW, et al. MiR-181 mediates cell differentiation by interrupting the Lin28 and let-7 feedback circuit. Cell Death Differ 2012; 19(3): 378-86.

131. Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 2008; 455(7216): 1124-8.

132. Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS. MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell 2009; 137(4): 647-58.

133. Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, Shannon MF, et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res 2008; 68(19): 7846-54.

134. Wang G, Guo X, Hong W, Liu Q, Wei T, Lu C, et al. Critical regulation of miR-200/ZEB2 pathway in Oct4/Sox2-induced mesenchymal-to-epithelial transition and induced pluripotent stem cell generation. Proc Natl Acad Sci U S A 2013; 110(8): 2858-63.

135. Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131(6): 1109-23.

136. Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D, et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009; 138(3): 592-603.

137. Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell 2010; 39(5): 761-72.

138. Gal H, Pandi G, Kanner AA, Ram Z, Lithwick-Yanai G, Amariglio N, et al. MIR-451 and Imatinib mesylate inhibit tumor growth of Glioblastoma stem cells. Biochem Biophys Res Commun 2008; 376(1): 86-90.

139. Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C, et al. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology 2009; 50(2): 472-80.

140. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 2011; 17(2): 211-5.

141. Zhang H, Li W, Nan F, Ren F, Wang H, Xu Y, et al. MicroRNA expression profile of colon cancer stem-like cells in HT29 adenocarcinoma cell line. Biochem Biophys Res Commun 2011; 404(1): 273-8.

142. Kosaka N, Yoshioka Y, Hagiwara K, Tominaga N, Katsuda T, Ochiya T. Trash or Treasure: extracellular microRNAs and cell-to-cell communication. Front Genet 2013; 4: 173.

143. Kosaka N, Iguchi H, Hagiwara K, Yoshioka Y, Takeshita F, Ochiya T. Neutral sphingomyelinase 2 (nSMase2)-dependent exosomal transfer of angiogenic microRNAs regulate cancer cell metastasis. J Biol Chem 2013; 288(15): 10849-59.

144. Bronisz A, Wang Y, Nowicki MO, Peruzzi P, Ansari KI, Ogawa D, et al. Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Cancer Res 2014; 74(3): 738-50.

145. Grange C, Tapparo M, Collino F, Vitillo L, Damasco C, Deregibus MC, et al. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res 2011; 71(15): 5346-56.