Cancer stem cells and novel targets for antitumor strategies

Current Pharmaceutical Design

Volumn 18, Issue 19, 2012, Pages 2838-2849

  Prud'homme, Gérald J ^a,b  

^a ST MICHAEL'S HOSPITAL   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

Author keywords

Aryl hydrocarbon receptor; Cancer stem cell; Epithelial to mesenchymal transition; Mammosphere; Neuropilin; Oct4; Tranilast; Transforming growth factor beta

Indexed keywords

ANTINEOPLASTIC AGENT; AROMATIC HYDROCARBON RECEPTOR; BETA CATENIN; CHEMOKINE RECEPTOR CXCR4; CURCUMIN; CYCLOPAMINE; GAMMA SECRETASE INHIBITOR; HERMES ANTIGEN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTEGRIN; INTERLEUKIN 6; INTERLEUKIN 8; KRUPPEL LIKE FACTOR 4; METFORMIN; MYC PROTEIN; NOTCH RECEPTOR; OCTAMER TRANSCRIPTION FACTOR 4; PIPERINE; SALINOMYCIN; SONIC HEDGEHOG PROTEIN; SULFORAPHANE; TESMILIFENE; TRANILAST; TRANSCRIPTION FACTOR SOX2; TRANSFORMING GROWTH FACTOR BETA; TRASTUZUMAB; UNINDEXED DRUG; VISMODEGIB; WNT PROTEIN; WNT2 PROTEIN;

ANTINEOPLASTIC ACTIVITY; CANCER RELAPSE; CANCER STEM CELL; CELL DIFFERENTIATION; CELL RENEWAL; CYTOKINE PRODUCTION; DRUG DESIGN; DRUG SCREENING; DRUG SYNTHESIS; EPITHELIAL MESENCHYMAL TRANSITION; HEMATOPOIETIC STEM CELL; HIGH THROUGHPUT SCREENING; HUMAN; METASTASIS; MULTIDRUG RESISTANCE; NONHUMAN; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TARGET CELL;

EID: 84862565810     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161212800626120     Document Type: Review

References (176)

1. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730-7.
2. O'Brien CA, Kreso A, Dick JE. Cancer stem cells in solid tumors: an overview. Semin Radiat Oncol 2009; 19: 71-7.
3. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med 2009; 15: 1010-2.
4. Croker AK, Allan AL. Cancer stem cells: implications for the progression and treatment of metastatic disease. J Cell Mol Med 2008; 12: 374-90.
5. Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 2009; 8: 806-23.
6. Alison MR, Lim SM, Nicholson LJ. Cancer stem cells: problems for therapy? J Pathol 2011; 223: 147-61.
7. Santilli G, Binda M, Zaffaroni N, Daidone MG. Breast cancerinitiating cells: Insights into novel treatment strategies. Cancers 2011; 3: 1405-25.
8. Scatena R, Bottoni P, Pontoglio A, Giardina B. Cancer stem cells: the development of new cancer therapeutics. Expert Opin Biol Ther 2011; 11: 875-92.
9. Prud'homme, GJ, Glinka Y, Toulina A, Ace O, Subramaniam V, Jothy S. Breast cancer stem-like cells are inhibited by a non-toxic aryl hydrocarbon receptor agonist. PLoS ONE 2010; 5(11): e13831. www.plosone.org
10. Levina V, Marrangoni AM, DeMarco R, Gorelik E, Lokshin AE. Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS One 2008; 3(8): e3077. www.plosone.org
11. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct side population of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA 2004; 101: 14228-33.
12. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007; 1: 313-23.
13. Chuthapisith S, Eremin J, El-Sheemey M, Eremin O. Breast cancer chemoresistance: emerging importance of cancer stem cells. Surg Oncol. 2010; 19: 27-32.
14. Dave B, Chang J. Treatment resistance in stem cells and breast cancer. J Mammary Gland Biol Neoplasia 2009; 14: 79-82.
15. Lee HE, Kim JH, Kim YJ, et al. An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer. Br J Cancer 2011; 104: 1730-8.
16. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008; 100: 672-79.
17. Ishizawa K, Rasheed ZA, Karisch R, et al. Tumor-initiating cells are rare in many human tumors. Cell Stem Cell 2010; 7: 279-82.
18. Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ. Efficient tumour formation by single human melanoma cells. Nature 2008; 456: 593-8.
19. Charafe-Jauffret E, Ginestier C, Birnbaum D. Breast cancer stem cells: tools and models to rely on. BMC Cancer 2009; 9: 202.
20. Keysar SB, Jimeno A. More than markers: biological significance of cancer stem cell-defining molecules. Mol Cancer Ther 2010; 9: 2450-7.
21. Perona R, López-Ayllón BD, de Castro Carpeño J, Belda-Iniesta C. A role for cancer stem cells in drug resistance and metastasis in non-small-cell lung cancer. Clin Transl Oncol 201; 13: 289-93.
22. Albers AE, Chen C, Köberle B, et al. Stem cells in squamous head and neck cancer. Crit Rev Oncol Hematol 2012; 81(3): 224-40.
23. Bohl SR, Pircher A, Hilbe W. Cancer stem cells: characteristics and their potential role for new therapeutic strategies. Onkologie 2011; 34: 269-74.
24. Oishi N, Wang XW. Novel therapeutic Strategies for Targeting Liver Cancer Stem Cells. Int J Biol Sci 2011; 7: 517-35.
25. Liu HG, Chen C, Yang H, Pan YF, Zhang XH. Cancer stem cell subsets and their relationships. J Transl Med 2011; 9: 50.
26. Silva IA, Bai S, McLean K, et al. Aldehyde dehydrogenase and CD133 define angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res 2011; 71: 3991-4001.
27. Furusawa J, Zhang H, Vural E, et al. Distinct Epigenetic Profiling in Head and Neck Squamous Cell Carcinoma Stem Cells. Otolaryngol Head Neck Surg 2011; 144: 900-9.
28. Holmberg J, He X, Peredo I, et al. Activation of neural and pluripotent stem cell signatures correlates with increased malignancy in human glioma. PLoS One 2011; 6(3): e18454. www.plosone.org
29. Kryczek I, Liu S, Roh M, et al. Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells. Int J Cancer 2012; 130: 29-39.
30. Dean M. ABC transporters, drug resistance, and cancer stem cells. J Mammary Gland Biol Neoplasia 2009; 14: 3-9.
31. Gatti L, Beretta GL, Cossa G, Zunino F, Perego P. ABC transporters as potential targets for modulation of drug resistance. Mini Rev Med Chem 2009; 9: 1102-12.
32. An Y, Ongkeko WM. ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol. 2009; 5: 1529-42.
33. Jonker JW, Freeman J, Bolscher E, et al. Contribution of the ABC transporters Bcrp1 and Mdr1a/1b to the side population phenotype in mammary gland and bone marrow of mice. Stem Cells 2005; 23: 1059-65.
34. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983-8.
35. Charafe-Jauffret E, Ginestier C, Iovino F, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 2009; 69: 1302-13.
36. Croker AK, Goodale D, Chu J, et al. High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med 2009; 13(8B): 2236-52.
37. Shipitsin M, Campbell LL, Argani P, et al. Molecular definition of breast tumor heterogeneity. Cancer Cell. 2007; 11: 259-73.
38. Tan AR, Alexe G, Reiss M. Transforming growth factor-beta signaling: emerging stem cell target in metastatic breast cancer? Breast Cancer Res Treat 2009; 115: 453-95.
39. Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 2008; 10(2): R25.
40. Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 2008; 27: 6120-30.
41. Wicha MS. Targeting breast cancer stem cells. Breast 2009; S3: S56-8.
42. Liu M, Sakamaki T, Casimiro MC, et al. The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res 2010; 70: 10464-73.
43. 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: 693-706.
44. Zhou J, Zhang H, Gu P, Bai J, Margolick JB, Zhang Y. NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells. Breast Cancer Res Treat 2008; 111: 419-27.
45. Hinohara K, Gotoh N. Inflammatory signaling pathways in selfrenewing breast cancer stem cells. Curr Opin Pharmacol 2010; 10: 650-4.
46. Sansone P, Storci G, Tavolari S, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 2007; 117: 3988-4002.
47. Ginestier C, Liu S, Diebel ME, et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest 2010; 120: 485-97.
48. Alison MR, Islam S, Wright NA. Stem cells in cancer: instigators and propagators? J Cell Sci 2010; 123(Pt 14): 2357-68.
49. Yamanaka S, Blau HM. Nuclear reprogramming to a pluripotent state by three approaches. Nature 2010; 465: 704-12.
50. Giorgetti A, Montserrat N, Rodriguez-Piza I, Azqueta C, Veiga A, Izpisúa Belmonte JC. Generation of induced pluripotent stem cells from human cord blood cells with only two factors: Oct4 and Sox2. Nat Protoc 2010; 5: 811-20.
51. Zhu S, Li W, Zhou H, et al. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 2010; 7: 651-5.
52. Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704-15.
53. May CD, Sphyris N, Evans KW, Werden SJ, Guo W, Mani SA. Epithelial-mesenchymal transition and cancer stem cells: a dangerously dynamic duo in breast cancer progression. Breast Cancer Res. 2011; 13: 202.
54. Xiang R, Liao D, Cheng T, et al. Downregulation of transcription factor SOX2 in cancer stem cells suppresses growth and metastasis of lung cancer. Br J Cancer 2011; 104: 1410-7.
55. Ji J, Werbowetski-Ogilvie TE, Zhong B, Hong SH, Bhatia M. Pluripotent transcription factors possess distinct roles in normal versus transformed human stem cells. PLoS One 2009; 4(11): e8065. www.plosone.org
56. Li Z, Rich JN. Hypoxia and hypoxia inducible factors in cancer stem cell maintenance. Curr Top Microbiol Immunol 2010; 345: 21-30.
57. Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev 2011; 7: 292-306.
58. Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 2011; 8: 97-106.
59. Liekens S, Schols D, Hatse S. CXCL12-CXCR4 axis in angiogenesis, metastasis and stem cell mobilization. Curr Pharm Des 2010; 16: 3903-20.
60. Juarez J, Bendall L, Bradstock K. Chemokines and their receptors as therapeutic targets: the role of the SDF-1/CXCR4 axis. Curr Pharm Des 2004; 10: 1245-59.
61. Shiozawa Y, Pedersen EA, Havens AM, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest 2011; 121: 1298-312.
62. Winquist RJ, Furey BF, Boucher DM. Cancer stem cells as the relevant biomass for drug discovery. Curr Opin Pharmacol 2010; 10: 385-90.
63. Winquist RJ, Boucher DM, Wood M, Furey BF. Targeting cancer stem cells for more effective therapies: Taking out cancer's locomotive engine. Biochem Pharmacol 2009; 78: 326-34.
64. Grimshaw MJ, Cooper L, Papazisis K, et al. Mammosphere culture of metastatic breast cancer cells enriches for tumorigenic breast cancer cells. Breast Cancer Res 2008; 10 (3): R52.
65. Steiniger SC, Coppinger JA, Krüger JA, Yates J 3rd, Janda KD. Quantitative mass spectrometry identifies drug targets in cancer stem cell-containing side population. Stem Cells 2008; 26: 3037-46.
66. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med 2011; 17: 313-9.
67. Dontu G, Abdallah WM, Foley JM, et al. In vitro propogation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev 2003; 17: 1253-70.
68. Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004; 64: 7011-21.
69. Clayton S, Mousa SA. Therapeutics formulated to target cancer stem cells: Is it in our future? Cancer Cell Int 2011; 11: 7.
70. Mimeault M, Batra SK. Novel therapies against aggressive and recurrent epithelial cancers by molecular targeting tumorand metastasis-initiating cells and their progenies. Anticancer Agents Med Chem 2010; 10: 137-51.
71. Saini V, Shoemaker RH. Potential for therapeutic targeting of tumor stem cells. Cancer Sci 2010; 101: 16-21.
72. Medina V, Calvo MB, Díaz-Prado S, Espada J. Hedgehog signalling as a target in cancer stem cells. Clin Transl Oncol 2009; 11: 199-207.
73. Espada J, Calvo MB, Díaz-Prado S, Medina V. Wnt signalling and cancer stem cells. Clin Transl Oncol 2009; 11: 411-27.
74. Bolós V, Blanco M, Medina V, Aparicio G, Díaz-Prado S, Grande E. Notch signalling in cancer stem cells. Clin Transl Oncol 2009; 11: 11-9.
75. Huang SM, Mishina YM, Liu S, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 2009; 461: 614-20.
76. Prasad CP, Rath G, Mathur S, Bhatnagar D, Ralhan R. Potent growth suppressive activity of curcumin in human breast cancer cells: Modulation of Wnt/beta-catenin signaling. Chem Biol Interact 2009; 181: 263-71.
77. Kakarala M, Brenner DE, Korkaya H, et al. Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 2010; 122: 777-85.
78. Hoey T, Yen WC, Axelrod F, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 2009; 5: 168-77.
79. Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA. The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 2011; 126: 355-64.
80. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Menendez JA. Metformin against TGF -induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis. Cell Cycle 2010; 9: 4461-8.
81. Liu B, Fan Z, Edgerton SM, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle 2009; 8: 2031-40.
82. Li Y, Zhang T, Korkaya H, Liu S, et al. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res 2010; 16: 2580-90.
83. Magnifico A, Albano L, Campaner S, et al. Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res 2009; 15: 2010-21.
84. Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 2008; 27: 6120-30.
85. Levina V, Marrangoni A, Wang T, et al. Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop. Cancer Res 2010; 70: 338-46.
86. Taube JH, Herschkowitz JI, Komurov K, et al. Core epithelial-tomesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci USA 2010; 107: 15449-54.
87. Biswas S, Guix M, Rinehart C, et al. Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J Clin Invest 2007; 117: 1305-13.
88. Bandyopadhyay A, Wang L, Agyin J, et al. Doxorubicin in combination with a small TGFbeta inhibitor: a potential novel therapy for metastatic breast cancer in mouse models. PLoS One. 2010; 5: e10365. www.plosone.org
89. Fan Q, He M, Sheng T, et al. Requirement of TGFbeta signaling for SMO-mediated carcinogenesis. J Biol Chem 2010; 285: 36570-6.
90. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010; 29: 4741-51.
91. Grandclement C, Borg C. Neuropilins: A new target of cancer therapy. Cancers 2011; 3: 1899-928.
92. Jarvis A, Allerston CK, Jia H, et al. Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction. J Med Chem 2010; 53: 2215-26.
93. Karjalainen K, Jaalouk DE, Bueso-Ramos CE, et al. Targeting neuropilin-1 in human leukemia and lymphoma. Blood 2011; 117: 920-7.
94. Pellet-Many C, Frankel P, Jia H, Zachary I. Neuropilins: structure, function and role in disease. Biochem J 2008; 411: 211-26.
95. Glinka Y, Prud'homme GJ. Neuropilin-1 is a receptor for trans forming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol 2008; 84: 302-10.
96. Glinka Y, Stoilova S, Mohammed N, Prud'homme GJ. Neuropilin 1 exerts co-receptor function for TGF-beta-1 on the membrane of cancer cells and enhances responses to both latent and active TGF beta. Carcinogenesis 2011; 32: 613-21.
97. Deonarain MP, Kousparou CA, Epenetos AA. Antibodies targeting cancer stem cells: a new paradigm in immunotherapy? Mabs 2009; 1: 12-25.
98. Todaro M, Alea MP, Di Stefano AB, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of inter leukin-4. Cell Stem Cell 2007; 1: 389-402.
99. Salnikov AV, Groth A, Apel A, et al. Targeting of cancer stem cell marker EpCAM by bispecific antibody EpCAMxCD3 inhibits pancreatic carcinoma. J Cell Mol Med 2009; 13: 4023-33.
100. Rentala S, Yalavarthy PD, Mangamoori LN. Alpha1 and beta1 integrins enhance the homing and differentiation of cultured prostate cancer stem cells. Asian J Androl 2010; 12: 548-55.
101. Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009; 138: 645-59.
102. Zhou J, Zhang H, Gu P, Margolick JB, Yin D, Zhang Y. Cancer stem/progenitor cell active compound 8-quinolinol in combination with paclitaxel achieves an improved cure of breast cancer in the mouse model. Breast Cancer Res Treat 2009; 115: 269-77.
103. Deng T, Liu JC, Pritchard KI, Eisen A, Zacksenhaus E. Preferential killing of breast tumor initiating cells by N,N-diethyl-2-[4 (phenylmethyl) phenoxy]ethanamine/ tesmilifene. Clin Cancer Res 2009; 15: 119-30.
104. Konneh M. Tranilast, Kissei Pharmaceuticals. Idrugs 1998; 1: 141-6.
105. Prud'homme GJ. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab Invest 2007; 87: 1077-91.
106. Chakrabarti R, Subramaniam V, Abdalla S, Jothy S, Prud'homme GJ. Tranilast inhibits the growth and metastasis of mammary carcinoma. Anti-Cancer Drugs 2009; 20: 334-45.
107. Subramaniam V, Chakrabarti R, Prud'homme GJ, Jothy S. Tranilast inhibits cell proliferation and migration and promotes apoptosis in murine breast cancer. Anti-Cancer Drugs 2010; 21: 351-61.
108. Furness SG, Whelan F. The pleiotropy of dioxin toxicity Xenobiotic misappropriation of the aryl hydrocarbon receptor's alternative physiological roles. Pharmacol Ther 2009; 124: 336-53.
109. Bradshaw TD, Bell DR. Relevance of the aryl hydrocarbon receptor (AhR) for clinical toxicology. Clin Toxicol (Phila) 2009; 47: 632-42.
110. Denison MS, Soshilov AA, He G, Degroot DE, Zhao B. Exactly The Same But Different: Promiscuity and Diversity in the Molecular Mechanisms of Action of the Aryl Hydrocarbon (Dioxin) Receptor. Toxicol Sci; 2011; 124: 1-22.
111. Esser C. The immune phenotype of AhR null mouse mutants: not a simple mirror of xenobiotic receptor over-activation. Biochem Pharmacol 2009; 77: 597-607.
112. Kerkvliet NI. AHR-mediated immunomodulation: the role of altered gene transcription. Biochem Pharmacol 2009; 77: 746-60.
113. Marshall NB, Kerkvliet NI. Dioxin and immune regulation. Ann N Y Acad Sci 2010; 1183: 25-37.
114. Abel J, Haarmann-Stemmann T. An introduction to the molecular basics of aryl hydrocarbon receptor biology. Biol Chem 2010; 391: 1235-48.
115. Kawajiri K, Kobayashi Y, Ohtake F, et al. Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands. Proc Natl Acad Sci USA 2009; 106: 13481-6.
116. Zhang S, Lei P, Liu X, et al. The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocr Relat Cancer 2009; 16: 835-44.
117. Ohtake F, Fujii-Kuriyama Y, Kato S. AhR acts as an E3 ubiquitin ligase to modulate steroid receptor functions. Biochem Pharmacol 2009; 77: 474-84.
118. Matthews J, Gustafsson JA. Estrogen receptor and aryl hydrocarbon receptor signaling pathways. Nucl Recept Signal 2006; 4: e016.
119. Wormke M, Stoner M, Saville B, et al. The aryl hydrocarbon receptor mediates degradation of estrogen receptor alpha through activation of proteasomes. Mol Cell Biol 2003; 23: 1843-55.
120. Gomez-Duran A, Carvajal-Gonzalez JM, Mulero-Navarro S, Santiago-Josefat B, Puga A, Fernandez-Salguero PM. Fitting a xenobiotic receptor into cell homeostasis: how the dioxin receptor interacts with TGF-beta signaling. Biochem Pharmacol 2009; 77: 700-12.
121. Ruby CE, Leid M, Kerkvliet NI. 2,3,7,8-Tetrachlorodibenzo-pdioxin suppresses tumor necrosis factor-alpha and anti-CD40 induced activation of NF-kappaB/Rel in dendritic cells: p50 homodimer activation is not affected. Mol Pharmacol 2002; 62: 722-8.
122. Patel RD, Murray IA, Flaveny CA, Kusnadi A, Perdew GH. Ah receptor represses acute-phase response gene expression without binding to its cognate response element. Lab Invest 2009; 89: 695-707.
123. Casado FL, Singh KP, Gasiewicz TA. The aryl hydrocarbon receptor: regulation of hematopoiesis and involvement in the progression of blood diseases. Blood Cells Mol Dis 2010; 44: 199-206.
124. Boitano AE, Wang J, Romeo R, et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 2010; 329: 1345-8.
125. Bunaciu RP, Yen A. Activation of the aryl hydrocarbon receptor AhR Promotes retinoic acid-induced differentiation of myeloblastic leukemia cells by restricting expression of the stem cell transcription factor Oct4. Cancer Res 2011; 71: 2371-80.
126. Blum R, Gupta R, Burger PE, et al. Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer. PLoS One 2009; 4: e5722. www.plosone.org
127. Fritz WA, Lin TM, Cardiff RD, Peterson RE. The aryl hydrocarbon receptor inhibits prostate carcinogenesis in TRAMP mice. Carcinogenesis 2007; 28: 497-505.
128. Fritz WA, Lin TM, Safe S, Moore RW, Peterson RE. The selective aryl hydrocarbon receptor modulator 6-methyl-1,3,8trichlorodibenzofuran inhibits prostate tumor metastasis in TRAMP mice. Biochem Pharmacol 2009; 77: 1151-60.
129. Safe S, Wormke M, Samudio I. Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in human breast cancer cells. J Mammary Gland Biol Neoplasia 2000; 5: 295-306.
130. Ahmed S, Valen E, Sandelin A, Matthews J. Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters. Toxicol Sci 2009; 111: 254-66.
131. Izumi K, Mizokami A, Li YQ, et al. Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses transforming growth factor beta1-associated osteoblastic changes. Prostate 2009; 69: 1222-34.
132. Sato S, Takahashi S, Asamoto M, et al. Tranilast suppresses prostate cancer growth and osteoclast differentiation in vivo and in vitro. Prostate 2010; 70: 229-38.
133. Izumi K, Mizokami A, Shima T, et al. Preliminary results of tranilast treatment for patients with advanced castration-resistant prostate cancer. Anticancer Res 2010; 30: 3077-81.
134. Wang T, Gavin HM, Arlt VM, et al. (2010) Aryl hydrocarbon receptor (AhR) activation during pregnancy, and in adult nulliparous mice, delays the subsequent development of DMBA-induced mammary tumors. Int J Cancer 2011; 128: 1509-23.
135. Hsu EL, Yoon D, Choi HH, et al. A proposed mechanism for the protective effect of dioxin against breast cancer. Toxicol Sci 2007; 98: 436-44.
136. Holcomb M, Safe S. Inhibition of 7,12-dimethylbenzanthracene-induced rat mammary tumor growth by 2,3,7,8 tetrachlorodibenzo-p-dioxin. Cancer Lett 1994; 82: 43-7.
137. Brooks J, Eltom SE. Malignant Transformation of Mammary Epithelial Cells by Ectopic Overexpression of the Aryl Hydrocarbon Receptor. Curr Cancer Drug Targets 2011; 11: 654-69.
138. Barhoover MA, Hall JM, Greenlee WF, Thomas RS. The AHR regulates cell cycle progression in human breast cancer cells via a functional interaction with CDK4. Mol Pharmacol 2010; 77: 195-201.
139. Bencko V, Rames J, Ondrusova M, et al. Human exposure to polyhalogenated hydrocarbons and incidence of selected malignancies -central European experience. Neoplasma 2009; 56: 353-7.
140. Hall JM, Barhoover MA, Kazmin D, McDonnell DP, Greenlee WF, Thomas RS. Activation of the aryl-hydrocarbon receptor inhibits invasive and metastatic features of human breast cancer cells and promotes breast cancer cell differentiation. Mol Endocrinol 2010; 24: 359-69.
141. Zhang S, Lei P, Liu X, et al. The aryl hydrocarbon receptor as a target for estrogen receptor-negative breast cancer chemotherapy. Endocr Relat Cancer 2009; 16: 835-44.
142. Shiozawa Y, Pedersen EA, Havens AM, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest 2011; 121: 1298-312.
143. Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK. CXCL12 (SDF1{alpha})-CXCR4/CXCR7 Pathway Inhibition: An Emerging Sensitizer for Anticancer Therapies? Clin Cancer Res 2011; 17: 2074-80.
144. Fiegl M, Samudio I, Clise-Dwyer K, Burks JK, Mnjoyan Z, Andreeff M. CXCR4 expression and biologic activity in acute myeloid leukemia are dependent on oxygen partial pressure. Blood 2009; 113: 1504-12.
145. Hendrix CW, Collier AC, Lederman MM, et al. Safety, pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J Acquir Immune Defic Syndr 2004; 37: 1253-62.
146. Flomenberg N, DiPersio J, Calandra G. Role of CXCR4 chemokine receptor blockade using AMD3100 for mobilization of autologous hematopoietic progenitor cells. Acta Haematol 2005; 14: 198-205.
147. Burger JA, Stewart DJ, Wald O, Peled A. Potential of CXCR4 antagonists for the treatment of metastatic lung cancer. Expert Rev Anticancer Ther 2011; 11: 621-30.
148. McDermott SP, Wicha MS. Targeting breast cancer stem cells. Mol Oncol 2010; 4: 404-19.
149. Morel AP, Lièvre M, Thomas C, Hinkal G, Ansieau S, Puisieux A. Generation of breast cancer stem cells through epithelialmesenchymal transition. PLoS One 2008; 3: e2888. www.plosone.org
150. Kong D, Banerjee S, Ahmad A, et al. Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One 2010; 5: e12445. www.plosone.org
151. Ellis LM. The role of neuropilins in cancer. Mol Cancer Ther 2006; 5: 1099-107.
152. Guttmann-Raviv N, Kessler O, Shraga-Heled N, Lange T, Herzog Y, Neufeld G. The neuropilins and their role in tumorigenesis and tumor progression. Cancer Lett 2006; 231: 1-11.
153. Bagri A, Tessier-Lavigne M, Watts RJ. Neuropilins in tumor biology. Clin Cancer Res 2009; 15: 1860-4.
154. Caunt M, Mak J, Liang WC, et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 2008; 13: 331-42.
155. Neufeld G, Kessler O. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer 2008; 8: 632-45.
156. Gaur P, Bielenberg DR, Samuel S, et al. Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis. Clin Cancer Res 2009; 15: 6763-70.
157. Sulpice E, Plouët J, Bergé M, Allanic D, Tobelem G, Merkulova-Rainon T. Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood 2008; 111: 2036-45.
158. Matsushita A, Götze T, Korc M. Hepatocyte growth factormediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res 2007; 67: 10309-16.
159. West DC, Rees CG, Duchesne L, et al. Interactions of multiple heparin binding growth factors with neuropilin-1 and potentiation of the activity of fibroblast growth factor-2. J Biol Chem 2005; 280: 13457-64.
160. Dhar K, Dhar G, Majumder M, Haque I, Mehta S, Van Veldhuizen PJ, Banerjee SK, Banerjee S, et al. Tumor cell-derived PDGF-B potentiates mouse mesenchymal stem cells-pericytes transition and recruitment through an interaction with NRP-1. Mol Cancer 2010; 9: 209.
161. Pellet-Many C, Frankel P, Evans IM, Herzog B, Jünemann-Ramírez M, Zachary I. Neuropilin-1 mediates PDGF stimulation of Vascular Smooth Muscle Cell migration and signalling via p130Cas. Biochem J 2011; 435: 609-18.
162. Evans IM, Yamaji M, Britton G, et al. Neuropilin-1 Signaling through p130Cas Tyrosine Phosphorylation Is Essential for Growth Factor-Dependent Migration of Glioma and Endothelial Cells. Mol Cell Biol 2011; 31: 1174-85.
163. Kim W, Seok Kang Y, Soo Kim J, Shin NY, Hanks SK, Song WK. The integrin-coupled signaling adaptor p130Cas suppresses Smad3 function in transforming growth factor-beta signaling. Mol Biol Cell 2008; 19: 2135-46.
164. Wendt MK, Smith JA, Schiemann WP. p130Cas is required for mammary tumor growth and transforming growth factor-betamediated metastasis through regulation of Smad2/3 activity. J Biol Chem 2009; 284: 34145-56
165. Cabodi S, del Pilar Camacho-Leal M, Di Stefano P, Defilippi P. Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer 2010; 10: 858-70.
166. Tian M, Neil JR, Schiemann WP. Transforming growth factorand the hallmarks of cancer. Cell Signal 2011; 23: 951-62.
167. Cunningham-Edmondson AC, Hanks SK. p130Cas substrate domain signaling promotes migration, invasion, and survival of estrogen receptor-negative breast cancer cells. Breast Cancer (London) 2009(1): 39-52.
168. Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci USA 2009; 106: 16157-62.
169. Sugahara KN, Teesalu T, Karmali PP, et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 2009; 16: 510-20.
170. Sugahara KN, Teesalu T, Karmali PP, et al. Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 2010; 328: 1031-5.
171. Ruoslahti E, Bhatia SN, Sailor MJ. Targeting of drugs and nanoparticles to tumors. J Cell Biol 2010; 188: 759-68.
172. Fuchs D, Heinold A, Opelz G, Daniel V, Naujokat C. Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem Biophys Res Commun 2009; 390: 743-9.
173. Story P, Doube A. A case of human poisoning by salinomycin, an agricultural antibiotic. N Z Med J 2004; 117: U799.
174. Lagas JS, Sparidans RW, van Waterschoot RA, Wagenaar E, Beijnen JH, Schinkel AH. P-glycoprotein limits oral availability, brain penetration, and toxicity of an anionic drug, the antibiotic salinomycin. Antimicrob Agents Chemother 2008; 52: 1034-9.
175. Zimmerman AL, Wu S. MicroRNAs, cancer and cancer stem cells. Cancer Lett 2011; 300: 10-9.
176. Chaffer CL, Brueckmann I, Scheel C, et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA 2011; 108: 7950-5.