Cell Biochemistry and Biophysics

, Volume 69, Issue 3, pp 389–398 | Cite as

Lung Cancer Stem Cells and Implications for Future Therapeutics

Review Paper

Abstract

Lung cancer is the most dreaded of all cancers because of the higher mortality rates associated with it worldwide. The various subtypes of lung cancer respond differently to a particular treatment regime, which makes the therapeutic interventions all the more complicated. The concept of cancer stem cells (CSCs) is based primarily on the clinical and experimental observations that indicate the existence of a subpopulation of cells with the capacity to self-renew and differentiate as well as show increased resistance to radiation and chemotherapy. They are considered as the factors responsible for the cases of tumor relapse. The CSCs may have significant role in the development of lung tumorigenesis based on the identification of the CSCs which respond during injury. The properties of multi-potency and self-renewal are shared in common by the lung CSCs with the normal pluripotent stem cells which can be isolated using the similar markers. This review deals with the origin and characteristics of the lung cancer stem cells. The role of different markers used to isolate lung CSCs like CD44, ALDH (aldehyde dehydrogenase), CD133 and ABCG2 (ATP binding cassette sub family G member 2) have been discussed in detail. Analysis of the developmental signaling pathways such as Wnt/β-catenin, Notch, hedgehog in the regulation and maintenance of the lung CSCs have been done. Finally, before targeting the lung CSC biomarkers for potential therapeutics, challenges faced in lung cancer stem cell research need to be taken into account. With the accepted notion that the CSCs are to blame for cancer relapse and drug resistance, targeting them can be an important aspect of lung cancer therapy in the future.

Keywords

Lung cancer Cancer stem cells (CSCs) CD44 ALDH (aldehyde dehydrogenase) CD133 ABCG2 (ATP binding cassette sub family G member 2) 

References

  1. 1.
    Herbst, R. S., Heymach, J. V., & Lippman, S. M. (2008). Lung cancer. New England Journal of Medicine, 359, 1367–1380.PubMedGoogle Scholar
  2. 2.
    Martel, C., Ferlay, J., Franceschi, S., et al. (2012). Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. The Lancet Oncology, 13, 607–615.Google Scholar
  3. 3.
    American Cancer Society. (2011). Cancer facts & figures 2011. Atlanta: American Cancer Society.Google Scholar
  4. 4.
    Brodowicz, T., Ciuleanu, T., Crawford, J., et al. (2012). Third CECOG consensus on the systemic treatment of non-small-cell lung cancer. Annals of Oncology, 23, 1223–1229.PubMedGoogle Scholar
  5. 5.
    D’Addario, G., & Felip, E. (2009). ESMO Guidelines Working Group. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Annals of Oncology, 20, 68–70.PubMedGoogle Scholar
  6. 6.
    D’Addario, G., Früh, M., Reck, M., et al. (2010). Metastatic non-small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 21, 116–119.Google Scholar
  7. 7.
    Goldstraw, P., Ball, D., Jett, J. R., et al. (2011). Non-small-cell lung cancer. Lancet, 378, 1727–1740.PubMedGoogle Scholar
  8. 8.
    Travis, W. D., Travis, L. B., & Devesa, S. S. (1995). Lung cancer. Cancer, 75, 191–202.PubMedGoogle Scholar
  9. 9.
    Alison, M. R., Lin, W. R., Lim, S. M., et al. (2012). Cancer stem cells: in the line of fire. Cancer Treatment Reviews, 38, 589–598.PubMedGoogle Scholar
  10. 10.
    Mani, S. A., Guo, W., Liao, M. J., et al. (2008). The epithelial mesenchymal transition generates cells with properties of stem cells. Cell, 133, 704–715.PubMedCentralPubMedGoogle Scholar
  11. 11.
    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.PubMedGoogle Scholar
  12. 12.
    Korkaya, H., & Wicha, M. S. (2007). Selective targeting of cancer stem cells: a new concept in cancer therapeutics. BioDrugs, 21, 299–310.PubMedGoogle Scholar
  13. 13.
    Perona, R., Lopez-Ayllon, B. D., de Castro Carpeno, J., et al. (2011). A role for cancer stem cells in drug resistance and metastasis in non-small-cell lung cancer. Clinical and Translational Oncology, 13, 289–293.PubMedGoogle Scholar
  14. 14.
    Li, J., & Zhou, B. P. (2011). Activation of beta-catenin and Akt pathways by twist are critical for the maintenance of EMT associated cancer stem cell-like characters. BMC Cancer, 11, 49.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Kelsey, C. R., Marks, L. B., Hollis, D., et al. (2009). Local recurrence after surgery for early stage lung cancer: An 11-year experience with 975 patients. Cancer, 115, 5218–5227.PubMedGoogle Scholar
  16. 16.
    Wisnivesky, J. P., Yankelevitz, D., & Henschke, C. I. (2005). Stage of lung cancer in relation to its size: Part 2. Evidence. Chest, 127, 1136–1139.PubMedGoogle Scholar
  17. 17.
    Howlader, N., Noon, A.M., Krapcho, M., et al. (2012). SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations). Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER website, April 2012.
  18. 18.
    Pao, W., Miller, V. A., Politi, K. A., et al. (2005). Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Medicine, 2, e73.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Katayama, R., Shaw, A. T., Khan, T. M., et al. (2012). Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Science Translational Medicine, 4, 120ra17.PubMedCentralPubMedGoogle Scholar
  20. 20.
    Janne, P. A., Freidlin, B., Saxman, S., et al. (2002). Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer, 95, 1528–1538.PubMedGoogle Scholar
  21. 21.
    Murray, N., Coy, P., Pater, J. L., et al. (1993). Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 11, 336–344.PubMedGoogle Scholar
  22. 22.
    Lapidot, T., Sirard, C., Vormoor, J., et al. (1994). A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature, 367, 645–648.PubMedGoogle Scholar
  23. 23.
    Rivera, C., Rivera, S., Loriot, Y., et al. (2011). Lung cancer stem cell: New insights on experimental models and preclinical data. Journal of Oncology, 2011, 549181.PubMedCentralPubMedGoogle Scholar
  24. 24.
    O’Flaherty, J. D., Barr, M., Fennell, D., et al. (2012). The cancer stem-cell hypothesis: Its emerging role in lung cancer biology and its relevance for future therapy. Journal of Thoracic Oncology, 7, 1880–1890.PubMedGoogle Scholar
  25. 25.
    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.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Visvader, J. E., & Lindeman, G. J. (2008). Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nature Reviews Cancer, 8, 755–768.PubMedGoogle Scholar
  27. 27.
    Visvader, J. E., & Lindeman, G. J. (2012). Cancer stem cells: Current status and evolving complexities. Cell Stem Cell, 10, 717–728.PubMedGoogle Scholar
  28. 28.
    Welte, Y., Adjaye, J., Lehrach, H. R., et al. (2010). Cancer stem cells in solid tumors: Elusive or illusive? Cell Communication and Signaling, 8, 6.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., et al. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 3983–3988.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Garvalov, B. K., & Acker, T. (2011). Cancer stem cells: A new framework for the design of tumor therapies. Journal of Molecular Medicine (Berlin), 89, 95–107.Google Scholar
  31. 31.
    Lundin, A., & Driscoll, B. (2013). Lung cancer stem cells: Progress and prospects. Cancer Letters, 338, 89–93.PubMedGoogle Scholar
  32. 32.
    He, S., Nakada, D., & Morrison, S. J. (2009). Mechanisms of stem cell self-renewal. Annual Review of Cell and Developmental Biology, 25, 377–406.PubMedGoogle Scholar
  33. 33.
    Eramo, A., Lotti, F., Sette, G., et al. (2008). Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death and Differentiation, 15, 504–514.PubMedGoogle Scholar
  34. 34.
    Bertolini, G., Roz, L., Perego, P., et al. (2009). Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proceedings of the National Academy of Sciences of the United States of America, 106, 16281–16286.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Chen, Y. C., Hsu, H. S., Chen, Y. W., et al. (2008). Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS One, 3, e2637.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Meng, X., Li, M., Wang, X., et al. (2009). Both CD133+ and CD133− subpopulations of A549 and H446 cells contain cancer-initiating cells. Cancer Science, 100, 1040–1046.PubMedGoogle Scholar
  37. 37.
    Salcido, C. D., Larochelle, A., Taylor, B. J., et al. (2010). Molecular characterisation of side population cells with cancer stem cell-like characteristics in small-cell lung cancer. British Journal of Cancer, 102, 1636–1644.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Ho, M. M., Ng, A. V., Lam, S., et al. (2007). Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Research, 67, 4827–4833.PubMedGoogle Scholar
  39. 39.
    Gutova, M., Najbauer, J., Gevorgyan, A., et al. (2007). Identification of uPAR-positive chemoresistant cells in small cell lung cancer. PLoS One, 2, e243.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Cui, F., Wang, J., Chen, D., et al. (2011). CD133 is a temporary marker of cancer stem cells in small cell lung cancer, but not in non-small cell lung cancer. Oncology Reports, 25, 701–708.PubMedGoogle Scholar
  41. 41.
    Akunuru, S., James Zhai, Q., & Zheng, Y. (2012). Non-small cell lung cancer stem/progenitor cells are enriched in multiple distinct phenotypic subpopulations and exhibit plasticity. Cell Death and Disease, 3, e352.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Niu, Q., Wang, W., Li, Y., et al. (2012). Low molecular weight heparin ablates lung cancer cisplatin-resistance by inducing proteasome-mediated ABCG2 protein degradation. PLoS One, 7, e41035.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Shi, Y., Fu, X., Hua, Y., et al. (2012). The side population in human lung cancer cell line NCI-H460 is enriched in stem-like cancer cells. PLoS One, 7, e33358.PubMedCentralPubMedGoogle Scholar
  44. 44.
    Wang, F., Mi, Y. J., Chen, X. G., et al. (2012). Axitinib targeted cancer stemlike cells to enhance efficacy of chemotherapeutic drugs via inhibiting the drug transport function of ABCG2. Molecular Medicine, 18, 887–898.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Nakatsugawa, M., Takahashi, A., Hirohashi, Y., et al. (2011). SOX2 is overexpressed in stemlike cells of human lung adenocarcinoma and augments the tumorigenicity. Laboratory Investigation, 91, 1796–1804.PubMedGoogle Scholar
  46. 46.
    Liang, D., & Shi, Y. (2012). Aldehyde dehydrogenase-1 is a specific marker for stem cells in human lung adenocarcinoma. Medical Oncology, 29, 633–639.PubMedGoogle Scholar
  47. 47.
    Sullivan, J. P., Spinola, M., Dodge, M., et al. (2010). Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on notch signaling. Cancer Research, 70, 9937–9948.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Kubo, T., Takigawa, N., Osawa, M., et al. (2013). Subpopulation of small-cell lung cancer cells expressing CD133 and CD87 show resistance to chemotherapy. Cancer Science, 104, 78–84.PubMedGoogle Scholar
  49. 49.
    Hegedus, C., Truta-Feles, K., Antalffy, G., et al. (2012). Interaction of the EGFR inhibitors gefitinib, vandetanib, pelitinib and neratinib with the ABCG2 multidrug transporter: implications for the emergence and reversal of cancer drug resistance. Biochemical Pharmacology, 84, 260–267.PubMedGoogle Scholar
  50. 50.
    Sung, J. M., Cho, H. J., Yi, H., et al. (2008). Characterization of a stem cell population in lung cancer A549 cells. Biochemical and Biophysical Research Communications, 371, 163–167.PubMedGoogle Scholar
  51. 51.
    Meng, X., Wang, X., & Wang, Y. (2009). More than 45 % of A549 and H446 cells are cancer initiating cells: evidence from cloning and tumorigenic analyses. Oncology Reports, 21, 995–1000.PubMedGoogle Scholar
  52. 52.
    Zhou, J., Wang, H., Cannon, V., et al. (2011). Side population rather than CD133(+) cells distinguishes enriched tumorigenicity in hTERT-immortalized primary prostate cancer cells. Molecular Cancer, 10, 112.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Shmelkov, S. V., Butler, J. M., Hooper, A. T., et al. (2008). CD133 expression is not restricted to stem cells, and both CD133+ and CD133− metastatic colon cancer cells initiate tumors. Journal of Clinical Investigation, 118, 2111–2120.PubMedCentralPubMedGoogle Scholar
  54. 54.
    Jaggupilli, A., & Elkord, E. (2012). Significance of CD44 and CD24 as cancer stem cell markers: An enduring ambiguity. Clinical and Developmental Immunology, 2012, 708036.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Du, L., Wang, H., He, L., et al. (2008). CD44 is of functional importance for colorectal cancer stem cells. Clinical Cancer Research, 14, 6751–6760.PubMedGoogle Scholar
  56. 56.
    Bapat, S. A. (2010). Human ovarian cancer stem cells. Reproduction, 140, 33–41.PubMedGoogle Scholar
  57. 57.
    Lee, H. J., Choe, G., Jheon, S., et al. (2010). CD24, a novel cancer biomarker, predicting disease-free survival of non-small cell lung carcinomas: A retrospective study of prognostic factor analysis from the viewpoint of forthcoming (seventh) new TNM classification. Journal of Thoracic Oncology, 5, 649–657.PubMedGoogle Scholar
  58. 58.
    Slomiany, M. G., Dai, L., Tolliver, L. B., et al. (2009). Inhibition of functional hyaluronan-CD44 interactions in CD133-positive primary human ovarian carcinoma cells by small hyaluronan oligosaccharides. Clinical Cancer Research, 15, 7593–7601.PubMedCentralPubMedGoogle Scholar
  59. 59.
    Leung, E. L., Fiscus, R. R., Tung, J. W., et al. (2010). Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One, 5, e14062.PubMedCentralPubMedGoogle Scholar
  60. 60.
    An, Y., & Ongkeko, W. M. (2009). ABCG2: The key to chemoresistance in cancer stem cells? Expert Opinion on Drug Metabolism and Toxicology, 5, 1529–1542.PubMedGoogle Scholar
  61. 61.
    Ross, D. D., & Nakanishi, T. (2010). Impact of breast cancer resistance protein on cancer treatment outcomes. Methods in Molecular Biology, 596, 251–290.PubMedGoogle Scholar
  62. 62.
    Krishnamurthy, P., Ross, D. D., Nakanishi, T., et al. (2004). The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. Journal of Biological Chemistry, 279, 24218–24225.PubMedGoogle Scholar
  63. 63.
    Ahmed, F., Arseni, N., Glimm, H., et al. (2008). Constitutive expression of the ATP-binding cassette transporter ABCG2 enhances the growth potential of early human hematopoietic progenitors. Stem Cells, 26, 810–818.PubMedGoogle Scholar
  64. 64.
    Levina, V., Marrangoni, A. M., & De Marco, R. (2008). Drugselected human lung cancer stem cells: Cytokine network, tumorigenic and metastatic properties. PLoS One, 3, e3077.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Rosner, M. H., Vigano, M. A., Ozato, K., et al. (1990). A POUdomain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature, 345, 686–692.PubMedGoogle Scholar
  66. 66.
    Hilbe, W., Dirnhofer, S., Oberwasserlechner, F., et al. (2004). CD133 positive endothelial progenitor cells contribute to the tumour vasculature in non-small cell lung cancer. Journal of Clinical Pathology, 57, 965–969.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Herpel, E., Jensen, K., Muley, T., et al. (2011). The cancer stem cell antigens CD133, BCRP1/ABCG2 and CD117/c-KIT are not associated with prognosis in resected early-stage non-small cell lung cancer. Anticancer Research, 31, 4491–4500.PubMedGoogle Scholar
  68. 68.
    Russo, J. E., & Hilton, J. (1998). Characterization of cytosolic aldehyde dehydrogenase from cyclophosphamide resistant L1210 cells. Cancer Research, 48, 2963–2968.Google Scholar
  69. 69.
    Huang, C. P., Tsai, M. F., Chang, T. H., et al. (2013). ALDH positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Cancer Letters, 328, 144–151.PubMedGoogle Scholar
  70. 70.
    Lu, Y., Thomson, J. M., Wong, H. Y., et al. (2007). Transgenic over-expression of the microRNA miR-17-92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells. Development Biology, 310, 442–453.Google Scholar
  71. 71.
    Karamboulas, C., & Ailles, L. (2013). Developmental signaling pathways in cancer stem cells of solid tumors. Biochimica et Biophysica Acta, 1830, 2481–2495.PubMedGoogle Scholar
  72. 72.
    Takebe, N., & Ivy, S. P. (2010). Controversies in cancer stem cells: targeting embryonic signaling pathways. Clinical Cancer Research, 16, 3106–3112.PubMedGoogle Scholar
  73. 73.
    Varjosalo, M., & Taipale, J. (2008). Hedgehog: Functions and mechanisms. Genes and Development, 22, 2454–2472.PubMedGoogle Scholar
  74. 74.
    Sasaki, H., Nishizaki, Y., Hui, C., et al. (1999). Regulation of GLI2 and GLI3 activities by an amino-terminal repression domain: Implication of GLI2 and GLI3 as primary mediators of Shh signaling. Development, 126, 3915–3924.PubMedGoogle Scholar
  75. 75.
    Clement, V., Sanchez, P., de Tribolet, N., et al. (2007). HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell selfrenewal, and tumorigenicity. Current Biology, 17, 165–172.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Peacock, C. D., Wang, Q., Gesell, G. S., et al. (2007). Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proceedings of the National Academy of Sciences of the United States of America, 104, 4048–4053.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Stecca, B., Mas, C., Clement, V., et al. (2007). Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proceedings of the National Academy of Sciences of the United States of America, 104, 5895–5900.PubMedCentralPubMedGoogle Scholar
  78. 78.
    Mukherjee, S., Frolova, N., Sadlonova, A., et al. (2006). Hedgehog signaling and response to cyclopamine differ in epithelial and stromal cells in benign breast and breast cancer. Cancer Biology and Therapy, 5, 674–683.PubMedCentralPubMedGoogle Scholar
  79. 79.
    Yuan, Z., Goetz, J. A., Singh, S., et al. (2007). Frequent requirement of hedgehog signaling in non-small cell lung carcinoma. Oncogene, 26, 1046–1055.PubMedGoogle Scholar
  80. 80.
    Watkins, D. N., Berman, D. M., Burkholder, S. G., et al. (2003). Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature, 422, 313–317.PubMedGoogle Scholar
  81. 81.
    Park, K. S., Martelotto, L. G., Peifer, M., et al. (2011). A crucial requirement for Hedgehog signaling in small cell lung cancer. Nature Medicine, 17, 1504–1508.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Collins, B. J., Kleeberger, W., & Ball, D. W. (2004). Notch in lung development and lung cancer. Seminars in Cancer Biology, 14, 357–364.PubMedGoogle Scholar
  83. 83.
    Richter, S., McWhirter, E., Chen, E. X., et al. (2012). A phase I study of R04929097, an oral gamma secretase inhibitor, in combination with gemcitabine, in patients with advanced solid tumors (PHL-078/CTEP 8575). Journal of Clinical Oncology, 30, 3082.Google Scholar
  84. 84.
    Ito, T., Udaka, N., Yazawa, T., et al. (2000). Basic helix-loop-helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium. Development, 127, 3913–3921.PubMedGoogle Scholar
  85. 85.
    Dang, T. P., Eichenberger, S., Gonzalez, A., et al. (2003). Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice. Oncogene, 22, 1988–1997.PubMedGoogle Scholar
  86. 86.
    Chen, H., Thiagalingam, A., Chopra, H., et al. (1997). Conservation of the Drosophila lateral inhibition pathway in human lung cancer: A hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression. Proceedings of the National Academy of Sciences of the United States of America, 94, 5355–5360.PubMedCentralPubMedGoogle Scholar
  87. 87.
    Osanyingbemi-Obidi, J., Dobromilskaya, I., Illei, P. B., et al. (2011). Notch signaling contributes to lung cancer clonogenic capacity in vitro but may be circumvented in tumorigenesis in vivo. Molecular Cancer Research, 9, 1746–1754.PubMedCentralPubMedGoogle Scholar
  88. 88.
    Konishi, J., Kawaguchi, K. S., Vo, H., et al. (2007). Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Research, 67, 8051–8057.PubMedGoogle Scholar
  89. 89.
    Weijzen, S., Rizzo, P., Braid, M., et al. (2002). Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nature Medicine, 8, 979–986.PubMedGoogle Scholar
  90. 90.
    Westhoff, B., Colaluca, I. N., D’Ario, G., et al. (2009). Alterations of the Notch pathway in lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 106, 22293–22298.PubMedCentralPubMedGoogle Scholar
  91. 91.
    Nicolas, M., Wolfer, A., Raj, K., et al. (2003). Notch1 functions as a tumor suppressor in mouse skin. Nature Genetics, 33, 416–421.PubMedGoogle Scholar
  92. 92.
    Klinakis, A., Lobry, C., Abdel-Wahab, O., et al. (2011). A novel tumour suppressor function for the Notch pathway in myeloid leukaemia. Nature, 473, 230–233.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Liu, Z., Turkoz, A., Jackson, E. N., et al. (2011). Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. Journal of Clinical Investigation, 121, 800–808.PubMedCentralPubMedGoogle Scholar
  94. 94.
    Phng, L. K., & Gerhardt, H. (2009). Angiogenesis: A team effort coordinated by Notch. Developmental Cell, 16, 196–208.PubMedGoogle Scholar
  95. 95.
    Radtke, F., Fasnacht, N., & Macdonald, H. R. (2010). Notch signaling in the immune system. Immunity, 32, 14–27.PubMedGoogle Scholar
  96. 96.
    Willert, K., & Jones, K. A. (2006). Wnt signaling: Is the party in the nucleus? Genes and Development, 20, 1394–1404.PubMedGoogle Scholar
  97. 97.
    He, B., Barg, R. N., You, L., et al. (2005). Wnt signaling in stem cells and non-small-cell lung cancer. Clinical Lung Cancer, 7, 54–60.PubMedGoogle Scholar
  98. 98.
    Uematsu, K., He, B., You, L., et al. (2003). Activation of the Wnt pathway in non small cell lung cancer: Evidence of dishevelled overexpression. Oncogene, 22, 7218–7221.PubMedGoogle Scholar
  99. 99.
    Teng, Y., Wang, X., Wang, Y., et al. (2010). Wnt/beta-catenin signaling regulates cancer stem cells in lung cancer A549 cells. Biochemical and Biophysical Research Communications, 392, 373–379.PubMedGoogle Scholar
  100. 100.
    Yeh, C. T., Wu, A. T., Chang, P. M., et al. (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, 1180–1188.PubMedGoogle Scholar
  101. 101.
    Serrano, D., Bleau, A. M., Fernandez-Garcia, I., et al. (2011). Inhibition of telomerase activity preferentially targets aldehyde dehydrogenase-positive cancer stem-like cells in lung cancer. Molecular Cancer, 10, 96.PubMedCentralPubMedGoogle Scholar
  102. 102.
    He, B., You, L., Uematsu, K., et al. (2004). A monoclonal antibody against Wnt-1 induces apoptosis in human cancer cells. Neoplasia, 6, 7–14.PubMedCentralPubMedGoogle Scholar
  103. 103.
    Tian, F., Mysliwietz, J., Ellwart, J., et al. (2012). Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations. Clinical and Experimental Medicine, 12, 25–30.PubMedGoogle Scholar
  104. 104.
    Levina, V., Marrangoni, A., Wang, T., et al. (2010). Elimination of human lung cancer stem cells through targeting of the stem cell factor-c-kit autocrine signaling loop. Cancer Research, 70, 338–346.PubMedGoogle Scholar
  105. 105.
    Hill, R. P. (2006). Identifying cancer stem cells in solid tumors: Case not proven. Cancer Research, 66, 1891–1895.PubMedGoogle Scholar
  106. 106.
    Kern, S. E., & Shibata, D. (2007). The fuzzy math of solid tumor stem cells: A perspective. Cancer Research, 67, 8985–8988.PubMedGoogle Scholar
  107. 107.
    Kelly, P. N., Dakic, A., Adams, J. M., et al. (2007). Tumor growth need not be driven by rare cancer stem cells. Science, 317, 337.PubMedGoogle Scholar
  108. 108.
    Quintana, E., Shackleton, M., Sabel, M. S., et al. (2008). Efficient tumour formation by single human melanoma cells. Nature, 456, 593–598.PubMedCentralPubMedGoogle Scholar
  109. 109.
    Li, Z., Bao, S., Wu, Q., et al. (2009). Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell, 15, 501–513.PubMedCentralPubMedGoogle Scholar
  110. 110.
    Heddleston, J. M., Li, Z., McLendon, R. E., et al. (2009). The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle, 8, 3274–3284.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Li, L., & Neaves, W. B. (2006). Normal stem cells and cancer stem cells: The niche matters. Cancer Research, 66, 4553–4557.PubMedGoogle Scholar
  112. 112.
    Gupta, P. B., Chaffer, C. L., & Weinberg, R. A. (2009). Cancer stem cells: Mirage or reality? Nature Medicine, 15, 1010–1012.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.School of Life SciencesJilin Agricultural UniversityChangchunChina
  2. 2.School of MedicineUniversity of MarylandBaltimoreUSA

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