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Stem Cells International
Volume 2018, Article ID 5416923, 16 pages
https://doi.org/10.1155/2018/5416923
Review Article

Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment

Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Asan, Republic of Korea

Correspondence should be addressed to Yun Kyung Lee; rk.ca.hcs@eelknuy and Hyog Young Kwon; rk.ca.hcs@nowkyh

Received 28 September 2017; Accepted 11 January 2018; Published 28 February 2018

Academic Editor: Pratima Basak

Copyright © 2018 Lan Thi Hanh Phi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. R. Siegel, D. Naishadham, and A. Jemal, “Cancer statistics, 2013,” CA: a Cancer Journal for Clinicians, vol. 63, no. 1, pp. 11–30, 2013. View at Publisher · View at Google Scholar · View at Scopus
  2. D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. Y. N. You, V. T. Lakhani, and S. A. Wells Jr., “The role of prophylactic surgery in cancer prevention,” World Journal of Surgery, vol. 31, no. 3, pp. 450–464, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. B. M. Putzer, M. Solanki, and O. Herchenroder, “Advances in cancer stem cell targeting: how to strike the evil at its root,” Advanced Drug Delivery Reviews, vol. 120, pp. 89–107, 2017. View at Publisher · View at Google Scholar · View at Scopus
  5. Y. A. Luqmani, “Mechanisms of drug resistance in cancer chemotherapy,” Medical Principles and Practice, vol. 14, no. 1, pp. 35–48, 2005. View at Publisher · View at Google Scholar
  6. P. A. Reid, P. Wilson, Y. Li, L. G. Marcu, and E. Bezak, “Current understanding of cancer stem cells: review of their radiobiology and role in head and neck cancers,” Head & Neck, vol. 39, no. 9, pp. 1920–1932, 2017. View at Publisher · View at Google Scholar · View at Scopus
  7. O. Tredan, C. M. Galmarini, K. Patel, and I. F. Tannock, “Drug resistance and the solid tumor microenvironment,” Journal of the National Cancer Institute, vol. 99, no. 19, pp. 1441–1454, 2007. View at Publisher · View at Google Scholar · View at Scopus
  8. D. A. Senthebane, A. Rowe, N. E. Thomford et al., “The role of tumor microenvironment in chemoresistance: to survive, keep your enemies closer,” International Journal of Molecular Sciences, vol. 18, no. 7, 2017. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Fesler, S. Guo, H. Liu, N. Wu, and J. Ju, “Overcoming chemoresistance in cancer stem cells with the help of microRNAs in colorectal cancer,” Epigenomics, vol. 9, no. 6, pp. 793–796, 2017. View at Publisher · View at Google Scholar · View at Scopus
  10. R. Di Fiore, R. Drago-Ferrante, F. Pentimalli et al., “MicroRNA-29b-1 impairs in vitro cell proliferation, self‑renewal and chemoresistance of human osteosarcoma 3AB-OS cancer stem cells,” International Journal of Oncology, vol. 45, no. 5, pp. 2013–2023, 2014. View at Publisher · View at Google Scholar · View at Scopus
  11. D. Chen, M. Wu, Y. Li et al., “Targeting BMI1+ cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma,” Cell Stem Cell, vol. 20, no. 5, pp. 621–634.e6, 2017. View at Publisher · View at Google Scholar · View at Scopus
  12. J. E. Visvader and G. J. Lindeman, “Cancer stem cells in solid tumours: accumulating evidence and unresolved questions,” Nature Reviews Cancer, vol. 8, no. 10, pp. 755–768, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. M. R. Alison, S. M. Lim, and L. J. Nicholson, “Cancer stem cells: problems for therapy?” The Journal of Pathology, vol. 223, no. 2, pp. 147–161, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Dean, T. Fojo, and S. Bates, “Tumour stem cells and drug resistance,” Nature Reviews Cancer, vol. 5, no. 4, pp. 275–284, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. A. Singh and J. Settleman, “EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer,” Oncogene, vol. 29, no. 34, pp. 4741–4751, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. M. H. Kiyohara, C. Dillard, J. Tsui et al., “EMP2 is a novel therapeutic target for endometrial cancer stem cells,” Oncogene, vol. 36, no. 42, pp. 5793–5807, 2017. View at Publisher · View at Google Scholar · View at Scopus
  17. J. Chen, Y. Li, T. S. Yu et al., “A restricted cell population propagates glioblastoma growth after chemotherapy,” Nature, vol. 488, no. 7412, pp. 522–526, 2012. View at Publisher · View at Google Scholar · View at Scopus
  18. D. Fang and H. Kitamura, “Cancer stem cells and epithelial–mesenchymal transition in urothelial carcinoma: possible pathways and potential therapeutic approaches,” International Journal of Urology, vol. 25, no. 1, pp. 7–17, 2018. View at Publisher · View at Google Scholar · View at Scopus
  19. M. Cojoc, K. Mäbert, M. H. Muders, and A. Dubrovska, “A role for cancer stem cells in therapy resistance: cellular and molecular mechanisms,” Seminars in Cancer Biology, vol. 31, pp. 16–27, 2015. View at Publisher · View at Google Scholar · View at Scopus
  20. L. I. Shlush, A. Mitchell, L. Heisler et al., “Tracing the origins of relapse in acute myeloid leukaemia to stem cells,” Nature, vol. 547, no. 7661, pp. 104–108, 2017. View at Publisher · View at Google Scholar · View at Scopus
  21. D. R. Pattabiraman and R. A. Weinberg, “Tackling the cancer stem cells — what challenges do they pose?” Nature Reviews Drug Discovery, vol. 13, no. 7, pp. 497–512, 2014. View at Publisher · View at Google Scholar · View at Scopus
  22. Z. J. Yang and R. J. Wechsler-Reya, “Hit ‘em where they live: targeting the cancer stem cell niche,” Cancer Cell, vol. 11, no. 1, pp. 3–5, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. P. Valent, D. Bonnet, R. de Maria et al., “Cancer stem cell definitions and terminology: the devil is in the details,” Nature Reviews Cancer, vol. 12, no. 11, pp. 767–775, 2012. View at Publisher · View at Google Scholar · View at Scopus
  24. C. Peitzsch, I. Kurth, L. Kunz-Schughart, M. Baumann, and A. Dubrovska, “Discovery of the cancer stem cell related determinants of radioresistance,” Radiotherapy and Oncology, vol. 108, no. 3, pp. 378–387, 2013. View at Publisher · View at Google Scholar · View at Scopus
  25. D. Bonnet and J. E. Dick, “Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell,” Nature Medicine, vol. 3, no. 7, pp. 730–7, 1997. View at Publisher · View at Google Scholar · View at Scopus
  26. S. A. Joosse and K. Pantel, “Biologic challenges in the detection of circulating tumor cells,” Cancer Research, vol. 73, no. 1, pp. 8–11, 2013. View at Publisher · View at Google Scholar · View at Scopus
  27. M. Al-Hajj, M. S. Wicha, A. Benito-Hernandez, S. J. Morrison, and M. F. Clarke, “Prospective identification of tumorigenic breast cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 7, pp. 3983–3988, 2003. View at Publisher · View at Google Scholar · View at Scopus
  28. T. N. Ignatova, V. G. Kukekov, E. D. Laywell, O. N. Suslov, F. D. Vrionis, and D. A. Steindler, “Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro,” Glia, vol. 39, no. 3, pp. 193–206, 2002. View at Publisher · View at Google Scholar · View at Scopus
  29. T. Schatton, G. F. Murphy, N. Y. Frank et al., “Identification of cells initiating human melanomas,” Nature, vol. 451, no. 7176, pp. 345–349, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. S. K. Singh, I. D. Clarke, M. Terasaki et al., “Identification of a cancer stem cell in human brain tumors,” Cancer Research, vol. 63, no. 18, pp. 5821–5828, 2003. View at Google Scholar
  31. A. Eramo, F. Lotti, G. Sette et al., “Identification and expansion of the tumorigenic lung cancer stem cell population,” Cell Death & Differentiation, vol. 15, no. 3, pp. 504–514, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. Z. F. Yang, D. W. Ho, M. N. Ng et al., “Significance of CD90+ cancer stem cells in human liver cancer,” Cancer Cell, vol. 13, no. 2, pp. 153–166, 2008. View at Publisher · View at Google Scholar · View at Scopus
  33. C. Li, D. G. Heidt, P. Dalerba et al., “Identification of pancreatic cancer stem cells,” Cancer Research, vol. 67, no. 3, pp. 1030–1037, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. C. A. O’Brien, A. Pollett, S. Gallinger, and J. E. Dick, “A human colon cancer cell capable of initiating tumour growth in immunodeficient mice,” Nature, vol. 445, no. 7123, pp. 106–110, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Zhang, C. Balch, M. W. Chan et al., “Identification and characterization of ovarian cancer-initiating cells from primary human tumors,” Cancer Research, vol. 68, no. 11, pp. 4311–4320, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. T. B. Brunner, L. A. Kunz-Schughart, P. Grosse-Gehling, and M. Baumann, “Cancer stem cells as a predictive factor in radiotherapy,” Seminars in Radiation Oncology, vol. 22, no. 2, pp. 151–174, 2012. View at Publisher · View at Google Scholar · View at Scopus
  37. P. Dalerba, R. W. Cho, and M. F. Clarke, “Cancer stem cells: models and concepts,” Annual Review of Medicine, vol. 58, no. 1, pp. 267–284, 2007. View at Publisher · View at Google Scholar · View at Scopus
  38. M. López-Lázaro, “The migration ability of stem cells can explain the existence of cancer of unknown primary site. Rethinking metastasis,” Oncoscience, vol. 2, no. 5, pp. 467–475, 2015. View at Publisher · View at Google Scholar · View at Scopus
  39. M. Lopez-Lazaro, “Stem cell division theory of cancer,” Cell Cycle, vol. 14, no. 16, pp. 2547-2548, 2015. View at Publisher · View at Google Scholar · View at Scopus
  40. Y. Wang, J. Yang, H. Zheng et al., “Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model,” Cancer Cell, vol. 15, no. 6, pp. 514–526, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. M. Nouri, J. Caradec, A. A. Lubik et al., “Therapy-induced developmental reprogramming of prostate cancer cells and acquired therapy resistance,” Oncotarget, vol. 8, no. 12, pp. 18949–18967, 2017. View at Publisher · View at Google Scholar · View at Scopus
  42. N. Barker, R. A. Ridgway, J. H. van Es et al., “Crypt stem cells as the cells-of-origin of intestinal cancer,” Nature, vol. 457, no. 7229, pp. 608–611, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. D. Rubio, J. Garcia-Castro, M. C. Martín et al., “Spontaneous human adult stem cell transformation,” Cancer Research, vol. 65, no. 8, pp. 3035–3039, 2005. View at Publisher · View at Google Scholar
  44. J. S. Burns, B. M. Abdallah, P. Guldberg, J. Rygaard, H. D. Schrøder, and M. Kassem, “Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells,” Cancer Research, vol. 65, no. 8, pp. 3126–3135, 2005. View at Publisher · View at Google Scholar
  45. C. Liu, Z. Chen, Z. Chen, T. Zhang, and Y. Lu, “Multiple tumor types may originate from bone marrow–derived cells,” Neoplasia, vol. 8, no. 9, pp. 716–724, 2006. View at Publisher · View at Google Scholar · View at Scopus
  46. I. Baccelli and A. Trumpp, “The evolving concept of cancer and metastasis stem cells,” Journal of Cell Biology, vol. 198, no. 3, pp. 281–293, 2012. View at Publisher · View at Google Scholar · View at Scopus
  47. C. H. M. Jamieson, L. E. Ailles, S. J. Dylla et al., “Granulocyte–macrophage progenitors as candidate leukemic stem cells in blast-crisis CML,” The New England Journal of Medicine, vol. 351, no. 7, pp. 657–667, 2004. View at Publisher · View at Google Scholar · View at Scopus
  48. U. Schüller, V. M. Heine, J. Mao et al., “Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma,” Cancer Cell, vol. 14, no. 2, pp. 123–134, 2008. View at Publisher · View at Google Scholar · View at Scopus
  49. Z. J. Yang, T. Ellis, S. L. Markant et al., “Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells,” Cancer Cell, vol. 14, no. 2, pp. 135–145, 2008. View at Publisher · View at Google Scholar · View at Scopus
  50. D. Friedmann-Morvinski, E. A. Bushong, E. Ke et al., “Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice,” Science, vol. 338, no. 6110, pp. 1080–1084, 2012. View at Publisher · View at Google Scholar · View at Scopus
  51. K. Chen, Y.-h. Huang, and J.-l. Chen, “Understanding and targeting cancer stem cells: therapeutic implications and challenges,” Acta Pharmacologica Sinica, vol. 34, no. 6, pp. 732–740, 2013. View at Publisher · View at Google Scholar · View at Scopus
  52. P. Dalerba, S. J. Dylla, I. K. Park et al., “Phenotypic characterization of human colorectal cancer stem cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 24, pp. 10158–10163, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. C. Ginestier, M. H. Hur, E. Charafe-Jauffret et al., “ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome,” Cell Stem Cell, vol. 1, no. 5, pp. 555–567, 2007. View at Publisher · View at Google Scholar · View at Scopus
  54. L. I. Shlush, S. Zandi, A. Mitchell et al., “Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia,” Nature, vol. 506, no. 7488, pp. 328–333, 2014. View at Publisher · View at Google Scholar · View at Scopus
  55. B. Auffinger, A. L. Tobias, Y. Han et al., “Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy,” Cell Death & Differentiation, vol. 21, no. 7, pp. 1119–1131, 2014. View at Publisher · View at Google Scholar · View at Scopus
  56. P. Hamerlik, J. D. Lathia, R. Rasmussen et al., “Autocrine VEGF–VEGFR2–Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth,” Journal of Experimental Medicine, vol. 209, no. 3, pp. 507–520, 2012. View at Publisher · View at Google Scholar · View at Scopus
  57. K. Shien, S. Toyooka, H. Yamamoto et al., “Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell–like properties in cancer cells,” Cancer Research, vol. 73, no. 10, pp. 3051–3061, 2013. View at Publisher · View at Google Scholar · View at Scopus
  58. T. Oskarsson, E. Batlle, and J. Massague, “Metastatic stem cells: sources, niches, and vital pathways,” Cell Stem Cell, vol. 14, no. 3, pp. 306–321, 2014. View at Publisher · View at Google Scholar · View at Scopus
  59. A. Puisieux, T. Brabletz, and J. Caramel, “Oncogenic roles of EMT-inducing transcription factors,” Nature Cell Biology, vol. 16, no. 6, pp. 488–494, 2014. View at Publisher · View at Google Scholar · View at Scopus
  60. S. A. Mani, W. Guo, M. J. Liao et al., “The epithelial-mesenchymal transition generates cells with properties of stem cells,” Cell, vol. 133, no. 4, pp. 704–715, 2008. View at Publisher · View at Google Scholar · View at Scopus
  61. S. Meidhof, S. Brabletz, W. Lehmann et al., “ZEB1‐associated drug resistance in cancer cells is reversed by the class I HDAC inhibitor mocetinostat,” EMBO Molecular Medicine, vol. 7, no. 6, pp. 831–847, 2015. View at Publisher · View at Google Scholar · View at Scopus
  62. H. Uramoto, T. Iwata, T. Onitsuka, H. Shimokawa, T. Hanagiri, and T. Oyama, “Epithelial−mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma,” Anticancer Research, vol. 30, no. 7, pp. 2513–7, 2010. View at Google Scholar
  63. M. Xie, L. Zhang, C. S. He et al., “Activation of Notch-1 enhances epithelial–mesenchymal transition in gefitinib-acquired resistant lung cancer cells,” Journal of Cellular Biochemistry, vol. 113, no. 5, pp. 1501–1513, 2012. View at Publisher · View at Google Scholar · View at Scopus
  64. P. C. Black, G. A. Brown, T. Inamoto et al., “Sensitivity to epidermal growth factor receptor inhibitor requires E-cadherin expression in urothelial carcinoma cells,” Clinical Cancer Research, vol. 14, no. 5, pp. 1478–1486, 2008. View at Publisher · View at Google Scholar · View at Scopus
  65. B. C. Fuchs, T. Fujii, J. D. Dorfman et al., “Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells,” Cancer Research, vol. 68, no. 7, pp. 2391–2399, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. J. F. Lo, C. C. Yu, S. H. Chiou et al., “The epithelial-mesenchymal transition mediator S100A4 maintains cancer-initiating cells in head and neck cancers,” Cancer Research, vol. 71, no. 5, pp. 1912–1923, 2011. View at Publisher · View at Google Scholar · View at Scopus
  67. K. Polyak and R. A. Weinberg, “Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits,” Nature Reviews Cancer, vol. 9, no. 4, pp. 265–273, 2009. View at Publisher · View at Google Scholar · View at Scopus
  68. F. A. Siebzehnrubl, D. J. Silver, B. Tugertimur et al., “The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance,” EMBO Molecular Medicine, vol. 5, no. 8, pp. 1196–1212, 2013. View at Publisher · View at Google Scholar · View at Scopus
  69. B. S. Koo, S. H. Lee, J. M. Kim et al., “Oct4 is a critical regulator of stemness in head and neck squamous carcinoma cells,” Oncogene, vol. 34, no. 18, pp. 2317–2324, 2015. View at Publisher · View at Google Scholar · View at Scopus
  70. C. E. Huang, C. C. Yu, F. W. Hu, M. Y. Chou, and L. L. Tsai, “Enhanced chemosensitivity by targeting Nanog in head and neck squamous cell carcinomas,” International Journal of Molecular Sciences, vol. 15, no. 9, pp. 14935–14948, 2014. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Y. Chou, F. W. Hu, C. H. Yu, and C. C. Yu, “Sox2 expression involvement in the oncogenicity and radiochemoresistance of oral cancer stem cells,” Oral Oncology, vol. 51, no. 1, pp. 31–39, 2015. View at Publisher · View at Google Scholar · View at Scopus
  72. G. Y. Chiou, T. W. Yang, C. C. Huang et al., “Musashi-1 promotes a cancer stem cell lineage and chemoresistance in colorectal cancer cells,” Scientific Reports, vol. 7, no. 1, p. 2172, 2017. View at Publisher · View at Google Scholar · View at Scopus
  73. H. Z. Cao, X. F. Liu, W. T. Yang, Q. Chen, and P. S. Zheng, “LGR5 promotes cancer stem cell traits and chemoresistance in cervical cancer,” Cell Death & Disease, vol. 8, no. 9, article e3039, 2017. View at Publisher · View at Google Scholar
  74. G. M. Seigel, L. M. Campbell, M. Narayan, and F. Gonzalez-Fernandez, “Cancer stem cell characteristics in retinoblastoma,” Molecular Vision, vol. 11, pp. 729–737, 2005. View at Google Scholar
  75. C. Hirschmann-Jax, A. E. Foster, G. G. Wulf et al., “A distinct “side population” of cells with high drug efflux capacity in human tumor cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 39, pp. 14228–14233, 2004. View at Publisher · View at Google Scholar · View at Scopus
  76. N. Haraguchi, T. Utsunomiya, H. Inoue et al., “Characterization of a side population of cancer cells from human gastrointestinal system,” Stem Cells, vol. 24, no. 3, pp. 506–513, 2006. View at Publisher · View at Google Scholar · View at Scopus
  77. A. Alisi, W. Cho, F. Locatelli, and D. Fruci, “Multidrug resistance and cancer stem cells in neuroblastoma and hepatoblastoma,” International Journal of Molecular Sciences, vol. 14, no. 12, pp. 24706–24725, 2013. View at Publisher · View at Google Scholar · View at Scopus
  78. A. M. Bleau, D. Hambardzumyan, T. Ozawa et al., “PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells,” Cell Stem Cell, vol. 4, no. 3, pp. 226–235, 2009. View at Publisher · View at Google Scholar · View at Scopus
  79. D. Raha, T. R. Wilson, J. Peng et al., “The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation,” Cancer Research, vol. 74, no. 13, pp. 3579–3590, 2014. View at Publisher · View at Google Scholar
  80. D. J. Pearce, D. Taussig, C. Simpson et al., “Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples,” Stem Cells, vol. 23, no. 6, pp. 752–760, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. Y. Su, Q. Qiu, X. Zhang et al., “Aldehyde dehydrogenase 1 A1–positive cell population is enriched in tumor-initiating cells and associated with progression of bladder cancer,” Cancer Epidemiology Biomarkers & Prevention, vol. 19, no. 2, pp. 327–337, 2010. View at Publisher · View at Google Scholar · View at Scopus
  82. M. R. Clay, M. Tabor, J. H. Owen et al., “Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase,” Head & Neck, vol. 32, no. 9, pp. 1195–1201, 2010. View at Publisher · View at Google Scholar · View at Scopus
  83. F. Jiang, Q. Qiu, A. Khanna et al., “Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer,” Molecular Cancer Research, vol. 7, no. 3, pp. 330–338, 2009. View at Publisher · View at Google Scholar · View at Scopus
  84. K. Nakahata, S. Uehara, S. Nishikawa et al., “Aldehyde dehydrogenase 1 (ALDH1) is a potential marker for cancer stem cells in embryonal rhabdomyosarcoma,” PLoS One, vol. 10, no. 4, article e0125454, 2015. View at Publisher · View at Google Scholar · View at Scopus
  85. C. P. Huang, M. F. Tsai, T. H. Chang et al., “ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors,” Cancer Letters, vol. 328, no. 1, pp. 144–151, 2013. View at Publisher · View at Google Scholar · View at Scopus
  86. J. A. Ajani, X. Wang, S. Song et al., “ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients,” Molecular Oncology, vol. 8, no. 1, pp. 142–149, 2014. View at Publisher · View at Google Scholar · View at Scopus
  87. A. Kreso, C. A. O'Brien, P. van Galen et al., “Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer,” Science, vol. 339, no. 6119, pp. 543–548, 2013. View at Publisher · View at Google Scholar · View at Scopus
  88. A. V. Kurtova, J. Xiao, Q. Mo et al., “Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance,” Nature, vol. 517, no. 7533, pp. 209–213, 2015. View at Publisher · View at Google Scholar · View at Scopus
  89. T. Ishimoto, O. Nagano, T. Yae et al., “CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc and thereby promotes tumor growth,” Cancer Cell, vol. 19, no. 3, pp. 387–400, 2011. View at Publisher · View at Google Scholar · View at Scopus
  90. M. Diehn, R. W. Cho, N. A. Lobo et al., “Association of reactive oxygen species levels and radioresistance in cancer stem cells,” Nature, vol. 458, no. 7239, pp. 780–783, 2009. View at Publisher · View at Google Scholar · View at Scopus
  91. H. Yin and J. Glass, “The phenotypic radiation resistance of CD44+/CD24−or low breast cancer cells is mediated through the enhanced activation of ATM signaling,” PLoS One, vol. 6, no. 9, article e24080, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. S. Bao, Q. Wu, R. E. McLendon et al., “Glioma stem cells promote radioresistance by preferential activation of the DNA damage response,” Nature, vol. 444, no. 7120, pp. 756–760, 2006. View at Publisher · View at Google Scholar · View at Scopus
  93. J. Wang, T. P. Wakeman, J. D. Lathia et al., “Notch promotes radioresistance of glioma stem cells,” Stem Cells, vol. 28, no. 1, pp. 17–28, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. K. Kise, Y. Kinugasa-Katayama, and N. Takakura, “Tumor microenvironment for cancer stem cells,” Advanced Drug Delivery Reviews, vol. 99, Part B, pp. 197–205, 2016. View at Publisher · View at Google Scholar · View at Scopus
  95. E. Y.-T. Lau, N. P.-Y. Ho, and T. K.-W. Lee, “Cancer stem cells and their microenvironment: biology and therapeutic implications,” Stem Cells International, vol. 2017, Article ID 3714190, 11 pages, 2017. View at Publisher · View at Google Scholar · View at Scopus
  96. A. Turdo, M. Todaro, and G. StassiS. Babashah, “Targeting cancer stem cells and the tumor microenvironment,” in Cancer Stem Cells: Emerging Concepts and Future Perspectives in Translational Oncology, pp. 445–476, Springer International Publishing, Cham, 2015. View at Google Scholar
  97. H. Adisetiyo, M. Liang, C. P. Liao et al., “Dependence of castration-resistant prostate cancer (CRPC) stem cells on CRPC-associated fibroblasts,” Journal of Cellular Physiology, vol. 229, no. 9, pp. 1170–1176, 2014. View at Publisher · View at Google Scholar · View at Scopus
  98. C. P. Liao, H. Adisetiyo, M. Liang, and P. Roy-Burman, “Cancer-associated fibroblasts enhance the gland-forming capability of prostate cancer stem cells,” Cancer Research, vol. 70, no. 18, pp. 7294–7303, 2010. View at Publisher · View at Google Scholar · View at Scopus
  99. W.-J. Chen, C.-C. Ho, Y.-L. Chang et al., “Cancer-associated fibroblasts regulate the plasticity of lung cancer stemness via paracrine signalling,” Nature Communications, vol. 5, p. 3472, 2014. View at Publisher · View at Google Scholar · View at Scopus
  100. Y. Kinugasa, T. Matsui, and N. Takakura, “CD44 expressed on cancer-associated fibroblasts is a functional molecule supporting the stemness and drug resistance of malignant cancer cells in the tumor microenvironment,” Stem Cells, vol. 32, no. 1, pp. 145–156, 2014. View at Publisher · View at Google Scholar · View at Scopus
  101. F. Cammarota and M. O. Laukkanen, “Mesenchymal stem/stromal cells in stromal evolution and cancer progression,” Stem Cells International, vol. 2016, Article ID 4824573, 11 pages, 2016. View at Publisher · View at Google Scholar · View at Scopus
  102. K. E. Hovinga, F. Shimizu, R. Wang et al., “Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate,” Stem Cells, vol. 28, no. 6, pp. 1019–1029, 2010. View at Publisher · View at Google Scholar · View at Scopus
  103. C. Calabrese, H. Poppleton, M. Kocak et al., “A perivascular niche for brain tumor stem cells,” Cancer Cell, vol. 11, no. 1, pp. 69–82, 2007. View at Publisher · View at Google Scholar · View at Scopus
  104. S. Krishnamurthy, Z. Dong, D. Vodopyanov et al., “Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells,” Cancer Research, vol. 70, no. 23, pp. 9969–9978, 2010. View at Publisher · View at Google Scholar · View at Scopus
  105. S. Krishnamurthy, K. A. Warner, Z. Dong et al., “Endothelial interleukin-6 defines the tumorigenic potential of primary human cancer stem cells,” Stem Cells, vol. 32, no. 11, pp. 2845–2857, 2014. View at Publisher · View at Google Scholar · View at Scopus
  106. Z. Zhang, Z. Dong, I. S. Lauxen, M. S. Filho, and J. E. Nor, “Endothelial cell-secreted EGF induces epithelial to mesenchymal transition and endows head and neck cancer cells with stem-like phenotype,” Cancer Research, vol. 74, no. 10, pp. 2869–2881, 2014. View at Publisher · View at Google Scholar · View at Scopus
  107. T. S. Zhu, M. A. Costello, C. E. Talsma et al., “Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells,” Cancer Research, vol. 71, no. 18, pp. 6061–6072, 2011. View at Publisher · View at Google Scholar · View at Scopus
  108. J. Lu, X. Ye, F. Fan et al., “Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1,” Cancer Cell, vol. 23, no. 2, pp. 171–185, 2013. View at Publisher · View at Google Scholar · View at Scopus
  109. S. Schwitalla, A. A. Fingerle, P. Cammareri et al., “Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties,” Cell, vol. 152, no. 1-2, pp. 25–38, 2013. View at Publisher · View at Google Scholar · View at Scopus
  110. L. Vermeulen, F. de Sousa E Melo, M. van der Heijden et al., “Wnt activity defines colon cancer stem cells and is regulated by the microenvironment,” Nature Cell Biology, vol. 12, no. 5, pp. 468–476, 2010. View at Publisher · View at Google Scholar · View at Scopus
  111. X. C. He, J. Zhang, W. G. Tong et al., “BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt–β-catenin signaling,” Nature Genetics, vol. 36, no. 10, pp. 1117–1121, 2004. View at Publisher · View at Google Scholar · View at Scopus
  112. L. A. Milner and A. Bigas, “Notch as a mediator of cell fate determination in hematopoiesis: evidence and speculation,” Blood, vol. 93, no. 8, pp. 2431–2448, 1999. View at Google Scholar
  113. O.-J. Kwon, J. M. Valdez, L. Zhang et al., “Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells,” Nature Communications, vol. 5, p. 4416, 2014. View at Publisher · View at Google Scholar · View at Scopus
  114. B. R. B. Pires, Í. S. S. De Amorim, L. D. E. Souza, J. A. Rodrigues, and A. L. Mencalha, “Targeting cellular signaling pathways in breast cancer stem cells and its implication for cancer treatment,” Anticancer Research, vol. 36, no. 11, pp. 5681–5692, 2016. View at Publisher · View at Google Scholar · View at Scopus
  115. B. Bao, A. S. Azmi, S. Ali et al., “The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness,” Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, vol. 1826, no. 2, pp. 272–296, 2012. View at Publisher · View at Google Scholar · View at Scopus
  116. B. Bao, S. Ali, A. Ahmad et al., “Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment,” PLoS One, vol. 7, no. 12, article e50165, 2012. View at Publisher · View at Google Scholar · View at Scopus
  117. K. P. Ng, A. Manjeri, K. L. Lee et al., “Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition,” Blood, vol. 123, no. 21, pp. 3316–3326, 2014. View at Publisher · View at Google Scholar · View at Scopus
  118. A. Murakami, F. Takahashi, F. Nurwidya et al., “Hypoxia increases gefitinib-resistant lung cancer stem cells through the activation of insulin-like growth factor 1 receptor,” PLoS One, vol. 9, no. 1, article e86459, 2014. View at Publisher · View at Google Scholar · View at Scopus
  119. V. Rausch, L. Liu, A. Apel et al., “Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment,” The Journal of Pathology, vol. 227, no. 3, pp. 325–335, 2012. View at Publisher · View at Google Scholar · View at Scopus
  120. F. Lotti, A. M. Jarrar, R. K. Pai et al., “Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A,” Journal of Experimental Medicine, vol. 210, no. 13, pp. 2851–2872, 2013. View at Publisher · View at Google Scholar · View at Scopus
  121. N. Nair, A. S. Calle, M. H. Zahra et al., “A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment,” Scientific Reports, vol. 7, no. 1, p. 6838, 2017. View at Publisher · View at Google Scholar · View at Scopus
  122. P. Luraghi, G. Reato, E. Cipriano et al., “MET signaling in colon cancer stem-like cells blunts the therapeutic response to EGFR inhibitors,” Cancer Research, vol. 74, no. 6, pp. 1857–1869, 2014. View at Publisher · View at Google Scholar · View at Scopus
  123. H. Korkaya, G.i. Kim, A. Davis et al., “Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population,” Molecular Cell, vol. 47, no. 4, pp. 570–584, 2012. View at Publisher · View at Google Scholar · View at Scopus
  124. N. E. Bhola, J. M. Balko, T. C. Dugger et al., “TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer,” The Journal of Clinical Investigation, vol. 123, no. 3, pp. 1348–1358, 2013. View at Publisher · View at Google Scholar · View at Scopus
  125. Y. G. Yang, I. N. Sari, M. F. Zia, S. R. Lee, S. J. Song, and H. Y. Kwon, “Tetraspanins: spanning from solid tumors to hematologic malignancies,” Experimental Hematology, vol. 44, no. 5, pp. 322–328, 2016. View at Publisher · View at Google Scholar · View at Scopus
  126. H. Y. Kwon, J. Bajaj, T. Ito et al., “Tetraspanin 3 is required for the development and propagation of acute myelogenous leukemia,” Cell Stem Cell, vol. 17, no. 2, pp. 152–164, 2015. View at Publisher · View at Google Scholar · View at Scopus
  127. Z. Zeng, I. J. Samudio, M. Munsell et al., “Inhibition of CXCR4 with the novel RCP168 peptide overcomes stroma-mediated chemoresistance in chronic and acute leukemias,” Molecular Cancer Therapeutics, vol. 5, no. 12, pp. 3113–3121, 2006. View at Publisher · View at Google Scholar · View at Scopus
  128. A. K. Azab, J. M. Runnels, C. Pitsillides et al., “CXCR4 inhibitor AMD3100 disrupts the interaction of multiple myeloma cells with the bone marrow microenvironment and enhances their sensitivity to therapy,” Blood, vol. 113, no. 18, pp. 4341–4351, 2009. View at Publisher · View at Google Scholar · View at Scopus
  129. T. Yamashina, M. Baghdadi, A. Yoneda et al., “Cancer stem-like cells derived from chemoresistant tumors have a unique capacity to prime tumorigenic myeloid cells,” Cancer Research, vol. 74, no. 10, pp. 2698–2709, 2014. View at Publisher · View at Google Scholar · View at Scopus
  130. Y. Zheng, Z. Cai, S. Wang et al., “Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug–induced apoptosis,” Blood, vol. 114, no. 17, pp. 3625–3628, 2009. View at Publisher · View at Google Scholar · View at Scopus
  131. J. B. Mitchem, D. J. Brennan, B. L. Knolhoff et al., “Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses,” Cancer Research, vol. 73, no. 3, pp. 1128–1141, 2013. View at Publisher · View at Google Scholar · View at Scopus
  132. M. Amit and Z. Gil, “Macrophages increase the resistance of pancreatic adenocarcinoma cells to gemcitabine by upregulating cytidine deaminase,” Oncoimmunology, vol. 2, no. 12, article e27231, 2013. View at Publisher · View at Google Scholar · View at Scopus
  133. O. G. McDonald, H. Wu, W. Timp, A. Doi, and A. P. Feinberg, “Genome-scale epigenetic reprogramming during epithelial-to-mesenchymal transition,” Nature Structural & Molecular Biology, vol. 18, no. 8, pp. 867–874, 2011. View at Publisher · View at Google Scholar · View at Scopus
  134. W. J. Harris, X. Huang, J. T. Lynch et al., “The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells,” Cancer Cell, vol. 21, no. 4, pp. 473–487, 2012. View at Publisher · View at Google Scholar · View at Scopus
  135. F. Crea, R. Danesi, and W. L. Farrar, “Cancer stem cell epigenetics and chemoresistance,” Epigenomics, vol. 1, no. 1, pp. 63–79, 2009. View at Publisher · View at Google Scholar · View at Scopus
  136. L. Qin, X. Zhang, L. Zhang et al., “Downregulation of BMI-1 enhances 5-fluorouracil-induced apoptosis in nasopharyngeal carcinoma cells,” Biochemical and Biophysical Research Communications, vol. 371, no. 3, pp. 531–535, 2008. View at Publisher · View at Google Scholar · View at Scopus
  137. R. Ferretti, A. Bhutkar, M. C. McNamara, and J. A. Lees, “BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance,” Genes & Development, vol. 30, no. 1, pp. 18–33, 2016. View at Publisher · View at Google Scholar · View at Scopus
  138. E. Proctor, M. Waghray, C. J. Lee et al., “Bmi1 enhances tumorigenicity and cancer stem cell function in pancreatic adenocarcinoma,” PLoS One, vol. 8, no. 2, article e55820, 2013. View at Publisher · View at Google Scholar · View at Scopus
  139. E. Wang, S. Bhattacharyya, A. Szabolcs et al., “Enhancing chemotherapy response with Bmi-1 silencing in ovarian cancer,” PLoS One, vol. 6, no. 3, article e17918, 2011. View at Publisher · View at Google Scholar · View at Scopus
  140. J. Wu, D. Hu, and R. Zhang, “Depletion of Bmi-1 enhances 5-fluorouracil-induced apoptosis and autophagy in hepatocellular carcinoma cells,” Oncology Letters, vol. 4, no. 4, pp. 723–726, 2012. View at Publisher · View at Google Scholar · View at Scopus
  141. A. V. Ougolkov, V. N. Bilim, and D. D. Billadeau, “Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2,” Clinical Cancer Research, vol. 14, no. 21, pp. 6790–6796, 2008. View at Publisher · View at Google Scholar · View at Scopus
  142. S. H. Kim, K. Joshi, R. Ezhilarasan et al., “EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner,” Stem Cell Reports, vol. 4, no. 2, pp. 226–238, 2015. View at Publisher · View at Google Scholar · View at Scopus
  143. C. M. Fillmore, C. Xu, P. T. Desai et al., “EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors,” Nature, vol. 520, no. 7546, pp. 239–242, 2015. View at Publisher · View at Google Scholar · View at Scopus
  144. A. M. Pietersen, H. M. Horlings, M. Hauptmann et al., “EZH2 and BMI1 inversely correlate with prognosis and TP53 mutation in breast cancer,” Breast Cancer Research, vol. 10, no. 6, article R109, 2008. View at Publisher · View at Google Scholar · View at Scopus
  145. B. Zhang, A. C. Strauss, S. Chu et al., “Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate,” Cancer Cell, vol. 17, no. 5, pp. 427–442, 2010. View at Publisher · View at Google Scholar · View at Scopus
  146. F. M. Frame, D. Pellacani, A. T. Collins et al., “HDAC inhibitor confers radiosensitivity to prostate stem-like cells,” British Journal of Cancer, vol. 109, no. 12, pp. 3023–3033, 2013. View at Publisher · View at Google Scholar · View at Scopus
  147. F. Bruzzese, A. Leone, M. Rocco et al., “HDAC inhibitor vorinostat enhances the antitumor effect of gefitinib in squamous cell carcinoma of head and neck by modulating ErbB receptor expression and reverting EMT,” Journal of Cellular Physiology, vol. 226, no. 9, pp. 2378–2390, 2011. View at Publisher · View at Google Scholar · View at Scopus
  148. K.-H. Song, C. H. Choi, H.-J. Lee et al., “HDAC1 upregulation by NANOG promotes multidrug resistance and a stem-like phenotype in immune edited tumor cells,” Cancer Research, vol. 77, no. 18, 2017. View at Publisher · View at Google Scholar · View at Scopus
  149. I. Ibanez de Caceres, M. Cortes-Sempere, C. Moratilla et al., “IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer,” Oncogene, vol. 29, no. 11, pp. 1681–1690, 2010. View at Publisher · View at Google Scholar · View at Scopus
  150. G. Strathdee, M. J. MacKean, M. Illand, and R. Brown, “A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer,” Oncogene, vol. 18, no. 14, pp. 2335–2341, 1999. View at Publisher · View at Google Scholar
  151. G. Gifford, J. Paul, P. A. Vasey, S. B. Kaye, and R. Brown, “The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients,” Clinical Cancer Research, vol. 10, no. 13, pp. 4420–4426, 2004. View at Publisher · View at Google Scholar · View at Scopus
  152. R. Brown, G. L. Hirst, W. M. Gallagher et al., “hMLH1 expression and cellular responses of ovarian tumour cells to treatment with cytotoxic anticancer agents,” Oncogene, vol. 15, no. 1, pp. 45–52, 1997. View at Publisher · View at Google Scholar
  153. H. J. Mackay, D. Cameron, M. Rahilly et al., “Reduced MLH1 expression in breast tumors after primary chemotherapy predicts disease-free survival,” Journal of Clinical Oncology, vol. 18, no. 1, pp. 87–93, 2000. View at Publisher · View at Google Scholar
  154. J. P. Sullivan, M. Spinola, M. Dodge et al., “Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling,” Cancer Research, vol. 70, no. 23, pp. 9937–9948, 2010. View at Publisher · View at Google Scholar · View at Scopus
  155. G. Dontu, K. W. Jackson, E. McNicholas, M. J. Kawamura, W. M. Abdallah, and M. S. Wicha, “Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells,” Breast Cancer Research, vol. 6, no. 6, pp. R605–R615, 2004. View at Publisher · View at Google Scholar · View at Scopus
  156. D. M. Park, J. Jung, J. Masjkur et al., “Hes3 regulates cell number in cultures from glioblastoma multiforme with stem cell characteristics,” Scientific Reports, vol. 3, no. 1, p. 1095, 2013. View at Publisher · View at Google Scholar · View at Scopus
  157. L. Yang, G. Xie, Q. Fan, and J. Xie, “Activation of the hedgehog-signaling pathway in human cancer and the clinical implications,” Oncogene, vol. 29, no. 4, pp. 469–481, 2010. View at Publisher · View at Google Scholar · View at Scopus
  158. W. F. Tam, P. S. Hahnel, A. Schuler et al., “STAT5 is crucial to maintain leukemic stem cells in acute myelogenous leukemias induced by MOZ-TIF2,” Cancer Research, vol. 73, no. 1, pp. 373–384, 2013. View at Publisher · View at Google Scholar · View at Scopus
  159. N. Takebe, L. Miele, P. J. Harris et al., “Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update,” Nature Reviews Clinical Oncology, vol. 12, no. 8, pp. 445–464, 2015. View at Publisher · View at Google Scholar · View at Scopus
  160. I. Kurth, C. Peitzsch, M. Baumann, and A. Dubrovska, “The role of cancer stem cells in tumor Radioresistance,” in Cancer Stem Cells, pp. 473–491, John Wiley & Sons, Hoboken, New Jersey, USA, 2014. View at Publisher · View at Google Scholar · View at Scopus
  161. T. Noda, H. Nagano, I. Takemasa et al., “Activation of Wnt/β-catenin signalling pathway induces chemoresistance to interferon-α/5-fluorouracil combination therapy for hepatocellular carcinoma,” British Journal of Cancer, vol. 100, no. 10, pp. 1647–1658, 2009. View at Publisher · View at Google Scholar · View at Scopus
  162. W. Yang, H. X. Yan, L. Chen et al., “Wnt/β-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells,” Cancer Research, vol. 68, no. 11, pp. 4287–4295, 2008. View at Publisher · View at Google Scholar · View at Scopus
  163. M. Flahaut, R. Meier, A. Coulon et al., “The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/β-catenin pathway,” Oncogene, vol. 28, no. 23, pp. 2245–2256, 2009. View at Publisher · View at Google Scholar · View at Scopus
  164. W. K. Chau, C. K. Ip, A. S. C. Mak, H. C. Lai, and A. S. T. Wong, “c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/β-catenin–ATP-binding cassette G2 signaling,” Oncogene, vol. 32, no. 22, pp. 2767–2781, 2013. View at Publisher · View at Google Scholar · View at Scopus
  165. X. Zeng, H. Zhao, Y. Li et al., “Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia,” Autophagy, vol. 11, no. 2, pp. 355–372, 2015. View at Publisher · View at Google Scholar · View at Scopus
  166. M. Xu, A. Gong, H. Yang et al., “Sonic hedgehog-glioma associated oncogene homolog 1 signaling enhances drug resistance in CD44+/Musashi-1+ gastric cancer stem cells,” Cancer Letters, vol. 369, no. 1, pp. 124–133, 2015. View at Publisher · View at Google Scholar · View at Scopus
  167. I. V. Ulasov, S. Nandi, M. Dey, A. M. Sonabend, and M. S. Lesniak, “Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133+ glioma stem cells to temozolomide therapy,” Molecular Medicine, vol. 17, no. 1-2, pp. 103–112, 2011. View at Publisher · View at Google Scholar · View at Scopus
  168. R. D. Meng, C. C. Shelton, Y. M. Li et al., “γ-Secretase inhibitors abrogate oxaliplatin-induced activation of the Notch-1 signaling pathway in colon cancer cells resulting in enhanced chemosensitivity,” Cancer Research, vol. 69, no. 2, pp. 573–582, 2009. View at Publisher · View at Google Scholar · View at Scopus
  169. S. M. McAuliffe, S. L. Morgan, G. A. Wyant et al., “Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 43, pp. E2939–E2948, 2012. View at Publisher · View at Google Scholar · View at Scopus
  170. Y. P. Liu, C. J. Yang, M. S. Huang et al., “Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating Notch signaling,” Cancer Research, vol. 73, no. 1, pp. 406–416, 2013. View at Publisher · View at Google Scholar · View at Scopus
  171. S. Alonso, R. J. Jones, and G. Ghiaur, “Retinoic acid, CYP26, and drug resistance in the stem cell niche,” Experimental Hematology, vol. 54, pp. 17–25, 2017. View at Publisher · View at Google Scholar · View at Scopus
  172. M. Krause, A. Dubrovska, A. Linge, and M. Baumann, “Cancer stem cells: radioresistance, prediction of radiotherapy outcome and specific targets for combined treatments,” Advanced Drug Delivery Reviews, vol. 109, pp. 63–73, 2017. View at Publisher · View at Google Scholar · View at Scopus
  173. R. Olson and C. Albright, “Recent progress in the medicinal chemistry of γ-secretase inhibitors,” Current Topics in Medicinal Chemistry, vol. 8, no. 1, pp. 17–33, 2008. View at Publisher · View at Google Scholar · View at Scopus
  174. S. Richter, P. L. Bedard, E. X. Chen et al., “A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575),” Investigational New Drugs, vol. 32, no. 2, pp. 243–249, 2014. View at Publisher · View at Google Scholar · View at Scopus
  175. P. A. Beachy, S. G. Hymowitz, R. A. Lazarus, D. J. Leahy, and C. Siebold, “Interactions between Hedgehog proteins and their binding partners come into view,” Genes & Development, vol. 24, no. 18, pp. 2001–2012, 2010. View at Publisher · View at Google Scholar · View at Scopus
  176. L. Dirix, “Discovery and exploitation of novel targets by approved drugs,” Journal of Clinical Oncology, vol. 32, no. 8, pp. 720-721, 2014. View at Publisher · View at Google Scholar · View at Scopus
  177. A. Sekulic, M. R. Migden, A. E. Oro et al., “Efficacy and safety of vismodegib in advanced basal-cell carcinoma,” The New England Journal of Medicine, vol. 366, no. 23, pp. 2171–2179, 2012. View at Publisher · View at Google Scholar · View at Scopus
  178. X. Li, V. Placencio, J. M. Iturregui et al., “Prostate tumor progression is mediated by a paracrine TGF-β/Wnt3a signaling axis,” Oncogene, vol. 27, no. 56, pp. 7118–7130, 2008. View at Publisher · View at Google Scholar · View at Scopus
  179. M. Kahn, “Can we safely target the WNT pathway?” Nature Reviews Drug Discovery, vol. 13, no. 7, pp. 513–532, 2014. View at Publisher · View at Google Scholar · View at Scopus
  180. D. C. Smith, L. S. Rosen, R. Chugh et al., “First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors,” Journal of Clinical Oncology, vol. 31, 15 Supplement, p. 2540, 2013. View at Google Scholar
  181. U.S. National Library of Medicine, “ClinicalTrials.Gov,” 2014, http://clinicaltrials.gov/show/NCT01345201.
  182. A. Jimeno, M. S. Gordon, R. Chugh et al., “A first-in-human phase 1 study of anticancer stem cell agent OMP-54F28 (FZD8-Fc), decoy receptor for WNT ligands, in patients with advanced solid tumors,” Journal of Clinical Oncology, vol. 32, 15 Supplement, p. 2505, 2014. View at Google Scholar
  183. D. Friedmann-Morvinski and I. M. Verma, “Dedifferentiation and reprogramming: origins of cancer stem cells,” EMBO Reports, vol. 15, no. 3, pp. 244–253, 2014. View at Publisher · View at Google Scholar · View at Scopus
  184. B. Du and J. Shim, “Targeting epithelial–mesenchymal transition (EMT) to overcome drug resistance in cancer,” Molecules, vol. 21, no. 8, 2016. View at Publisher · View at Google Scholar · View at Scopus
  185. R. Malek, H. Wang, K. Taparra, and P. T. Tran, “Therapeutic targeting of epithelial plasticity programs: focus on the epithelial-mesenchymal transition,” Cells, Tissues, Organs, vol. 203, no. 2, pp. 114–127, 2017. View at Publisher · View at Google Scholar · View at Scopus
  186. S. Knoll, S. Emmrich, and B. M. Putzer, “The E2F1-miRNA cancer progression network,” Advances in Experimental Medicine and Biology, vol. 774, pp. 135–147, 2013. View at Publisher · View at Google Scholar · View at Scopus
  187. A. A. Dar, S. Majid, D. de Semir, M. Nosrati, V. Bezrookove, and M. Kashani-Sabet, “miRNA-205 suppresses melanoma cell proliferation and induces senescence via regulation of E2F1 protein,” Journal of Biological Chemistry, vol. 286, no. 19, pp. 16606–16614, 2011. View at Publisher · View at Google Scholar · View at Scopus
  188. V. Alla, B. S. Kowtharapu, D. Engelmann et al., “E2F1 confers anticancer drug resistance by targeting ABC transporter family members and Bcl-2 via the p73/DNp73-miR-205 circuitry,” Cell Cycle, vol. 11, no. 16, pp. 3067–3078, 2012. View at Publisher · View at Google Scholar · View at Scopus
  189. P. A. Gregory, A. G. Bert, E. L. Paterson et al., “The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1,” Nature Cell Biology, vol. 10, no. 5, pp. 593–601, 2008. View at Publisher · View at Google Scholar · View at Scopus
  190. C. Palena and D. H. Hamilton, “Immune targeting of tumor epithelial–mesenchymal transition via brachyury-based vaccines,” Advances in Cancer Research, vol. 128, pp. 69–93, 2015. View at Publisher · View at Google Scholar · View at Scopus
  191. J. Godlewski, M. O. Nowicki, A. Bronisz et al., “Targeting of the Bmi-1 oncogene/stem cell renewal factor by microRNA-128 inhibits glioma proliferation and self-renewal,” Cancer Research, vol. 68, no. 22, pp. 9125–9130, 2008. View at Publisher · View at Google Scholar · View at Scopus
  192. C. A. O'Brien, A. Kreso, P. Ryan et al., “ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21,” Cancer Cell, vol. 21, no. 6, pp. 777–792, 2012. View at Publisher · View at Google Scholar · View at Scopus
  193. J. Deng, M. Yang, R. Jiang, N. An, X. Wang, and B. Liu, “Long non-coding RNA HOTAIR regulates the proliferation, self-renewal capacity, tumor formation and migration of the cancer stem-like cell (CSC) subpopulation enriched from breast cancer cells,” PLoS One, vol. 12, no. 1, article e0170860, 2017. View at Publisher · View at Google Scholar · View at Scopus
  194. S. J. Song, L. Poliseno, M. S. Song et al., “MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling,” Cell, vol. 154, no. 2, pp. 311–324, 2013. View at Publisher · View at Google Scholar · View at Scopus
  195. F. Yu, H. Yao, P. Zhu et al., “let-7 regulates self renewal and tumorigenicity of breast cancer cells,” Cell, vol. 131, no. 6, pp. 1109–1123, 2007. View at Publisher · View at Google Scholar · View at Scopus
  196. Y. Shimono, M. Zabala, R. W. Cho et al., “Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells,” Cell, vol. 138, no. 3, pp. 592–603, 2009. View at Publisher · View at Google Scholar · View at Scopus
  197. D. Iliopoulos, M. Lindahl-Allen, C. Polytarchou, H. A. Hirsch, P. N. Tsichlis, and K. Struhl, “Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells,” Molecular Cell, vol. 39, no. 5, pp. 761–772, 2010. View at Publisher · View at Google Scholar · View at Scopus
  198. D. Iliopoulos, A. Rotem, and K. Struhl, “Inhibition of miR-193a expression by Max and RXRα activates K-Ras and PLAU to mediate distinct aspects of cellular transformation,” Cancer Research, vol. 71, no. 15, pp. 5144–5153, 2011. View at Publisher · View at Google Scholar · View at Scopus
  199. N. Bitarte, E. Bandres, V. Boni et al., “MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells,” Stem Cells, vol. 29, no. 11, pp. 1661–1671, 2011. View at Publisher · View at Google Scholar · View at Scopus
  200. P. Bu, K. Y. Chen, J. H. Chen et al., “A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells,” Cell Stem Cell, vol. 12, no. 5, pp. 602–615, 2013. View at Publisher · View at Google Scholar · View at Scopus
  201. C. Liu, K. Kelnar, B. Liu et al., “The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44,” Nature Medicine, vol. 17, no. 2, pp. 211–215, 2011. View at Publisher · View at Google Scholar · View at Scopus
  202. Y. Y. Wu, Y. L. Chen, Y. C. Jao, I. S. Hsieh, K. C. Chang, and T. M. Hong, “miR-320 regulates tumor angiogenesis driven by vascular endothelial cells in oral cancer by silencing neuropilin 1,” Angiogenesis, vol. 17, no. 1, pp. 247–260, 2014. View at Publisher · View at Google Scholar · View at Scopus
  203. C. Visus, Y. Wang, A. Lozano-Leon et al., “Targeting ALDHbright human carcinoma–initiating cells with ALDH1A1-specific CD8+ T cells,” Clinical Cancer Research, vol. 17, no. 19, pp. 6174–6184, 2011. View at Publisher · View at Google Scholar · View at Scopus
  204. L. Jin, K. J. Hope, Q. Zhai, F. Smadja-Joffe, and J. E. Dick, “Targeting of CD44 eradicates human acute myeloid leukemic stem cells,” Nature Medicine, vol. 12, no. 10, pp. 1167–1174, 2006. View at Publisher · View at Google Scholar · View at Scopus
  205. Y. Guo, J. Ma, J. Wang et al., “Inhibition of human melanoma growth and metastasis in vivo by anti-CD44 monoclonal antibody,” Cancer Research, vol. 54, no. 6, pp. 1561–1565, 1994. View at Google Scholar
  206. S. K. Swaminathan, M. R. Olin, C. L. Forster, K. S. S. Cruz, J. Panyam, and J. R. Ohlfest, “Identification of a novel monoclonal antibody recognizing CD133,” Journal of Immunological Methods, vol. 361, no. 1-2, pp. 110–115, 2010. View at Publisher · View at Google Scholar · View at Scopus
  207. F. Ferrari, S. Bellone, J. Black et al., “Solitomab, an EpCAM/CD3 bispecific antibody construct (BiTE®), is highly active against primary uterine and ovarian carcinosarcoma cell lines in vitro,” Journal of Experimental & Clinical Cancer Research, vol. 34, no. 1, p. 123, 2015. View at Publisher · View at Google Scholar · View at Scopus
  208. M. Sen, D. M. Wankowski, N. K. Garlie et al., “Use of anti-CD3 × anti-HER2/neu bispecific antibody for redirecting cytotoxicity of activated T cells toward HER2/neu+ tumors,” Journal of Hematotherapy & Stem Cell Research, vol. 10, no. 2, pp. 247–260, 2001. View at Publisher · View at Google Scholar · View at Scopus
  209. F. Dammeijer, L. A. Lievense, M. E. Kaijen-Lambers et al., “Depletion of tumor-associated macrophages with a CSF-1R kinase inhibitor enhances antitumor immunity and survival induced by DC immunotherapy,” Cancer Immunology Research, vol. 5, no. 7, pp. 535–546, 2017. View at Publisher · View at Google Scholar · View at Scopus
  210. D. R. Yang, X. F. Ding, J. Luo et al., “Increased chemosensitivity via targeting testicular nuclear receptor 4 (TR4)-Oct4-interleukin 1 receptor antagonist (IL1Ra) axis in prostate cancer CD133+ stem/progenitor cells to battle prostate cancer,” Journal of Biological Chemistry, vol. 288, no. 23, pp. 16476–16483, 2013. View at Publisher · View at Google Scholar · View at Scopus
  211. S. Y. Kim, J. W. Kang, X. Song et al., “Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells,” Cellular Signalling, vol. 25, no. 4, pp. 961–969, 2013. View at Publisher · View at Google Scholar · View at Scopus
  212. C. Ginestier, S. Liu, M. E. Diebel et al., “CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts,” The Journal of Clinical Investigation, vol. 120, no. 2, pp. 485–497, 2010. View at Publisher · View at Google Scholar · View at Scopus
  213. S. L. Topalian, F. S. Hodi, J. R. Brahmer et al., “Safety, activity, and immune correlates of anti–PD-1 antibody in cancer,” The New England Journal of Medicine, vol. 366, no. 26, pp. 2443–2454, 2012. View at Publisher · View at Google Scholar · View at Scopus
  214. S. M. Ansell, A. M. Lesokhin, I. Borrello et al., “PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma,” The New England Journal of Medicine, vol. 372, no. 4, pp. 311–319, 2015. View at Publisher · View at Google Scholar · View at Scopus
  215. Y. Hu and L. Fu, “Targeting cancer stem cells: a new therapy to cure cancer patients,” American Journal of Cancer Research, vol. 2, no. 3, pp. 340–356, 2012. View at Google Scholar
  216. S. R. Pine, B. Marshall, and L. Varticovski, “Lung cancer stem cells,” Disease Markers, vol. 24, no. 4-5, pp. 257–266, 2008. View at Publisher · View at Google Scholar
  217. T. Chanmee, P. Ontong, K. Kimata, and N. Itano, “Key roles of hyaluronan and its CD44 receptor in the stemness and survival of cancer stem cells,” Frontiers in Oncology, vol. 5, 2015. View at Publisher · View at Google Scholar · View at Scopus
  218. Y. J. Kim, E. L. Siegler, N. Siriwon, and P. Wang, “Therapeutic strategies for targeting cancer stem cells,” Journal of Cancer Metastasis and Treatment, vol. 2, no. 7, pp. 233–242, 2016. View at Publisher · View at Google Scholar
  219. D. L. Dragu, L. G. Necula, C. Bleotu, C. C. Diaconu, and M. Chivu-Economescu, “Therapies targeting cancer stem cells: current trends and future challenges,” World Journal of Stem Cells, vol. 7, no. 9, pp. 1185–1201, 2015. View at Google Scholar
  220. L. Han, S. Shi, T. Gong, Z. Zhang, and X. Sun, “Cancer stem cells: therapeutic implications and perspectives in cancer therapy,” Acta Pharmaceutica Sinica B, vol. 3, no. 2, pp. 65–75, 2013. View at Publisher · View at Google Scholar
  221. C. Zhang, C. Li, F. He, Y. Cai, and H. Yang, “Identification of CD44+CD24+ gastric cancer stem cells,” Journal of Cancer Research and Clinical Oncology, vol. 137, no. 11, pp. 1679–1686, 2011. View at Publisher · View at Google Scholar · View at Scopus
  222. S. Takaishi, T. Okumura, S. Tu et al., “Identification of gastric cancer stem cells using the cell surface marker CD44,” Stem Cells, vol. 27, no. 5, pp. 1006–1020, 2009. View at Publisher · View at Google Scholar · View at Scopus
  223. A. T. Collins, P. A. Berry, C. Hyde, M. J. Stower, and N. J. Maitland, “Prospective identification of tumorigenic prostate cancer stem cells,” Cancer Research, vol. 65, no. 23, pp. 10946–10951, 2005. View at Publisher · View at Google Scholar · View at Scopus
  224. M. J. Son, K. Woolard, D. H. Nam, J. Lee, and H. A. Fine, “SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma,” Cell Stem Cell, vol. 4, no. 5, pp. 440–452, 2009. View at Publisher · View at Google Scholar · View at Scopus
  225. M. E. Prince, R. Sivanandan, A. Kaczorowski et al., “Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 3, pp. 973–978, 2007. View at Publisher · View at Google Scholar · View at Scopus
  226. S. K. Singh, C. Hawkins, I. D. Clarke et al., “Identification of human brain tumour initiating cells,” Nature, vol. 432, no. 7015, pp. 396–401, 2004. View at Publisher · View at Google Scholar · View at Scopus