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Cancer Stem Cells: Acquisition, Characteristics, Therapeutic Implications, Targeting Strategies and Future Prospects

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Abstract

Since last two decades, the major cancer research has focused on understanding the characteristic properties and mechanism of formation of Cancer stem cells (CSCs), due to their ability to initiate tumor growth, self-renewal property and multi-drug resistance. The discovery of the mechanism of acquisition of stem-like properties by carcinoma cells via epithelial-mesenchymal transition (EMT) has paved a way towards a deeper understanding of CSCs and presented a possible avenue for the development of therapeutic strategies. In spite of years of research, various challenges, such as identification of CSC subpopulation, lack of appropriate experimental models, targeting cancer cells and CSCs specifically without harming normal cells, are being faced while dealing with CSCs. Here, we discuss the biology and characteristics of CSCs, mode of acquisition of stemness (via EMT) and development of multi-drug resistance, the role of tumor niche, the process of dissemination and metastasis, therapeutic implications of CSCs and necessity of targeting them. We emphasise various strategies being developed to specifically target CSCs, including those targeting biomarkers, key pathways and microenvironment. Finally, we focus on the challenges that need to be subdued and propose the aspects that need to be addressed in future studies in order to broaden the understanding of CSCs and develop novel strategies to eradicate them in clinical applications.

Cancer Stem Cells(CSCs) have gained much attention in the last few decades due to their ability to initiate tumor growth and, self-renewal property and multi-drug resistance. Here, we represent the CSC model of cancer, Characteristics of CSCs, acquisition of stemness and metastatic dissemination of cancer, Therapeutic implications of CSCs and Various strategies being employed to target and eradicate CSCs.

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References

  1. Anon, (2017). [online] Available at: http://seer.Cancer.Gov/index.Html. NCI, 2011. [Accessed 14 Dec. 2017]

  2. Matsuo, K., Fullerton, M. E., & Moeini, A. (2016). Treatment patterns and survival outcomes in patients with cervical cancer complicated by complete uterine prolapse: A systematic review of literature. International Urogynecology Journal, 27, 29–38.

    Article  PubMed  Google Scholar 

  3. Simoes, M. C., Sousa, J. J., & Pais, A. A. (2015). Skin cancer and new treatment perspectives: A review. Cancer Letters, 357, 8–42.

    Article  CAS  PubMed  Google Scholar 

  4. Ali Mansoori, G., Mohazzabi, P., McCormack, P., & Jabbari, S. (2007). ‘Nanotechnology in cancer prevention, detection and treatment: bright future lies ahead’, World Review of Science, Technology and Sustainable Development, Vol. 4, Nos., 2(/3), 226–257.

    Google Scholar 

  5. Singh, R., & Lillard, J. W., Jr. (2009 June). Nanoparticle-based targeted drug delivery. Experimental and Molecular Pathology, 86(3), 215–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hong, M.; Tan, H.Y.; Li, S.; Cheung, F.; Wang, N.; Nagamatsu,T.; Feng, Y.; ‘Cancer Stem Cells: The Potential Targets of Chinese Medicines and Their Active Compounds’, International Journal of Molecular Sciences 2016, 17, 893.

  7. Hanahan, D., & Weinberg, R. A. (2000). The Hallmarks of Cancer. Cell, 100(1), 57–70.

    Article  CAS  Google Scholar 

  8. Gottesman, M. M. (2002). Mechanisms of cancer drug resistance. Annual Review of Medicine, 53(1), 615–627.

    Article  CAS  PubMed  Google Scholar 

  9. Furth, J., Kahn, M. and Breedis, C. (1937). The Transmission of Leukemia of Mice with a Single Cell. Cancer Research. Available at: http://cancerres.aacrjournals.org/content/31/2/276\. Access 17 September 2018

  10. Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine, 3, 730–737.

    Article  CAS  PubMed  Google Scholar 

  11. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., & Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 3983–3988. https://doi.org/10.1073/pnas.0530291100.

  12. Alamgeer M, Peacock CD, Matsui W, Ganju V, Watkins DN. Cancer stem cells in lung cancer: Evidence and controversies. Respirology 2013; 18: 757-764 [PMID: 23586700, https://doi.org/10.1111/resp.12094]

  13. Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. The Journal of Clinical Investigation 2013; 123: 1911-1918 [PMID: 23635789, https://doi.org/10.1172/JCI66024]

  14. Han J, Fujisawa T, Husain SR, Puri RK. Identification and characterization of cancer stem cells in human head and neck squamous cell carcinoma. BMC Cancer 2014; 14: 173 [PMID: 24612587 https://doi.org/10.1186/1471-2407-14-173]

  15. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identi cation of pancreatic cancer stem cells. Cancer Research 2007; 67: 1030-1037 [PMID: 17283135 https://doi.org/10.1158/0008-5472.CAN-06-2030]

  16. Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R, Gordon SA, Shimada Y, Wang TC. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 2009; 27: 1006-1020 [PMID: 19415765 https://doi.org/10.1002/stem.30]

  17. Vaiopoulos AG, Kostakis ID, Koutsilieris M, Papavassiliou AG. Colorectal cancer stem cells. Stem Cells 2012; 30: 363-371 [PMID: 22232074 https://doi.org/10.1002/stem.1031]

  18. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB. Identification of a cancer stem cell in human brain tumors. Cancer Research 2003; 63: 5821-5828 [PMID: 14522905]

  19. Yang, Y. M., & Chang, J. W. (2008). Bladder cancer initiating cells (BCICs) are among EMA(-)CD44v6(+) subset: novel methods for isolating undetermined cancer stem (initiating) cells. Cancer Investigation, 26, 725–733.

    Article  CAS  PubMed  Google Scholar 

  20. Schatton, T., Murphy, G. F., Frank, N. Y., et al. (2008). Identification of cells initiating human melanomas. Nature, 451, 345–U311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, Taniguchi H. Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 2006; 44: 240-251 [PMID: 16799977 https://doi.org/10.1002/hep.21227]

  22. Polyak, K., & Weinberg, R. A. (2009). Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nature Reviews. Cancer, 9, 265–273.

    Article  CAS  PubMed  Google Scholar 

  23. Jayachandran, A., Dhungel, B., & Steel, J. C. (2016). Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma. Journal of Hematology & Oncology, 9, 74.

    Article  CAS  Google Scholar 

  24. Nieto, M. A. (2013). Epithelial plasticity: a common theme in embryonic and cancer cells. Science., 342, 1234850.

    Article  CAS  PubMed  Google Scholar 

  25. Thiery, J. P., Acloque, H., Huang, R. Y., & Nieto, M. A. (2009). Epithelial-mesenchymal transitions in development and disease. Cell., 139, 871–890.

    Article  CAS  PubMed  Google Scholar 

  26. Morel, A. P., Lièvre, M., Thomas, C., Hinkal, G., Ansieau, S., & Puisieux, A. (2008). Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One, 3, e2888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bharti, R., Dey, G., & Mandal, M. (2016). Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: A snapshot of IL-6 mediated involvement. Cancer Letters, 375, 51–61.

    Article  CAS  PubMed  Google Scholar 

  28. Sun Y, Mao X, Fan C, Liu C, Guo A, Guan S, Jin Q, Li B, Yao F, Jin F. CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis. Tumor Biology 2014; 35: 7765-7773 [PMID: 24810923 https://doi.org/10.1007/s13277-014-1816-1]

  29. Puisieux, A., Brabletz, T., & Caramel, J. (2014). Oncogenic roles of EMT-inducing transcription factors. Nature Cell Biology, 16, 488–494.

    Article  CAS  PubMed  Google Scholar 

  30. Doherty, M. R., Smigiel, J. M., Junk, D. J., et al. (2016). Cancer stem cell plasticity drives therapeutic resistance. Cancers (Basel), 8, pii: E8.

    Article  CAS  Google Scholar 

  31. Ye, X., et al. (2015). Distinct EMT programs control normal mammary stem cells and tumour-initiating cells. Nature, 525, 256–260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, W., Gao, Q., Han, S., Pan, F., & Fan, W. (2014). The CCL2/CCR2 axis enhances IL-6- induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling. Tumour Biology. https://doi.org/10.1007/s13277-014-2717-z.

  33. Spaderna, S., Schmalhofer, O., Hlubek, F., Jung, A., Kirchner, T., & Brabletz, T. (2007). Epithelial-mesenchymal and mesenchymal-epithelial transitions during cancer progression. Verhandlungen der Deutschen Gesellschaft für Pathologie, 91, 21–28.

    CAS  PubMed  Google Scholar 

  34. Nimmakayala, R., Batra, S., & Ponnusamy, M. (2019). Unraveling the journey of cancer stem cells from origin to metastasis. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1871(1), 50–63. https://doi.org/10.1016/j.bbcan.2018.10.006.

    Article  CAS  Google Scholar 

  35. Chen, L., Wang, A., Dong, B., Pu, K., Yuan, L., & Zhu, Y. (2012). A new prospect in cancer therapy: targeting cancer stem cells to eradicate cancer. Chinese Journal of Cancer, 31(12), 564–572.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Dragu, D. L., Necula, L. G., Bleotu, C., Diaconu, C. C., & Chivu Economescu, M. (2015). Therapies targeting cancer stem cells: Current trends and future challenges. World J Stem Cells, 7(9), 1185–1201. https://doi.org/10.4252/wjsc.v7.i9.1185.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Jordan, C. T., Guzman, M. L., & Noble, M. (2006). Cancer stem cells. The New England Journal of Medicine, 355, 1253–1261.

    Article  CAS  PubMed  Google Scholar 

  38. Gilbert, C. A., & Ross, A. H. (2009). Cancer stem cells: cell culture, markers, and targets for new therapies. Journal of Cellular Biochemistry, 108, 1031–1038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Deonarain, M. P., Kousparou, C. A., & Epenetos, A. A. (2009). Antibodies targeting cancer stem cells: a new paradigm in immunotherapy? MAbs, 1, 12–25.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Tang, C., Ang, B. T., & Pervaiz, S. (2007). Cancer stem cell: target for anti-cancer therapy. The FASEB Journal, 21, 3777–3785.

    Article  CAS  PubMed  Google Scholar 

  41. Ishibashi, T.; Yokota, T.; Tanaka, H.; Ichii, M.; Sudo, T.; Satoh, Y.; Doi, Y.; Ueda, T.; Tanimura, A.; Hamanaka, Y.; et al. ESAM is a novel human hematopoietic stem cell marker associated with a subset of human leukemias. Exp. Hematol. 2016, 44, 269.e1–281.e1.

  42. Plesa, A., Elhamri, M., Clapisson, G., Mattei, E., Gazzo, S., Hequet, O., Tigaud, I., Michallet, M., Dumontet, C., & Thomas, X. (2015). Higher percentage of CD34+ CD38 ́ cells detected by multiparameter flow cytometry from leukapheresis products predicts unsustained complete remission in acute myeloid leukemia. Leukemia & Lymphoma, 56, 622–629.

    Article  CAS  Google Scholar 

  43. Lu, M., Zhou, L., Zheng, X., Quan, Y., Wang, X., Zhou, X., & Ren, J. (2015). A novel molecular marker of breast cancer stem cells identified by cell-selex method. Cancer Biomarkers, 15, 163–170.

    Article  CAS  PubMed  Google Scholar 

  44. Isfoss, B. L., Busch, C., Hermelin, H., Vermedal, A. T., Kile, M., Braathen, G. J., Majak, B., & Berner, A. (2014). Stem cell marker-positive stellate cells and mast cells are reduced in benign-appearing bladder tissue in patients with urothelial carcinoma. Virchows Archiv, 464, 473–488.

    Article  CAS  PubMed  Google Scholar 

  45. Singh, S. K., Hawkins, C., Clarke, I. D., Squire, J. A., Bayani, J., Hide, T., et al. (2004). Identification of human brain tumor initiating cells. Nature, 432, 396–401.

    Article  CAS  PubMed  Google Scholar 

  46. Wang, B. B., Li, Z. J., Zhang, F. F., Hou, H. T., Yu, J. K., & Li, F. (2016). Clinical significance of stem cell marker CD133 expression in colorectal cancer. Histology and Histopathology, 31, 299–306.

    CAS  PubMed  Google Scholar 

  47. Liu, D., Sun, J., Zhu, J., Zhou, H., Zhang, X., & Zhang, Y. (2014). Expression and clinical significance of colorectal cancer stem cell marker EPCAM/CD44 in colorectal cancer. Oncology Letters, 7, 1544–1548.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Sulpice, L., Rayar, M., Turlin, B., Boucher, E., Bellaud, P., Desille, M., Meunier, B., Clement, B., Boudjema, K., & Coulouarn, C. (2014). Epithelial cell adhesion molecule is a prognosis marker for intrahepatic cholangiocarcinoma. The Journal of Surgical Research, 192, 117–123.

    Article  CAS  PubMed  Google Scholar 

  49. Kim, S. W., Yang, H. G., Kang, M. C., Lee, S., Namkoong, H., Lee, S. W., & Sung, Y. C. (2014). KIAA1114, a full-length protein encoded by the trophinin gene, is a novel surface marker for isolating tumor-initiating cells of multiple hepatocellular carcinoma subtypes. Oncotarget, 5, 1226–1240.

    PubMed  PubMed Central  Google Scholar 

  50. Wakamatsu, Y., Sakamoto, N., Oo, H. Z., et al. (2012). Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathology International, 62, 112–119.

    Article  PubMed  Google Scholar 

  51. Trepant, A. L., Bouchart, C., Rorive, S., Sauvage, S., Decaestecker, C., Demetter, P., & Salmon, I. (2015). Identification of OLIG2 as the most specific glioblastoma stem cell marker starting from comparative analysis of data from similar DNA chip microarray platforms. Tumor Biology, 36, 1943–1953.

    Article  CAS  PubMed  Google Scholar 

  52. Richichi, C., Brescia, P., Alberizzi, V., Fornasari, L., & Pelicci, G. (2013). Marker-independent method for isolating slow-dividing cancer stem cells in human glioblastoma. Neoplasia, 15, 840–847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Linge, A., Lock, S., Gudziol, V., Nowak, A., Lohaus, F., von Neubeck, C., Jutz, M., Abdollahi, A., Debus, J., Tinhofer, I., et al. (2016). Low cancer stem cell marker expression and low hypoxia identify good prognosis subgroups in HPV(-) HNSCC after postoperative radiochemotherapy: A multicenter study of the DKTK-ROG. Clinical Cancer Research.

  54. Cheung, P. F., Cheung, T. T., Yip, C. W., Ng, L. W., Fung, S. W., Lo, C. M., Fan, S. T., & Cheung, S. T. (2016). Hepatic cancer stem cell marker granulin-epithelin precursor and -catenin expression associate with recurrence in hepatocellular carcinoma. Oncotarget.

  55. Vilchez, V., Turcios, L., Zaytseva, Y., Stewart, R., Lee, E. Y., Maynard, E., Shah, M. B., Daily, M. F., Tzeng, C. D., Davenport, D., et al. (2016). Cancer stem cell marker expression alone and in combination with microvascular invasion predicts poor prognosis in patients undergoing transplantation for hepatocellular carcinoma. American Journal of Surgery.

  56. Du, Y., Ma, C., Wang, Z., Liu, Z., Liu, H., & Wang, T. (2013). Nanog, a novel prognostic marker for lung cancer. Surgical Oncology, 22, 224–229.

    Article  PubMed  Google Scholar 

  57. Robillard, N., Jego, G., Pellat-Deceunynck, C., Pineau, D., Puthier, D., Mellerin, M. P., Barille, S., Rapp, M. J., & Harousseau, J. L. (1998). Amiot, M.; et al. CD28, a marker associated with tumoral expansion in multiple myeloma. Clin. Cancer Research, 4, 1521–1526.

    CAS  Google Scholar 

  58. Fang, D., Nguyen, T. K., Leishear, K., Finko, R., Kulp, A. N., Hotz, S., et al. (2005). A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Research, 65, 9328–9337.

    Article  CAS  PubMed  Google Scholar 

  59. Liu, W., Selcuk, F., Rutgen, B. C., Moulay, M., Willenbrock, S., Hammer, S. E., Sterenczak, K. A., Junghanss, C., & Hewicker-Trautwein, M. (2015). Nolte, I.; et al. Evaluation of stem cell marker expression in canine B-cell lymphoma cell lines, B-cell lymphoma-generated spheres and primary samples. Anticancer Research, 35, 2805–2816.

    CAS  PubMed  Google Scholar 

  60. Hardingham, J. E., Kotasek, D., Sage, R. E., Gooley, L. T., Mi, J. X., Dobrovic, A., Norman, J. E., Bolton, A. E., & Dale, B. M. (1995). Significance of molecular marker-positive cells after autologous peripheral-blood stem-cell transplantation for non-Hodgkin’s lymphoma. Journal of Clinical Oncology, 13, 1073–1079.

  61. Yang, C. H., Wang, H. L., Lin, Y. S., Kumar, K. P., Lin, H. C., Chang, C. J., Lu, C. C., Huang, T. T., & Martel, J. (2014). Ojcius, D.M.; et al. Identification of CD24 as a cancer stem cell marker in human nasopharyngeal carcinoma. PLoS One, e99412, 9.

    Google Scholar 

  62. Zheng, D., Liao, S., Zhu, G., Luo, G., Xiao, S., He, J., Pei, Z., Li, G., & Zhou, Y. (2016). CD38 is a putative functional marker for side population cells in human nasopharyngeal carcinoma cell lines. Molecular Carcinogenesis, 55, 300–311.

    Article  CAS  PubMed  Google Scholar 

  63. Shabahang, M., Buras, R. R., Davoodi, F., Schumaker, L. M., Nauta, R. J., & Evans, S. R. (1993). 1,25-Dihydroxyvitamin D3 receptor as a marker of human colon carcinoma cell line differentiation and growth inhibition. Cancer Research, 53, 3712–3718.

    CAS  PubMed  Google Scholar 

  64. Simeone, D. M. (2008). Pancreatic cancer stem cells: implications for the treatment of pancreatic cancer. Clinical Cancer Research, 14, 5646–5648.

    Article  CAS  PubMed  Google Scholar 

  65. Salnikov, A. V., Gladkich, J., Moldenhauer, G., Volm, M., Mattern, J., & Herr, I. (2010). CD133 is indicative for a resistance phenotype but does not represent a prognostic marker for survival of non-small cell lung cancer patients. International Journal of Cancer, 126, 950–958.

    CAS  PubMed  Google Scholar 

  66. Guzman, M. L., & Jordan, C. T. (2004). Considerations for targeting malignant stem cells in leukemia. Cancer Control, 11, 97–104.

    Article  PubMed  Google Scholar 

  67. Pastrana E, Silva-Vargas V, Doetsch F. Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 2011; 8: 486-498 [PMID: 21549325 https://doi.org/10.1016/j.stem.2011.04.007]

  68. Ho, M. M., Ng, A. V., Lam, S., & Hung, J. Y. (2007). Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Research, 67, 4827–4833.

    Article  CAS  PubMed  Google Scholar 

  69. Matsui, W., Wang, Q., Barber, J. P., Brennan, S., Smith, B. D., Borrello, I., et al. (2008). Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Research, 6, 190–197.

    Article  CAS  Google Scholar 

  70. Kruger, J. A., Kaplan, C. D., Luo, Y., Zhou, H., Markowitz, D., Xiang, R., et al. (2006). Characterization of stem cell-like cancer cells in immune-competent mice. Blood, 108, 3906–3912.

    Article  CAS  PubMed  Google Scholar 

  71. Deeley, R. G., Westlake, C., & Cole, S. P. C. (2006). Transmembrane transport of Endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiological Reviews, 86, 849–899.

    Article  CAS  PubMed  Google Scholar 

  72. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. The Journal of Experimental Medicine 1996; 183: 1797-1806 [PMID: 8666936]

  73. Scharenberg CW, Harkey MA, Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood 2002; 99: 507-512 [PMID: 11781231]

  74. Christgen M, Ballmaier M, Bruchhardt H, von Wasielewski R, Kreipe H, Lehmann U. Identi cation of a distinct side population of cancer cells in the Cal-51 human breast carcinoma cell line. Molecular and Cellular Biochemistry 2007; 306: 201-212 [PMID: 17660947 https://doi.org/10.1007/s11010-007-9570-y]

  75. Chow EK, Fan LL, Chen X, Bishop JM. Oncogene-specific formation of chemoresistant murine hepatic cancer stem cells. Hepatology 2012; 56: 1331-1341 [PMID: 22505225 https://doi.org/10.1002/hep.25776]

  76. Ingham, P. W., & McMahon, A. P. (2001). Hedgehog signaling in animal development: paradigms and principles. Genes & Development, 15, 3059–3087.

    Article  CAS  Google Scholar 

  77. Zhang, Y., & Kalderon, D. (2001). Hedgehog acts as a somatic stem cell factor in the Drosophila ovary. Nature., 410, 599–604.

    Article  CAS  PubMed  Google Scholar 

  78. Artavanis-Tsakonas, S., Rand, M. D., & Lake, R. J. (1999). Notch signaling: cell fate control and signal integration in development. Science, 284, 770–776.

    Article  CAS  Google Scholar 

  79. Dontu, G., Jackson, K. W., McNicholas, E., Kawamura, M. J., Abdallah, W. M., & Wicha, M. S. (2004). Role of Notch signaling in cell-fate determi- nation of human mammary stem/progenitor cells. Breast Cancer Research, 6, R605–R615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Farnie, G., & Clarke, R. B. (2007). Mammary stem cells and breast cancer— role of Notch signalling. Stem Cell Reviews, 3, 169–175.

    Article  CAS  PubMed  Google Scholar 

  81. Ahmed, I., Roy, B., Chandrakesan, P., Venugopal, A., Xia, L., Jensen, R., Anant, S., & Umar, S. (2013). Evidence of functional cross talk between the notch and nf-kappab pathways in nonneoplastic hyperproliferating colonic epithelium. American Journal of Physiology. Gastrointestinal and Liver Physiology, 304(4), G356–G370.

    Article  CAS  PubMed  Google Scholar 

  82. Hambardzumyan, D., Becher, O. J., & Holland, E. C. (2008). Cancer stem cells and survival pathways. Cell Cycle, 7, 1371–1378.

    Article  CAS  PubMed  Google Scholar 

  83. Malanchi, I., Peinado, H., Kassen, D., Hussenet, T., Metzger, D., Chambon, P., et al. (2008). Cutaneous cancer stem cell maintenance is dependent on [bgr]-catenin signalling. Nature, 452, 650–653.

    Article  CAS  PubMed  Google Scholar 

  84. Zeng, Y. A., & Nusse, R. (2010). Wnt proteins are self-renewal factors for mammary stem cells and promote their long-term expansion in culture. Cell Stem Cell, 6, 568–577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., et al. (2003). A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature., 423, 409–414.

    Article  CAS  PubMed  Google Scholar 

  86. Reya, T., & Clevers, H. (2005). Wnt signalling in stem cells and cancer. Nature, 434, 843–850.

    Article  CAS  PubMed  Google Scholar 

  87. Jamieson, C. H., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., et al. (2004). Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. The New England Journal of Medicine, 351, 657–667.

    Article  CAS  PubMed  Google Scholar 

  88. Jemal, A., Siegel, R., Xu, J., & Ward, E. (2010). Cancer Statistics, 2010. CA: a Cancer Journal for Clinicians, 60(5), 277–300.

    Google Scholar 

  89. Keshtgar, M., Davidson, T., Pigott, K., Falzon, M., & Jones, A. (2010). Current status and advances in management of early breast cancer. International Journal of Surgery, 8(3), 199–202.

    Article  CAS  PubMed  Google Scholar 

  90. McDermott, S. P., & Wicha, M. S. (2010). Targeting breast cancer stem cells. Molecular Oncology, 4(5), 404–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Therasse, P., Arbuck, S. G., Eisenhauer, E. A., et al. (2000). New Guidelines to Evaluate the Response to Treatment in Solid Tumors. Journal of the National Cancer Institute, 92(3), 205–216.

    Article  CAS  PubMed  Google Scholar 

  92. Savona, M. R., Malcovati, L., Komrokji, R., Tiu, R. V., Mughal, T. I., Orazi, A., Kiladjian, J. J., Padron, E., Solary, E., Tibes, R., Itzykson, R., Cazzola, M., Mesa, R., Maciejewski, J., Fenaux, P., Garcia-Manero, G., Gerds, A., Sanz, G., Niemeyer, C. M., Cervantes, F., Germing, U., & Cross, N. C. (2015). List AF and Group MMIW: An international consortium proposal of uniform response criteria for myelodysplastic/ myeloproliferative neoplasms (mds/mpn) in adults. Blood, 125(12), 1857–1865.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhou, B. B., Zhang, H., Damelin, M., Geles, K. G., Grindley, J. C., & Dirks, P. B. (2009). Tumor-initiating cells: challenges and opportunities for anticancer drug discovery. Nature Reviews. Drug Discovery, 8(10), 806–823.

    Article  CAS  PubMed  Google Scholar 

  94. Colak, S., & Medema, J. P. (2014). Cancer stem cells – important players in tumor therapy resistance. The FEBS Journal, 281(21), 4779–4791.

    Article  CAS  PubMed  Google Scholar 

  95. Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N., & Struhl, K. (2009). Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemo- therapy to Block Tumor Growth and Prolong Remission. Cancer Research, 69(19), 7507–7511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shafee, N., Smith, C. R., Wei, S., et al. (2008). Cancer Stem Cells Contribute to Cisplatin Resistance in Brca1/p53-Mediated Mouse Mammary Tumors. Cancer Research, 68(9), 3243–3250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bao, S., Wu, Q., McLendon, R. E., et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage re- sponse. Nature, 444(7120), 756–760.

    Article  CAS  PubMed  Google Scholar 

  98. Tanei, T., Morimoto, K., Shimazu, K., et al. (2009). Association of Breast Cancer Stem Cells Identified by Aldehyde Dehydrogenase 1 Ex- pression with Resistance to Sequential Paclitaxel and Epirubicin- Based Chemotherapy for Breast Cancers. Clinical Cancer Research, 15(12), 4234–4241.

    Article  CAS  PubMed  Google Scholar 

  99. Yokoyama, Y., Sato, S., Fukushi, Y., Sakamoto, T., Futagami, M., & Saito, Y. (1999). Significance of multi-drug-resistant proteins in predicting chemotherapy response and prognosis in epithelial ovarian cancer. The Journal of Obstetrics and Gynaecology Research, 25(6), 387–394.

    Article  CAS  PubMed  Google Scholar 

  100. Crowder, S. W., Balikov, D. A., Hwang, Y. S., & Sung, H. J. (2014). Cancer stem cells under hypoxia as a chemoresistance factor in breast and brain. Curr Pathobiol Rep, 2(1), 33–40.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Gupta, P. B., Fillmore, C. M., Jiang, G., et al. (2011). Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells. Cell, 146(4), 633–644.

    Article  CAS  PubMed  Google Scholar 

  102. Grichnik, J. M. (2006). Genomic instability and tumor stem cells. The Journal of Investigative Dermatology, 126(6), 1214–1216.

    Article  CAS  PubMed  Google Scholar 

  103. Dallas, N. A., Xia, L., Fan, F., Gray, M. J., Gaur, P., van Buren, G., Samuel, S., Kim, M. P., Lim, S. J., & Ellis, L. M. (2009). Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I recep- tor inhibition. Cancer Research, 69, 1951–1957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Journal of the National Cancer Institute 2008; 100:672–679. [PubMed: 18445819]

  105. Meirelles K, Benedict LA, Dombkowski D, Pepin D, Preffer FI, Teixeira J, Tanwar PS, Young RH, MacLaughlin DT, Donahoe PK, Wei X. Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance. Proceedings of the National Academy of Sciences of the United States of America 2012; 109:2358–2363. [PubMed: 22308459]

  106. Zielske SP, Spalding AC, Wicha MS, Lawrence TS. Ablation of breast cancer stem cells with radiation. Translational Oncology 2011; 4:227–233. [PubMed: 21804918].

  107. Scadden, D. T. (2006). The stem-cell niche as an entity of action. Nature, 441(7097), 1075–1079.

    Article  CAS  PubMed  Google Scholar 

  108. Oskarsson T, Batlle E, Massague J. Metastatic Stem Cells: Sources, Niches, and Vital Pathways. Cell Stem Cell 2014; 14:306–321. [PubMed: 24607405].

  109. Ye, J., Wu, D., Wu, P., Chen, Z., & Huang, J. (2014). The cancer stem cell niche: cross talk between cancer stemcells and their microenvironment. Tumor Biology, 35, 3945–3951.

    Article  CAS  PubMed  Google Scholar 

  110. Lee, J., et al. (2006). Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum- cultured cell lines. Cancer Cell, 9(5), 391–403.

    Article  CAS  PubMed  Google Scholar 

  111. Zheng, X., et al. (2007). Most C6 cells are cancer stem cells: evidence from clonal and population analyses. Cancer Research, 67(8), 3691–3697.

    Article  CAS  PubMed  Google Scholar 

  112. Pandita, A., et al. (2004). Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR. Genes, Chromosomes & Cancer, 39(1), 29–36.

    Article  CAS  Google Scholar 

  113. Ricci-Vitiani, L., et al. (2010). Tumor vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature, 468(7325), 824–828.

    Article  CAS  PubMed  Google Scholar 

  114. Noll, J., Vandyke, K. and Zannettino, A. (2014). The Role of the “Cancer Stem Cell Niche” in Cancer Initiation and Progression. Adult Stem Cell Niches.

    Book  Google Scholar 

  115. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, Kamiyama M, Hruban RH, Eshleman JR, Nowak MA, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010; 467:1114–1117. [PubMed: 20981102].

  116. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, Wu Y, Port JL, Altorki N, Port ER, Ruggero D, Shmelkov SV, Jensen KK, Rafii S, Lyden D. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005; 438:820–827. [PubMed: 16341007]

  117. Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bauerle T, Wallwiener M, et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nature Biotechnology 2013; 31:539–544. [PubMed: 23609047]

  118. Dieter SM, Ball CR, Hoffmann CM, Nowrouzi A, Herbst F, Zavidij O, Abel U, Arens A, Weichert W, Brand K, et al. Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell 2011; 9:357–365. [PubMed: 21982235]

  119. Kreso A, O’Brien CA, van Galen P, Gan OI, Notta F, Brown AM, Ng K, Ma J, Wienholds E, Dunant C, et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science. 2013; 339:543–548. [PubMed: 23239622]

  120. Meacham CE, Morrison SJ. Tumor heterogeneity and cancer cell plasticity. Nature. 2013; 501:328– 337. [PubMed: 24048065]

  121. LaBarge MA. The difficulty of targeting cancer stem cell niches. Clinical Cancer Research 2010; 16:3121– 3129. [PubMed: 20530700]

  122. Baccelli, I., & Trumpp, A. (2012). The evolving concept of cancer and metastasis stem cells. The Journal of Cell Biology, 198(3), 281–293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Dalerba, P., Cho, R. W., & Clarke, M. F. (2007). Cancer stem cells: models and concepts. Annual Review of Medicine, 58, 267–284.

    Article  CAS  PubMed  Google Scholar 

  124. Heissig, B., et al. (2002). Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell, 109(5), 625–637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Andressen, C., et al. (1998). Beta1 integrin deficiency impairs migration and differentiation of mouse embryonic stem cell derived neurons. Neuroscience Letters, 251(3), 165–168.

    Article  CAS  PubMed  Google Scholar 

  126. Hirsch, E., et al. (1996). Impaired migration but not differentiation of haematopoietic stem cells in the absence of beta1 integrins. Nature, 380(6570), 171–175.

    Article  CAS  PubMed  Google Scholar 

  127. Crowe, D. L., & Ohannessian, A. (2004). Recruitment of focal adhesion kinase and paxillin to beta1 integrin promotes cancer cell migration via mitogen activated protein kinase activation. BMC Cancer, 4, 18.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Curran, S., & Murray, G. I. (1999). Matrix metalloproteinases in tumor invasion and metastasis. The Journal of Pathology, 189(3), 300–308.

    Article  CAS  PubMed  Google Scholar 

  129. Kang, H., et al. (2005). The elevated level of CXCR4 is correlated with nodal metastasis of human breast cancer. Breast, 14(5), 360–367.

    Article  PubMed  Google Scholar 

  130. Lapidot, T., & Kollet, O. (2002). The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune- deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia, 16(10), 1992–2003.

    Article  CAS  PubMed  Google Scholar 

  131. Yu, Z., Willmarth, N. E., Zhou, J., Katiyar, S., Wang, M., Liu, Y., McCue, P. A., Quong, A. A., Lisanti, M. P., & Pestell, R. G. (2010). microRNA 17/20 inhibits cellular invasion and tumor metastasis in breast cancer by heterotypic signaling. Proc NatlAcad Sci USA., 107, 8231–8236.

    Article  Google Scholar 

  132. Liu, R., et al. (2007). The prognostic role of a gene signature from tumorigenic breast-cancer cells. The New England Journal of Medicine, 356(3), 217–226.

    Article  CAS  PubMed  Google Scholar 

  133. Liu, H., et al. (2010). Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proceedings of the National Academy of Sciences of the United States of America, 107(42), 18115–18120.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Pang, R., et al. (2010). A subpopulation of CD26+cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell, 6(6), 603–615.

    Article  CAS  PubMed  Google Scholar 

  135. Justilien, V., et al. (2012). Matrix metalloproteinase-10 is required for lung cancer stem cell maintenance, tumor initiation and metastatic potential. PLoS One, 7(4), e35040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Charafe-Jauffret, E., et al. (2009). Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Research, 69(4), 1302–1313.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Noll, J. E., et al. (2014). Myeloma plasma cells alter the bone marrow microenvironment by stimulating the proliferation of mesenchymal stromal cells. Haematologica, 99(1), 163–171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Bennewith KL, Durand RE. Quantifying transient hypoxia in human tumor xenografts by flow cytometry. Cancer Research 2004; 64:6183–6189. [PubMed: 15342403]

  139. Brurberg KG, Thuen M, Ruud EB, Rofstad EK. Fluctuations in pO 2 in irradiated human melanoma xenografts. Radiation Research 2006; 165:16–25. [PubMed: 16392958]

  140. Wei J, Wu A, Kong LY, Wang Y, Fuller G, Fokt I, Melillo G, Priebe W, Heimberger AB. Hypoxia potentiates glioma-mediated immunosuppression. PLoS One 2011; 6:e16195. [PubMed: 21283755]

  141. Liu L, Wise DR, Diehl JA, Simon MC. Hypoxic reactive oxygen species regulate the integrated stress response and cell survival. The Journal of Biological Chemistry 2008; 283:31153–31162. [PubMed: 18768473]

  142. Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, et al. Transcriptional evidence for the “Reverse Warburg Effect” in human breast cancer tumor stroma and metastasis: similarities with oxidative stress, inflammation, Alzheimer’s disease, and “Neuron-Glia Metabolic Coupling”. Aging. 2010; 2:185–199. [PubMed: 20442453]

  143. Anido J, Saez-Borderias A, Gonzalez-Junca A, Rodon L, Folch G, Carmona MA, Prieto-Sanchez RM, Barba I, Martinez-Saez E, Prudkin L, et al. TGF-β Receptor Inhibitors Target the CD44high/Id1high Glioma-Initiating Cell Population in Human Glioblastoma. Cancer Cell 2010; 18:655–668. [PubMed: 21156287]

  144. Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, Bell G, Guo W, Rubin J, Richardson AL, Weinberg RA. Paracrine and Autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011; 145:926–940. [PubMed: 21663795]

  145. Charles N, Ozawa T, Squatrito M, Bleau AM, Brennan CW, Hambardzumyan D, Holland EC. Perivascular Nitric Oxide Activates Notch Signaling and Promotes Stem-like Character in PDGF- Induced Glioma Cells. Cell Stem Cell 2010; 6:141–152. [PubMed: 20144787]

  146. Quail DF, Taylor MJ, Postovit LM. Microenvironmental regulation of cancer stem cell phenotypes. Current Stem Cell Research & Therapy 2012; 7:197–216. [PubMed: 22329582]

  147. Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE. HIF-1alpha induces cell cycle arrest by functionally counter-acting Myc. The EMBO Journal 2004; 23:1949–1956. [PubMed: 15071503]

  148. Louie, E., et al. (2010). Identification of a stem-like cell population by exposing metastatic breast cancer cell lines to repetitive cycles of hypoxia and reoxygenation. Breast Cancer Research, 12(6), R94.

    Article  CAS  PubMed  Google Scholar 

  149. Heddleston, J. M., et al. (2010). Hypoxia inducible factors in cancer stem cells. British Journal of Cancer, 102(5), 789–795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Kim, Y., et al. (2009). Hypoxic tumor microenvironment and cancer cell differentiation. Current Molecular Medicine, 9(4), 425–434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kitamura T, Qian B-Z, Pollard JW. Immune cell promotion of metastasis. Nature Reviews. Immunology 2015; 15:73–86. [PubMed: 25614318]

  152. Dean, M., Fojo, T., & Bates, S. (2005). Tumor stem cells and drug resistance. Nature Reviews. Cancer, 5, 275–284. https://doi.org/10.1038/nrc1590.

    Article  CAS  PubMed  Google Scholar 

  153. Eyler, C. E., & Rich, J. N. (2008). Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. Journal of Clinical Oncology, 26, 2839–2845. https://doi.org/10.1200/JCO.2007.15.1829.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Curiel, T. J. (2012). Immunotherapy: a useful strategy to help combat multidrug resistance. Drug Resistance Updates, 15, 106–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F., & Dick, J. E. (2006). Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nature Medicine, 12, 1167–1174.

    Article  CAS  PubMed  Google Scholar 

  156. Jin, L., Lee, E. M., Ramshaw, H. S., Bus eld, S. J., Peoppl, A. G., Wilkinson, L., et al. (2009). Monoclonal antibody-mediated targeting of CD123, IL-3 receptor α chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell, 5, 31–42.

    Article  CAS  PubMed  Google Scholar 

  157. Kikushige, Y., Shima, T., Takayanagi, S., Urata, S., Miyamoto, T., Iwasaki, H., et al. (2010). TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell, 7, 708–717.

    Article  CAS  PubMed  Google Scholar 

  158. Goodison S, Urquidi V, Tarin D. CD44 cell adhesion molecules. Molecular Pathology 1999; 52: 189-196 [PMID: 10694938]

  159. Alkilany, A. M., Thompson, L. B., Boulos, S. P., Sisco, P. N., & Murphy, C. J. (2012). Gold nanorods: Their potential for photothermal therapeutics and drug delivery, tempered by the complexity of their biological interactions. Advanced Drug Delivery Reviews, 64, 190–199.

    Article  CAS  PubMed  Google Scholar 

  160. Tang, W., Hao, X., He, F., Li, L., & Xu, L. (2011). Anti-CD44 antibody treatment inhibits pancreatic cancer metastasis and post-radiotherapy recurrence. Cancer Research, 71, 565. https://doi.org/10.1158/1538-7445.am2011-565.

  161. Masuko K, Okazaki S, Satoh M, Tanaka G, Ikeda T, Torii R, Ueda E, Nakano T, Danbayashi M, Tsuruoka T, Ohno Y, Yagi H, Yabe N, Yoshida H, Tahara T, Kataoka S, Oshino T, Shindo T, Niwa S, Ishimoto T, Baba H, Hashimoto Y, Saya H, Masuko T. Anti- tumor effect against human cancer xenografts by a fully human monoclonal antibody to a variant 8-epitope of CD44R1 expressed on cancer stem cells. PLoS One 2012; 7: e29728 [PMID: 22272243 https://doi.org/10.1371/journal.pone.0029728]

  162. Olsson E, Honeth G, Bendahl PO, Saal LH, Gruvberger-Saal S, Ringnér M, Vallon-Christersson J, Jönsson G, Holm K, Lövgren K, Fernö M, Grabau D, Borg A, Hegardt C. CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers. BMC Cancer 2011; 11: 418 [PMID: 21957977 https://doi.org/10.1186/1471-2407-11-418]

  163. Cherciu I, Bărbălan A, Pirici D, Mărgăritescu C, Săftoiu A. Stem cells, colorectal cancer and cancer stem cell markers correlations. Current Health Sciences Journal 2014; 40: 153-161 [PMID: 25729599 https://doi.org/10.12865/CHSJ.40.03.01]

  164. Zinzi, L., Contino, M., Cantore, M., Capparelli, E., Leopoldo, M., & Colabufo, N. A. (2014). ABC transporters in CSCs membranes as a novel target for treating tumor relapse. Frontiers in Pharmacology, 5, 163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Morrison, R., Schleicher, S. M., Sun, Y., Niermann, K. J., Kim, S., Spratt, D. E., Chung, C. H., & Lu, B. (2011). Targeting the mechanisms of resistance to chemotherapy and radiotherapy with the cancer stem cell hypothesis. Journal of Oncology, 2011, 941876.

    Article  CAS  PubMed  Google Scholar 

  166. Swaminathan SK, Roger E, Toti U, Niu L, Ohlfest JR, Panyam J. CD133-targeted paclitaxel delivery inhibits local tumor recurrence in a mouse model of breast cancer. Journal of Controlled Release 2013; 171: 280-287 [PMID: 23871962 https://doi.org/10.1016/j.jconrel.2013.07.014]

  167. Skubitz AP, Taras EP, Boylan KL, Waldron NN, Oh S, Panoskaltsis- Mortari A, Vallera DA. Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression. Gynecologic Oncology 2013; 130: 579-587 [PMID: 23721800 https://doi.org/10.1016/j.ygyno.2013.05.027]

  168. Wang, C. H., Chiou, S. H., Chou, C. P., Chen, Y. C., Huang, Y. J., & Peng, C. A. (2011). Photothermolysis of glioblastoma stem-like cells targeted by carbon nanotubes conjugated with CD133 monoclonal antibody. Nanomedicine, 7, 69–79.

    Article  CAS  PubMed  Google Scholar 

  169. Stratford EW, Bostad M, Castro R, Skarpen E, Berg K, Høgset A, Myklebost O, Selbo PK. Photochemical internalization of CD133- targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity. Biochimica et Biophysica Acta 2013; 1830: 4235-4243 [PMID: 23643966 https://doi.org/10.1016/j.bbagen.2013.04.033]

  170. Huang J, Li C, Wang Y, Lv H, Guo Y, Dai H, Wicha MS, Chang AE, Li Q. Cytokine-induced killer (CIK) cells bound with anti- CD3/anti-CD133 bispeci c antibodies target CD133(high) cancer stem cells in vitro and in vivo. Clinical Immunology 2013; 149: 156-168 [PMID: 23994769 https://doi.org/10.1016/j.clim.2013.07.006]

  171. Pan Q, Li Q, Liu S, Ning N, Zhang X, Xu Y, Chang AE, Wicha MS. Concise Review: Targeting Cancer Stem Cells Using Immunologic Approaches. Stem Cells 2015; 33: 2085-2092 [PMID: 25873269 https://doi.org/10.1002/stem.2039]

  172. Kwiatkowska-Borowczyk EP, Gąbka-Buszek A, Jankowski J, Mackiewicz A. Immunotargeting of cancer stem cells. Contemp Oncol (Pozn) 2015; 19: A52-A59 [PMID: 25691822 https://doi.org/10.5114/wo.2014.47129]

  173. Lobry C, Oh P, Aifantis I. Oncogenic and tumor suppressor functions of Notch in cancer: it’s NOTCH what you think. The Journal of Experimental Medicine 2011; 208: 1931-1935 [PMID: 21948802 https://doi.org/10.1084/jem.20111855]

  174. Lobry C, Oh P, Mansour MR, Look AT, Aifantis I. Notch signaling: switching an oncogene to a tumor suppressor. Blood 2014; 123: 2451-2459 [PMID: 24608975 https://doi.org/10.1182/blood-2013-08-355818]

  175. Osanyingbemi-Obidi J, Dobromilskaya I, Illei PB, Hann CL, Rudin CM. Notch signaling contributes to lung cancer clonogenic capacity in vitro but may be circumvented in tumorigenesis in vivo. Molecular Cancer Research 2011; 9: 1746-1754 [PMID: 21994468 https://doi.org/10.1158/1541-7786.MCR-11-0286]

  176. Hassan KA, Wang L, Korkaya H, Chen G, Maillard I, Beer DG, Kalemkerian GP, Wicha MS. Notch pathway activity identi es cells with cancer stem cell-like properties and correlates with worse survival in lung adenocarcinoma. Clinical Cancer Research 2013; 19: 1972-1980 [PMID: 23444212 https://doi.org/10.1158/1078-0432.CCR-12-0370]

  177. Reedijk, M., Odorcic, S., Chang, L., et al. (2005). High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is as- sociated with poor overall survival. Cancer Research, 65(18), 8530–8537.

    Article  CAS  PubMed  Google Scholar 

  178. Dickson, B. C., Mulligan, A. M., Zhang, H., et al. (2007). High-level JAG1 mRNA and protein predict poor outcome in breast cancer. Modern Pathology, 20(6), 685–693.

    Article  CAS  PubMed  Google Scholar 

  179. Kim HA, Koo BK, Cho JH, Kim YY, Seong J, Chang HJ, Oh YM, Stange DE, Park JG, Hwang D, Kong YY. Notch1 counteracts WNT/β-catenin signaling through chromatin modification in colorectal cancer. The Journal of Clinical Investigation 2012; 122: 3248-3259 [PMID: 22863622 https://doi.org/10.1172/JCI61216]

  180. Harrison H, Farnie G, Howell SJ, Rock RE, Stylianou S, Brennan KR, Bundred NJ, Clarke RB. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Research 2010; 70: 709-718 [PMID: 20068161 https://doi.org/10.1158/0008-5472.CAN-09-1681]

  181. Zhou T, Benda C, Dunzinger S, Huang Y, Ho JC, Yang J, Wang Y, Zhang Y, Zhuang Q, Li Y, Bao X, Tse HF, Grillari J, Grillari- Voglauer R, Pei D, Esteban MA. Generation of human induced pluripotent stem cells from urine samples. Nature Protocols 2012; 7: 2080-2089 [PMID: 23138349 https://doi.org/10.1038/nprot.2012.115]

  182. Fouladi, M., Stewart, C. F., Olson, J., Wagner, L. M., Onar- Thomas, A., Kocak, M., Packer, R. J., Goldman, S., Gururangan, S., Gajjar, A., Demuth, T., Kun, S., Boyett, J. M., & Gilbertson, R. J. (2011). Journal of Clinical Oncology, 29, 3529–3534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Wang, Z., Zhang, Y., Banerjee, S., Li, Y., & Sarkar, F. H. (2006). Inhibition of nuclear factor kappab activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells. International Journal of Cancer, 118(8), 1930–1936.

    Article  CAS  PubMed  Google Scholar 

  184. Wang, Z., Zhang, Y., Banerjee, S., Li, Y., & Sarkar, F. H. (2006). Notch-1 down- regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells. Cancer, 106(11), 2503–2513.

    Article  CAS  PubMed  Google Scholar 

  185. Wang, Z., Zhang, Y., Li, Y., Banerjee, S., Liao, J., & Sarkar, F. H. (2006). Down- regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Molecular Cancer Therapeutics, 5(3), 483–493.

    Article  CAS  PubMed  Google Scholar 

  186. Cecchinato, V., Chiaramonte, R., Nizzardo, M., et al. (2007). Resveratrol- induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells. Biochemical Pharmacology, 74(11), 1568–1574.

    Article  CAS  PubMed  Google Scholar 

  187. Koduru, S., Kumar, R., Srinivasan, S., Evers, M. B., & Damodaran, C. (2010). Notch-1 inhibition by Withaferin-A: a therapeutic target against co- lon carcinogenesis. Molecular Cancer Therapeutics, 9(1), 202–210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Wang, X. N., Wu, Q., Yang, X., Zhang, L. S., Wu, Y. P., & Lu, C. (2010). Effects of Celastrol on growth inhibition of U937 leukemia cells through the regulation of the Notch1/NF-kappaB signaling pathway in vitro. Chinese Journal of Cancer, 29(4), 385–390.

    Article  PubMed  Google Scholar 

  189. Li Y, Maitah MY, Ahmad A, Kong D, Bao B, Sarkar FH. Targeting the Hedgehog signaling pathway for cancer therapy. Expert Opinion on Therapeutic Targets 2012; 16: 49-66 [PMID: 22243133 https://doi.org/10.1517/14728222.2011.617367]

  190. Marini, K. D., Payne, B. J., Watkins, D. N., & Martelotto, L. G. (2011). Mechanisms of Hedgehog signalling in cancer. Growth Factors, 29(6), 221–234.

    Article  CAS  PubMed  Google Scholar 

  191. Campbell V, Copland M. Hedgehog signaling in cancer stem cells: a focus on hematological cancers. Stem Cells Cloning 2015; 8: 27-38 [PMID: 25691811 https://doi.org/10.2147/SCCAA.S58613]

  192. Brechbiel J, Miller-Moslin K, Adjei AA. Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer. Cancer Treatment Reviews 2014; 40: 750-759 [PMID: 24613036 https://doi.org/10.1016/j.ctrv.2014.02.003]

  193. Chen J K, Taipale J, Cooper M K, Beachy P A, (2002). Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes & Development, 16(21), pp.2743-2748. Genes & Development 2002, 16, 2743–2748.

  194. Eimer, S., Dugay, F., Airiau, K., Avril, T., Quillien, V., Belaud-Rotureau, M. A., & Belloc, F. (2012). Neuro-Oncology, 14, 1441–1451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Mueller, M. T., Hermann, P. C., Witthauer, J., et al. (2009). Combined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer. Gastroenterology, 137(3), 1102–1113.

    Article  CAS  PubMed  Google Scholar 

  196. Karhadkar, S. S., Steven Bova, G., Abdallah, N., Dhara, S., Gardner, D., Maitra, A., et al. (2004). Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature, 431, 707–712.

    Article  CAS  PubMed  Google Scholar 

  197. Nanta, R., Kumar, D., Meeker, D., Rodova, M., Van Veldhuizen, P. J., Shankar, S., & Srivastava, R. K. (2013). Oncogenesis, 2, e42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Gao, C., & Chen, Y. G. (2010). Dishevelled: The hub of Wnt signaling. Cellular Signalling, 22(5), 717–727.

    Article  CAS  PubMed  Google Scholar 

  199. Amado NG, Predes D, Moreno MM, Carvalho IO, Mendes FA, Abreu JG. Flavonoids and Wnt/β-catenin signaling: potential role in colorectal cancer therapies. International Journal of Molecular Sciences 2014; 15: 12094-12106 [PMID: 25007066 https://doi.org/10.3390/ijms150712094]

  200. Crane, A. M., Kramer, P., Bui, J. H., Chung, W. J., Li, X. S., Gonzalez- Garay, M. L., Hawkins, F., Liao, W., Mora Crane, A., Kramer, P., Bui, J., Chung, W., Li, X., Gonzalez-Garay, M., Hawkins, F., Liao, W., Mora, D., Choi, S., Wang, J., Sun, H., Paschon, D., Guschin, D., Gregory, P., Kotton, D., Holmes, M., Sorscher, E., & Davis, B. (2015). Targeted Correction and Restored Function of the CFTR Gene in Cystic Fibrosis Induced Pluripotent Stem Cells. Stem Cell Reports, 4(4), 569–577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Nayak, A., Satapathy, S. R., Das, D., Siddharth, S., Tripathi, N., Bharatam, P. V., & Kundu, C. (2016). Scientific Reports, 6, 20600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Zhang X, Lou Y, Zheng X, Wang H, Sun J, Dong Q, Han B. Wnt blockers inhibit the proliferation of lung cancer stem cells. Drug Design, Development and Therapy 2015; 9: 2399-2407 [PMID: 25960639 https://doi.org/10.2147/DDDT.S76602]

  203. Wen, Z., Feng, S., Wei, L., Wang, Z., Hong, D., & Wang, Q. (2015). International Journal of Molecular Medicine, 36, 1657–1663.

    Article  CAS  PubMed  Google Scholar 

  204. Han, S., Woo, J. K., Jung, Y., Jeong, D., Kang, M., Yoo, Y. J., Lee, H., Oh, S. H., Ryu, J. H., & Kim, W. Y. (2016). Biochemical and Biophysical Research Communications, 469, 1153–1158.

    Article  CAS  PubMed  Google Scholar 

  205. Ghantous, A., Gali-Muhtasib, H., Vuorela, H., Saliba, N. A., & Darwiche, N. (2010). Drug Discovery Today, 15, 668–678.

    Article  CAS  PubMed  Google Scholar 

  206. Yeh, C., Wu, A., Chang, P., Chen, K., Yang, C., Yang, S., Ho, C., Chen, C., Kuo, Y., Lee, P., Liu, Y., Yen, C., Hsiao, M., Lu, P., Lai, J., Wang, L., Wu, C., Chiou, J., Yang, P., & Huang, C. (2012). Trifluoperazine, an Antipsychotic Agent, Inhibits Cancer Stem Cell Growth and Overcomes Drug Resistance of Lung Cancer. American Journal of Respiratory and Critical Care Medicine, 186(11), 1180–1188.

    Article  CAS  PubMed  Google Scholar 

  207. Shukla, S., Sinha, S., Khan, S., Kumar, S., Singh, K., Mitra, K., Maurya, R., & Meeran, S. M. (2016). Scientific Reports, 6, 21860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Pradeep, C. R., & Kuttan, G. (2002). Effect of piperine on the inhibition of lung metastasis induced B16F-10 melanoma cells in mice. Clinical & Experimental Metastasis, 19(8), 703–708.

    Article  CAS  Google Scholar 

  209. Selvendiran, K., Banu, S. M., & Sakthisekaran, D. (2004). Protective effect of piperine on benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Clinica Chimica Acta, 350(1-2), 73–78.

    Article  CAS  Google Scholar 

  210. Mukherjee, S., Mazumdar, M., Chakraborty, S., Manna, A., Saha, S., Khan, P., Bhattacharjee, P., Guha, D., Adhikary, A., Mukhjerjee, S., & Das, T. (2014). Stem Cell Research & Therapy, 5, 116.

    Article  CAS  Google Scholar 

  211. Korkaya, H., Liu, S., & Wicha, M. S. (2011). Regulation of cancer stem cells by cytokine networks: attacking cancer’s in ammatory roots. Clinical Cancer Research, 17, 6125–6129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Scheller, J., & Rose-John, S. (2006). Interleukin-6 and its receptor: from bench to bedside. Medical Microbiology and Immunology, 195, 173–183.

    Article  CAS  PubMed  Google Scholar 

  213. Trikha, M., Corringham, R., Klein, B., & Rossi, J. F. (2003). Targeted anti- interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clinical Cancer Research, 9, 4653–4665.

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Guo, Y., Xu, F., Lu, T., Duan, Z., & Zhang, Z. (2012). Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treatment Reviews, 38, 904–910.

    Article  CAS  PubMed  Google Scholar 

  215. Ginestier, C., Liu, S., Diebel, M. E., Korkaya, H., Luo, M., Brown, M., Wicinski, J., Cabaud, O., Charafe-Jauffret, E., Birnbaum, D., Guan, J. L., Dontu, G., & Wicha, M. S. (2010). CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. The Journal of Clinical Investigation, 120, 485–497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Hartman, Z. C., Poage, G. M., den Hollander, P., Tsimelzon, A., Hill, J., Panupinthu, N., Zhang, Y., Mazumdar, A., Hilsenbeck, S. G., Mills, G. B., & Brown, P. H. (2013). Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proin ammatory cytokines IL-6 and IL-8. Cancer Research, 73, 3470–3480.

    Article  CAS  PubMed  Google Scholar 

  217. Panneerselvam J, Jin J, Shanker M, Lauderdale J, Bates J, Wang Q, Zhao YD, Archibald SJ, Hubin TJ, Ramesh R. IL-24 inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis. PLoS One 2015; 10: e0122439 [PMID: 25775124 https://doi.org/10.1371/journal.pone.0122439]

  218. Sun, Y. F., Xu, Y., Yang, X. R., et al. (2013). Circulating stem cell-like epithelial cell adhesion molecule-positive tumour cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology, 57, 1458–1468.

    Article  CAS  Google Scholar 

  219. Welschinger R, Liedtke F, Basnett J, Dela Pena A, Juarez JG, Bradstock KF, Bendall LJ. Plerixafor (AMD3100) induces prolonged mobilization of acute lymphoblastic leukemia cells and increases the proportion of cycling cells in the blood in mice. Experimental Hematology 2013; 41: 293-302.e1 [PMID: 23178377 https://doi.org/10.1016/j.exphem.2012.11.004]

  220. Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, Kieran MW, Luster AD, Segal RA. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proceedings of the National Academy of Sciences of the United States of America 2003; 100: 13513-13518 [PMID: 14595012 https://doi.org/10.1073/pnas.2235846100]

  221. Singh B, Cook KR, Martin C, Huang EH, Mosalpuria K, Krishnamurthy S, Cristofanilli M, Lucci A. Evaluation of a CXCR4 antagonist in a xenograft mouse model of inflammatory breast cancer. Clinical & Experimental Metastasis 2010; 27: 233-240 [PMID: 20229045 https://doi.org/10.1007/s10585-010-9321-4]

  222. Hoellenriegel J, Zboralski D, Maasch C, Rosin NY, Wierda WG, Keating MJ, Kruschinski A, Burger JA. The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization. Blood 2014; 123: 1032-1039 [PMID: 24277076 https://doi.org/10.1182/blood-2013-03-493924]

  223. Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacologica Sinica 2013; 34: 732-740 [PMID: 23685952 https://doi.org/10.1038/aps.2013.27]

  224. Burkhardt JK, Hofstetter CP, Santillan A, Shin BJ, Foley CP, Ballon DJ, Pierre Gobin Y, Boockvar JA. Orthotopic glioblastoma stem-like cell xenograft model in mice to evaluate intra- arterial delivery of bevacizumab: from bedside to bench. Journal of Clinical Neuroscience 2012; 19: 1568-1572 [PMID: 22985932, https://doi.org/10.1016/j.jocn.2012.03.012]

  225. Prager GW, Poettler M, Unseld M, Zielinski CC. Angiogenesis in cancer: Anti-VEGF escape mechanisms. Transl Lung Cancer Res 2012; 1: 14-25 [PMID: 25806151, https://doi.org/10.3978/j.issn.2218-6751.2 011.11.02]

  226. Folkins, C., Man, S., Xu, P., Shaked, Y., Hicklin, D. J., & Kerbel, R. S. (2007). Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem — like cell fraction in glioma xenograft tumors. Cancer Research, 67, 3560–3564.

    Article  CAS  PubMed  Google Scholar 

  227. Burroughs SK, Kaluz S, Wang D, Wang K, Van Meir EG, Wang B. Hypoxia inducible factor pathway inhibitors as anticancer therapeutics. Future Medicinal Chemistry 2013; 5: 553-572 [PMID: 23573973, https://doi.org/10.4155/fmc.13.17]

  228. Zhao J, Du F, Shen G, Zheng F, Xu B. The role of hypoxia- inducible factor-2 in digestive system cancers. Cell Death & Disease 2015; 6: e1600 [PMID: 25590810, https://doi.org/10.1038/cddis.2014.565]

  229. Xu Z, Wang D, Xu S, Liu X, Zhang X, Zhang H. Preparation of a camptothecin prodrug with glutathione-responsive disul de linker for anticancer drug delivery. Chemistry, an Asian Journal 2014; 9: 199-205 [PMID: 24136878, https://doi.org/10.1002/asia.201301030]

  230. Xu Z, Liu S, Kang Y, Wang M. Glutathione- and pH-responsive nonporous silica prodrug nanoparticles for controlled release and cancer therapy. Nanoscale 2015; 7: 5859-5868 [PMID: 25757484, https://doi.org/10.1039/c5nr00297d]

  231. Tsuruo, T., Iida, H., Tsukagoshi, S., & Sakurai, Y. (1981). Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Research, 41, 1967–1972.

    CAS  PubMed  Google Scholar 

  232. Ding, P. R., Tiwari, A. K., Ohnuma, S., Lee, J. W., An, X., Dai, C. L., Lu, Q. S., Singh, S., Yang, D. H., Talele, T. T., Ambudkar, S. V., & Chen, Z. S. (2011). The phosphodiesterase-5 inhibitor vardena l is a potent inhibitor of ABCB1/P-glycoprotein transporter. PLoS One, 6, e19329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Control 2003; 10: 159-165 [PMID: 12712010]

  234. Dönmez, Y., & Gündüz, U. (2011). Reversal of multidrug resistance by small interfering RNA (siRNA) in doxorubicin-resistant MCF-7 breast cancer cells. Biomedicine & Pharmacotherapy, 65, 85–89.

    Article  CAS  Google Scholar 

  235. Ganoth A, Merimi KC, Peer D. Overcoming multidrug resistance with nanomedicines. Expert Opinion on Drug Delivery 2015; 12: 223-238 [PMID: 25224685, https://doi.org/10.1517/17425247.2015.960920]

  236. Gu, W., Yeo, E., McMillan, N., & Yu, C. (2011). Silencing oncogene expression in cervical cancer stem-like cells inhibits their cell growth and self- renewal ability. Cancer Gene Therapy, 18, 897–905.

    Article  CAS  PubMed  Google Scholar 

  237. Puca, F., Colamaio, M., Federico, A., Gemei, M., Tosti, N., Bastos, A. U., Del Vecchio, L., Pece, S., Battista, S., & Fusco, A. (2014). HMGA1 silencing restores normal stem cell characteristics in colon cancer stem cells by increasing p53 levels. Oncotarget, 5, 3234–3245.

    Article  PubMed  PubMed Central  Google Scholar 

  238. Wang, T., Gantier, M. P., Xiang, D., Bean, A. G., Bruce, M., Zhou, S. F., Khasraw, M., Ward, A., Wang, L., Wei, M. Q., AlShamaileh, H., Chen, L., She, X., Lin, J., Kong, L., Shigdar, S., & Duan, W. (2015). EpCAM aptamer-mediated survivin silencing sensitized cancer stem cells to doxorubicin in a breast cancer model. Theranostics, 5, 1456–1472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Taylor, W. F., & Jabbarzadeh, E. (2017). The use of natural products to target cancer stem cells. American Journal of Cancer Research, 7(7), 1588–1605.

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Moselhy, J., Srinivasan, A., Ankem, M. K., & Damodaran, C. (2015). Natural Products That Target Cancer Stem Cells. Anticancer Research, 35, 5773–5788.

    CAS  PubMed  Google Scholar 

  241. Qin, W., Huang, G., Chen, Z., & Zhang, Y. (2017). Nanomaterials in Targeting Cancer Stem Cells for Cancer Therapy. Frontiers in Pharmacology, 8, 1. https://doi.org/10.3389/fphar.2017.00001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Takebe, N. et al. Nature Reviews. Clinical Oncology 8, 97–106 (2011); published online 14 December 2010; https://doi.org/10.1038/nrclinonc.2010.196

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  1. Amity Institute of Biotechnology, Amity University, Mumbai-Pune Expressway, Bhatan, Panvel, Mumbai, Maharashtra, 410206, India

    Anoop K. Yadav & Neetin S. Desai

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Yadav, A.K., Desai, N.S. Cancer Stem Cells: Acquisition, Characteristics, Therapeutic Implications, Targeting Strategies and Future Prospects. Stem Cell Rev and Rep 15, 331–355 (2019). https://doi.org/10.1007/s12015-019-09887-2

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