Stem Cell Reviews and Reports

, Volume 8, Issue 3, pp 994–1010

Overcoming Challenges of Ovarian Cancer Stem Cells: Novel Therapeutic Approaches

  • Cristóbal Aguilar-Gallardo
  • Emily Cecilia Rutledge
  • Ana M. Martínez-Arroyo
  • Juan José Hidalgo
  • Santiago Domingo
  • Carlos Simón
Article

Abstract

Understanding the genetic and molecular mechanisms of ovarian cancer has been the focus of research efforts working toward the greater goal of improving cancer therapy for patients with residual disease after initial treatment with conventional surgery and neoadjuvant chemotherapy. The focus of this review will be centered on new therapeutic strategies based on Cancer Stem Cells studies of chemoresistant subpopulations, the prevention of metastasis, and individualized therapy in order to find the most successful combination of treatments to effectively treat human ovarian cancer. We reviewed recent literature (1993–2011) of novel treatment approaches to ovarian cancer stem cells. As the focus of ovarian cancer investigation has centered on the cancer stem cell model and the complexities that it presents in the development of effective treatments, the future of treating ovarian cancer lies in utilizing individualized treatment systems that include enhancing existing treatments, aiming for novel therapy targets, managing the plasticity of stem cells to induce cellular differentiation, and regulating oncogenic signaling pathways.

Keywords

Ovarian cancer stem cells Microenvironment New therapeutic approaches 

References

  1. 1.
    National Cancer Institute: Surveillance epidemiology and End Results. http://seer.cancer.gov/statfacts/html/ovary.html.Retrieved December 18, 2010.
  2. 2.
    Ferlay, J., Parkin, D. M., & Steliarova-Foucher, E. (2008). Estimates of cancer incidence and mortality in Europe in. European Journal of Cancer, 46, 765–781.CrossRefGoogle Scholar
  3. 3.
    European commission: Public Health. Available at: http://ec.europa.eu/health/ph_information/dissemination/diseases/cancer.htm. Retrieved December 15, 2010.
  4. 4.
    Leitao, M. M., Jr., & Chi, D. S. (2009). Surgical management of recurrent ovarian cancer. Seminars in Oncology, 36, 106–111.PubMedCrossRefGoogle Scholar
  5. 5.
    Krasner, C., & Duska, L. (2009). Management of women with newly diagnosed ovarian cancer. Seminars in Oncology, 36, 91–105.PubMedCrossRefGoogle Scholar
  6. 6.
    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.PubMedCrossRefGoogle Scholar
  7. 7.
    Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J., & Maitland, N. J. (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Research, 65, 10946–10951.PubMedCrossRefGoogle Scholar
  8. 8.
    Dalerba, P., Dylla, S. J., Park, I. K., et al. (2007). Phenotypic characterization of human colorectal cancer stem cells. Proceedings of the National Academy of Sciences of the United States of America, 104, 10158–10163.PubMedCrossRefGoogle Scholar
  9. 9.
    Li, C., Heidt, D. G., Dalerba, P., et al. (2007). Identification of pancreatic cancer stem cells. Cancer Research, 67, 1030–1037.PubMedCrossRefGoogle Scholar
  10. 10.
    Galli, R., Binda, E., Orfanelli, U., et al. (2004). Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Research, 64, 7011–7021.PubMedCrossRefGoogle Scholar
  11. 11.
    Singh, S. K., Clarke, I. D., Terasaki, M., et al. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Research, 63, 5821–5828.PubMedGoogle Scholar
  12. 12.
    Zhang, S., Balch, C., Chan, M. W., et al. (2008). Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Research, 68, 4311–4320.PubMedCrossRefGoogle Scholar
  13. 13.
    Baba, T., Convery, P. A., Matsumura, N., et al. (2009). Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene, 28, 209–218.PubMedCrossRefGoogle Scholar
  14. 14.
    Curley, M. D., Therrien, V. A., Cummings, C. L., et al. (2009). CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells, 27, 2875–2883.PubMedGoogle Scholar
  15. 15.
    Bapat, S. A., Mali, A. M., Koppikar, C. B., & Kurrey, N. K. (2005). Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. Cancer Research, 65, 3025–3029.PubMedGoogle Scholar
  16. 16.
    Clarke, M. F., Dick, J. E., Dirks, P. B., et al. (2006). Cancer stem cells–perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Research, 66, 9339–9344.PubMedCrossRefGoogle Scholar
  17. 17.
    Ginestier, C., Hur, M. H., Charafe-Jauffret, E., et al. (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 1, 555–567.PubMedCrossRefGoogle Scholar
  18. 18.
    Al-Hajj, M., & Clarke, M. F. (2004). Self-renewal and solid tumor stem cells. Oncogene, 23, 7274–7282.PubMedCrossRefGoogle Scholar
  19. 19.
    Ruiz-Vela, A., Aguilar-Gallardo, C., & Simon, C. (2009). Building a framework for embryonic microenvironments and cancer stem cells. Stem Cell Reviews, 5, 319–327.PubMedCrossRefGoogle Scholar
  20. 20.
    Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 363:943–53.Google Scholar
  21. 21.
    Schwartz, P. E. (2002). Neoadjuvant chemotherapy for the management of ovarian cancer. Best Practice & Research. Clinical Obstetrics & Gynaecology, 16, 585–596.CrossRefGoogle Scholar
  22. 22.
    Phillips, T. M., McBride, W. H., & Pajonk, F. (2006). The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation. Journal of the National Cancer Institute, 98, 1777–1785.PubMedCrossRefGoogle Scholar
  23. 23.
    Bao, S., Wu, Q., McLendon, R. E., et al. (2006). Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature, 444, 756–760.PubMedCrossRefGoogle Scholar
  24. 24.
    Blagosklonny, M. V. (2007). Cancer stem cell and cancer stemloids: from biology to therapy. Cancer Biology & Therapy, 6, 1684–1690.CrossRefGoogle Scholar
  25. 25.
    Ishii, H., Iwatsuki, M., Ieta, K., et al. (2008). Cancer stem cells and chemoradiation resistance. Cancer Science, 99, 1871–1877.PubMedCrossRefGoogle Scholar
  26. 26.
    Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144, 646–674.PubMedCrossRefGoogle Scholar
  27. 27.
    Gupta, P. B., Onder, T. T., Jiang, G., et al. (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 138, 645–659.PubMedCrossRefGoogle Scholar
  28. 28.
    DeNardo, D. G., Andreu, P., & Coussens, L. M. (2010). Interactions between lymphocytes and myeloid cells regulate pro- versus anti-tumor immunity. Cancer Metastasis Reviews, 29, 309–316.PubMedCrossRefGoogle Scholar
  29. 29.
    Grivennikov, S. I., Greten, F. R., & Karin, M. (2010). Immunity, inflammation, and cancer. Cell, 140, 883–899.PubMedCrossRefGoogle Scholar
  30. 30.
    Qian, B. Z., & Pollard, J. W. (2010). Macrophage diversity enhances tumor progression and metastasis. Cell, 141, 39–51.PubMedCrossRefGoogle Scholar
  31. 31.
    Karnoub, A. E., Dash, A. B., Vo, A. P., et al. (2007). Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature, 449, 557–563.PubMedCrossRefGoogle Scholar
  32. 32.
    Lara, P. C., Lloret, M., Clavo, B., et al. (2009). Severe hypoxia induces chemo-resistance in clinical cervical tumors through MVP over-expression. Radiation Oncology, 4, 29.PubMedCrossRefGoogle Scholar
  33. 33.
    Elloul, S., Vaksman, O., Stavnes, H. T., Trope, C. G., Davidson, B., & Reich, R. (2010). Mesenchymal-to-epithelial transition determinants as characteristics of ovarian carcinoma effusions. Clinical & Experimental Metastasis, 27, 161–172.CrossRefGoogle Scholar
  34. 34.
    Pistollato, F., Abbadi, S., Rampazzo, E., et al. (2010). Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem cells Dayton, Ohio, 28, 851–862.PubMedGoogle Scholar
  35. 35.
    Greijer, A. E., van der Groep, P., Kemming, D., et al. (2005). Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). The Journal of Pathology, 206, 291–304.PubMedCrossRefGoogle Scholar
  36. 36.
    Levine, A.J., Puzio-Kuter, A.M. (2010) The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science 3;330(6009):1340–4.Google Scholar
  37. 37.
    DeBerardinis, R. J. (2008). Is cancer a disease of abnormal cellular metabolism? New angles on an old idea. Genetics in Medicine, 10, 767–777.PubMedCrossRefGoogle Scholar
  38. 38.
    Hildebrandt, M. A., Gu, J., & Wu, X. (2009). Pharmacogenomics of platinum-based chemotherapy in NSCLC. Expert Opinion on Drug Metabolism & Toxicology, 5, 745–755.CrossRefGoogle Scholar
  39. 39.
    Surowiak, P., Materna, V., Kaplenko, I., et al. (2006). ABCC2 (MRP2, cMOAT) can be localized in the nuclear membrane of ovarian carcinomas and correlates with resistance to cisplatin and clinical outcome. Clinical Cancer Research, 12, 7149–7158.PubMedCrossRefGoogle Scholar
  40. 40.
    Baekelandt, M. M., Holm, R., Nesland, J. M., Trope, C. G., & Kristensen, G. B. (2000). P-glycoprotein expression is a marker for chemotherapy resistance and prognosis in advanced ovarian cancer. Anticancer Research, 20, 1061–1067.PubMedGoogle Scholar
  41. 41.
    Lu, L., Katsaros, D., Wiley, A., Rigault de la Longrais, I. A., Puopolo, M., & Yu, H. (2007). Expression of MDR1 in epithelial ovarian cancer and its association with disease progression. Oncology Research, 16, 395–403.PubMedGoogle Scholar
  42. 42.
    van Herwaarden, A. E., Wagenaar, E., Karnekamp, B., Merino, G., Jonker, J. W., & Schinkel, A. H. (2006). Breast cancer resistance protein (Bcrp1/Abcg2) reduces systemic exposure of the dietary carcinogens aflatoxin B1, IQ and Trp-P-1 but also mediates their secretion into breast milk. Carcinogenesis, 27, 123–130.PubMedCrossRefGoogle Scholar
  43. 43.
    Zhou, S., Schuetz, J. D., Bunting, K. D., et al. (2001). The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Medicine, 7, 1028–1034.PubMedCrossRefGoogle Scholar
  44. 44.
    Alvi, A. J., Clayton, H., Joshi, C., et al. (2003). Functional and molecular characterisation of mammary side population cells. Breast Cancer Research, 5, R1–R8.PubMedCrossRefGoogle Scholar
  45. 45.
    Cervello, I., Gil-Sanchis, C., Mas, A., et al. (2010). Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells. PLoS One, 5, e10964.PubMedCrossRefGoogle Scholar
  46. 46.
    Hosonuma, S., Kobayashi, Y., Kojo, S., et al. (2011). Clinical significance of side population in ovarian cancer cells. Human Cell, 24, 9–12.PubMedCrossRefGoogle Scholar
  47. 47.
    Szotek, P. P., Pieretti-Vanmarcke, R., Masiakos, P. T., et al. (2006). Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proceedings of the National Academy of Sciences of the United States of America, 103, 11154–11159.PubMedCrossRefGoogle Scholar
  48. 48.
    Hu, L., McArthur, C., & Jaffe, R. B. (2010). Ovarian cancer stem-like side-population cells are tumourigenic and chemoresistant. British Journal of Cancer, 102, 1276–1283.PubMedCrossRefGoogle Scholar
  49. 49.
    Jones, R. J., Matsui, W. H., & Smith, B. D. (2004). Cancer stem cells: are we missing the target? Journal of the National Cancer Institute, 96, 583–585.PubMedCrossRefGoogle Scholar
  50. 50.
    Burger, H., Loos, W. J., Eechoute, K., Verweij, J., Mathijssen, R. H. J., & Wiemer, E. A. C. (2011). Drug transporters of platinum-based anticancer agents and their clinical significance. Drug Resistance Updates, 14, 22–34.PubMedCrossRefGoogle Scholar
  51. 51.
    Kamazawa, S., Kigawa, J., Kanamori, Y., et al. (2002). Multidrug resistance gene-1 is a useful predictor of Paclitaxel-based chemotherapy for patients with ovarian cancer. Gynecologic Oncology, 86, 171–176.PubMedCrossRefGoogle Scholar
  52. 52.
    Yang, G. F., He, W. P., Cai, M. Y., et al. (2010). Intensive expression of Bmi-1 is a new independent predictor of poor outcome in patients with ovarian carcinoma. BMC Cancer, 10, 133.PubMedCrossRefGoogle Scholar
  53. 53.
    Wang, E., Bhattacharyya, S., Szabolcs, A., et al. (2011). Enhancing chemotherapy response with Bmi-1 silencing in ovarian cancer. PLoS One, 6, e17918.PubMedCrossRefGoogle Scholar
  54. 54.
    Rodriguez-Antona, C. (2010). Pharmacogenomics of paclitaxel. Pharmacogenomics, 11, 621–623.PubMedCrossRefGoogle Scholar
  55. 55.
    Wicha, M. S., Liu, S., & Dontu, G. (2006). Cancer stem cells: an old idea–a paradigm shift. Cancer Research, 66, 1883–1890. discussion 95-6.PubMedCrossRefGoogle Scholar
  56. 56.
    Sell, S., & Pierce, G. B. (1994). Maturation arrest of stem cell differentiation is a common pathway for the cellular origin of teratocarcinomas and epithelial cancers. Laboratory Investigation, 70, 6–22.PubMedGoogle Scholar
  57. 57.
    Cavenee, W. K., Dryja, T. P., Phillips, R. A., et al. (1983). Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature, 305, 779–784.PubMedCrossRefGoogle Scholar
  58. 58.
    Nowell, P. C. (1993). Foundations in cancer research. Chromosomes and cancer: the evolution of an idea. Advances in Cancer Research, 62, 1–17.PubMedCrossRefGoogle Scholar
  59. 59.
    Wallace-Brodeur, R. R., & Lowe, S. W. (1999). Clinical implications of p53 mutations. Cellular and Molecular Life Sciences, 55, 64–75.PubMedCrossRefGoogle Scholar
  60. 60.
    Herr, I., & Debatin, K. M. (2001). Cellular stress response and apoptosis in cancer therapy. Blood, 98, 2603–2614.PubMedCrossRefGoogle Scholar
  61. 61.
    Reed, E. C. (1999). Cancer Chemotherapy and Biological Response Modifiers, 18, 144–151.PubMedGoogle Scholar
  62. 62.
    Rolitsky, C. D., Theil, K. S., McGaughy, V. R., Copeland, L. J., & Niemann, T. H. (1999). HER-2/neu amplification and overexpression in endometrial carcinoma. International Journal of Gynecological Pathology, 18, 138–143.PubMedCrossRefGoogle Scholar
  63. 63.
    Slamon, D. J., Godolphin, W., Jones, L. A., et al. (1989). Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science, 244, 707–712.PubMedCrossRefGoogle Scholar
  64. 64.
    Kim, J. W., Lee, C. G., Lyu, M. S., et al. (1997). A new cell line from human undifferentiated carcinoma of the ovary: establishment and characterization. Journal of Cancer Research and Clinical Oncology, 123, 82–90.PubMedCrossRefGoogle Scholar
  65. 65.
    Perez-Caro, M., Cobaleda, C., Gonzalez-Herrero, I., et al. (2009). Cancer induction by restriction of oncogene expression to the stem cell compartment. EMBO Journal, 28, 8–20.PubMedCrossRefGoogle Scholar
  66. 66.
    Bapat, S. A. (2010). Human ovarian cancer stem cells. Reproduction, 140, 33–41.PubMedCrossRefGoogle Scholar
  67. 67.
    Lawrenson, K., & Gayther, S. A. (2009). Ovarian cancer: a clinical challenge that needs some basic answers. PLoS Medicine, 6, e25.PubMedCrossRefGoogle Scholar
  68. 68.
    Deonarain, M. P., Kousparou, C. A., & Epenetos, A. A. (2009). Antibodies targeting cancer stem cells: a new paradigm in immunotherapy? MAbs, 1, 12–25.PubMedCrossRefGoogle Scholar
  69. 69.
    Ferrandina, G., Bonanno, G., Pierelli, L., et al. (2008). Expression of CD133-1 and CD133-2 in ovarian cancer. International Journal of Gynecological Cancer, 18, 506–514.PubMedCrossRefGoogle Scholar
  70. 70.
    Smith, L. M., Nesterova, A., Ryan, M. C., et al. (2008). CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers. British Journal of Cancer, 99, 100–109.PubMedCrossRefGoogle Scholar
  71. 71.
    Naor, D., Sionov, R. V., & Ish-Shalom, D. (1997). CD44: structure, function, and association with the malignant process. Advances in Cancer Research, 71, 241–319.PubMedCrossRefGoogle Scholar
  72. 72.
    Steffensen, K. D., Alvero, A. B., Yang, Y., et al. (2011). Prevalence of epithelial ovarian cancer stem cells correlates with recurrence in early-stage ovarian cancer. J Oncol, 2011, 620523.PubMedCrossRefGoogle Scholar
  73. 73.
    Alvero, A. B., Chen, R., Fu, H. H., et al. (2009). Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle, 8, 158–166.PubMedCrossRefGoogle Scholar
  74. 74.
    Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours. Eur J Cancer 46:1271–7.Google Scholar
  75. 75.
    Heider, K. H., Kuthan, H., Stehle, G., & Munzert, G. (2004). CD44v6: a target for antibody-based cancer therapy. Cancer Immunology, Immunotherapy, 53, 567–579.PubMedCrossRefGoogle Scholar
  76. 76.
    De Stefano I, Battaglia A, Zannoni GF, et al. Hyaluronic acid-paclitaxel: effects of intraperitoneal administration against CD44(+) human ovarian cancer xenografts. Cancer Chemother Pharmacol.Google Scholar
  77. 77.
    Visvader, J. E., & Lindeman, G. J. (2008). Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Reviews. Cancer, 8, 755–768.PubMedCrossRefGoogle Scholar
  78. 78.
    Bellone, S., Siegel, E. R., Cocco, E., et al. (2009). Overexpression of epithelial cell adhesion molecule in primary, metastatic, and recurrent/chemotherapy-resistant epithelial ovarian cancer: implications for epithelial cell adhesion molecule-specific immunotherapy. International Journal of Gynecological Cancer, 19, 860–866.PubMedCrossRefGoogle Scholar
  79. 79.
    Fields, A. L., Keller, A., Schwartzberg, L., et al. (2009). Adjuvant therapy with the monoclonal antibody Edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. Journal of Clinical Oncology, 27, 1941–1947.PubMedCrossRefGoogle Scholar
  80. 80.
    Xiang, W., Wimberger, P., Dreier, T., et al. (2003). Cytotoxic activity of novel human monoclonal antibody MT201 against primary ovarian tumor cells. Journal of Cancer Research and Clinical Oncology, 129, 341–348.PubMedCrossRefGoogle Scholar
  81. 81.
    Richter CE, Cocco E, Bellone S, et al. High-grade, chemotherapy-resistant ovarian carcinomas overexpress epithelial cell adhesion molecule (EpCAM) and are highly sensitive to immunotherapy with MT201, a fully human monoclonal anti-EpCAM antibody. Am J Obstet Gynecol 203:582 e1–7.Google Scholar
  82. 82.
    Fletcher, J. I., Haber, M., Henderson, M. J., & Norris, M. D. (2010). ABC transporters in cancer: more than just drug efflux pumps. Nature Reviews. Cancer, 10, 147–156.PubMedCrossRefGoogle Scholar
  83. 83.
    Schatton, T., Frank, N. Y., & Frank, M. H. (2009). Identification and targeting of cancer stem cells. Bioessays, 31, 1038–1049.PubMedCrossRefGoogle Scholar
  84. 84.
    Soignet, S. L., Benedetti, F., Fleischauer, A., et al. (1998). Clinical study of 9-cis retinoic acid (LGD1057) in acute promyelocytic leukemia. Leukemia, 12(10), 1518–1521.PubMedCrossRefGoogle Scholar
  85. 85.
    Sell, S. (2004). Stem cell origin of cancer and differentiation therapy. Critical Reviews in Oncology/Hematology, 51, 1–28.PubMedCrossRefGoogle Scholar
  86. 86.
    Stefansson, O. A., & Esteller, M. (2011). EZH2-mediated epigenetic repression of DNA repair in promoting breast tumor initiating cells. Breast Cancer Research, 13, 309.PubMedCrossRefGoogle Scholar
  87. 87.
    Chang, C. J., Yang, J. Y., Xia, W., et al. (2011). EZH2 promotes expansion of breast tumor initiating cells through activation of RAF1-beta-catenin signaling. Cancer Cell, 19, 86–100.PubMedCrossRefGoogle Scholar
  88. 88.
    Taddei, A., Roche, D., Bickmore, W. A., & Almouzni, G. (2005). The effects of histone deacetylase inhibitors on heterochromatin: implications for anticancer therapy? EMBO Reports, 6, 520–524.PubMedCrossRefGoogle Scholar
  89. 89.
    Bergmann, M., Romirer, I., Sachet, M., et al. (2001). A genetically engineered influenza A virus with ras-dependent oncolytic properties. Cancer Research, 61, 8188–8193.PubMedGoogle Scholar
  90. 90.
    Behbod, F., & Rosen, J. M. (2005). Will cancer stem cells provide new therapeutic targets? Carcinogenesis, 26, 703–711.PubMedCrossRefGoogle Scholar
  91. 91.
    Blagosklonny, M. V. (2005). Teratogens as anti-cancer drugs. Cell Cycle, 4, 1518–1521.PubMedCrossRefGoogle Scholar
  92. 92.
    Taipale, J., Chen, J. K., Cooper, M. K., et al. (2000). Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature, 406, 1005–1009.PubMedCrossRefGoogle Scholar
  93. 93.
    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.PubMedCrossRefGoogle Scholar
  94. 94.
    Banker, D. E., Mayer, S. J., Li, H. Y., Willman, C. L., Appelbaum, F. R., & Zager, R. A. (2004). Cholesterol synthesis and import contribute to protective cholesterol increments in acute myeloid leukemia cells. Blood, 104, 1816–1824.PubMedCrossRefGoogle Scholar
  95. 95.
    Stirewalt, D. L., Appelbaum, F. R., Willman, C. L., Zager, R. A., & Banker, D. E. (2003). Mevastatin can increase toxicity in primary AMLs exposed to standard therapeutic agents, but statin efficacy is not simply associated with ras hotspot mutations or overexpression. Leukemia Research, 27, 133–145.PubMedCrossRefGoogle Scholar
  96. 96.
    Wu, J., Wong, W. W., Khosravi, F., Minden, M. D., & Penn, L. Z. (2004). Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Cancer Research, 64, 6461–6468.PubMedCrossRefGoogle Scholar
  97. 97.
    Martelli, A. M., Nyakern, M., Tabellini, G., et al. (2006). Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia, 20, 911–928.PubMedCrossRefGoogle Scholar
  98. 98.
    Krause, D. S., & Van Etten, R. A. (2007). Right on target: eradicating leukemic stem cells. Trends in Molecular Medicine, 13, 470–481.PubMedCrossRefGoogle Scholar
  99. 99.
    Kersten, S., & Wahli, W. (2000). Peroxisome proliferator activated receptor agonists. EXS, 89, 141–151.PubMedGoogle Scholar
  100. 100.
    Grommes, C., Landreth, G. E., & Heneka, M. T. (2004). Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. The Lancet Oncology, 5, 419–429.PubMedCrossRefGoogle Scholar
  101. 101.
    Koeffler, H. P. (2003). Peroxisome proliferator-activated receptor gamma and cancers. Clinical Cancer Research, 9, 1–9.PubMedGoogle Scholar
  102. 102.
    Kopelovich, L., Fay, J. R., Glazer, R. I., & Crowell, J. A. (2002). Peroxisome proliferator-activated receptor modulators as potential chemopreventive agents. Molecular Cancer Therapeutics, 1, 357–363.PubMedGoogle Scholar
  103. 103.
    Tontonoz, P., Singer, S., Forman, B. M., et al. (1997). Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proceedings of the National Academy of Sciences of the United States of America, 94, 237–241.PubMedCrossRefGoogle Scholar
  104. 104.
    Sarraf, P., Mueller, E., Jones, D., et al. (1998). Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nature Medicine, 4, 1046–1052.PubMedCrossRefGoogle Scholar
  105. 105.
    Morrison, S. J., Wandycz, A. M., Hemmati, H. D., Wright, D. E., & Weissman, I. L. (1997). Identification of a lineage of multipotent hematopoietic progenitors. Development, 124, 1929–1939.PubMedGoogle Scholar
  106. 106.
    Ruiz-Vela, A., Aguilar-Gallardo, C., Martinez-Arroyo, A.M., Soriano-Navarro, M., Ruiz, V., Simon, C. (2011). Specific unsaturated fatty acids enforce the transdifferentiation of human cancer cells toward adipocyte-like cells. Stem Cell Rev.Google Scholar
  107. 107.
    Semple, R. K., Chatterjee, V. K., & O’Rahilly, S. (2006). PPAR gamma and human metabolic disease. The Journal of Clinical Investigation, 116, 581–589.PubMedCrossRefGoogle Scholar
  108. 108.
    Vignati, S., Albertini, V., Rinaldi, A., et al. (2006). Cellular and molecular consequences of peroxisome proliferator-activated receptor-gamma activation in ovarian cancer cells. Neoplasia, 8, 851–861.PubMedCrossRefGoogle Scholar
  109. 109.
    Holland, C. M., Saidi, S. A., Evans, A. L., et al. (2004). Transcriptome analysis of endometrial cancer identifies peroxisome proliferator-activated receptors as potential therapeutic targets. Molecular Cancer Therapeutics, 3, 993–1001.PubMedGoogle Scholar
  110. 110.
    Shigeto, T., Yokoyama, Y., Xin, B., & Mizunuma, H. (2007). Peroxisome proliferator-activated receptor alpha and gamma ligands inhibit the growth of human ovarian cancer. Oncology Reports, 18, 833–840.PubMedGoogle Scholar
  111. 111.
    Xin, B., Yokoyama, Y., Shigeto, T., Futagami, M., & Mizunuma, H. (2007). Inhibitory effect of meloxicam, a selective cyclooxygenase-2 inhibitor, and ciglitazone, a peroxisome proliferator-activated receptor gamma ligand, on the growth of human ovarian cancers. Cancer, 110, 791–800.PubMedCrossRefGoogle Scholar
  112. 112.
    Yang, Y. C., Tsao, Y. P., Ho, T. C., & Choung, I. P. (2007). Peroxisome proliferator-activated receptor-gamma agonists cause growth arrest and apoptosis in human ovarian carcinoma cell lines. International Journal of Gynecological Cancer, 17, 418–425.PubMedCrossRefGoogle Scholar
  113. 113.
    Gotlieb, W. H., Saumet, J., Beauchamp, M. C., et al. (2008). In vitro metformin anti-neoplastic activity in epithelial ovarian cancer. Gynecologic Oncology, 110, 246–250.PubMedCrossRefGoogle Scholar
  114. 114.
    Rattan, R., Graham, R. P., Maguire, J. L., Giri, S., & Shridhar, V. (2011). Metformin suppresses ovarian cancer growth and metastasis with enhancement of cisplatin cytotoxicity in vivo. Neoplasia, 13, 483–491.PubMedGoogle Scholar
  115. 115.
    Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N., & Struhl, K. (2009). Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Research, 69, 7507–7511.PubMedCrossRefGoogle Scholar
  116. 116.
    Davis, M. E., Chen, Z. G., & Shin, D. M. (2008). Nanoparticle therapeutics: an emerging treatment modality for cancer. Nature Reviews. Drug Discovery, 7, 771–782.PubMedCrossRefGoogle Scholar
  117. 117.
    Chen, Z. G. (2010). Small-molecule delivery by nanoparticles for anticancer therapy. Trends in Molecular Medicine, 16, 594–602.PubMedCrossRefGoogle Scholar
  118. 118.
    Sutton, D., Nasongkla, N., Blanco, E., & Gao, J. (2007). Functionalized micellar systems for cancer targeted drug delivery. Pharmaceutical Research, 24, 1029–1046.PubMedCrossRefGoogle Scholar
  119. 119.
    Boddy, A. V., Plummer, E. R., Todd, R., et al. (2005). A phase I and pharmacokinetic study of paclitaxel poliglumex (XYOTAX), investigating both 3-weekly and 2-weekly schedules. Clinical Cancer Research, 11, 7834–7840.PubMedCrossRefGoogle Scholar
  120. 120.
    Sabbatini, P., Aghajanian, C., Dizon, D., et al. (2004). Phase II study of CT-2103 in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Journal of Clinical Oncology, 22, 4523–4531.PubMedCrossRefGoogle Scholar
  121. 121.
    Eldar-Boock, A., Miller, K., Sanchis, J., Lupu, R., Vicent, M. J., & Satchi-Fainaro, R. (2011). Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel. Biomaterials, 32, 3862–3874.PubMedCrossRefGoogle Scholar
  122. 122.
    Folkman, J. (2007). Angiogenesis: an organizing principle for drug discovery? Nature Reviews. Drug Discovery, 6, 273–286.PubMedCrossRefGoogle Scholar
  123. 123.
    Leskela, S., Leandro-Garcia, L. J., Mendiola, M., et al. (2011). The miR-200 family controls beta-tubulin III expression and is associated with paclitaxel-based treatment response and progression-free survival in ovarian cancer patients. Endocrine-Related Cancer, 18, 85–95.PubMedCrossRefGoogle Scholar
  124. 124.
    Korpal, M., Lee, E. S., Hu, G., & Kang, Y. (2008). The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. Journal of Biological Chemistry, 283, 14910–14914.PubMedCrossRefGoogle Scholar
  125. 125.
    Hu, X., Macdonald, D. M., Huettner, P. C., et al. (2009). A miR-200 microRNA cluster as prognostic marker in advanced ovarian cancer. Gynecologic Oncology, 114, 457–464.PubMedCrossRefGoogle Scholar
  126. 126.
    Wu, Q., Guo, R., Lin, M., Zhou, B., & Wang, Y. (2011). MicroRNA-200a inhibits CD133/1+ ovarian cancer stem cells migration and invasion by targeting E-cadherin repressor ZEB2. Gynecologic Oncology, 122, 149–154.PubMedCrossRefGoogle Scholar
  127. 127.
    Bhattacharya, R., Nicoloso, M., Arvizo, R., et al. (2009). MiR-15a and MiR-16 control Bmi-1 expression in ovarian cancer. Cancer Research, 69, 9090–9095.PubMedCrossRefGoogle Scholar
  128. 128.
    Bell, D. A. (2005). Origins and molecular pathology of ovarian cancer. Modern Pathology, 18(Suppl 2), S19–S32.PubMedCrossRefGoogle Scholar
  129. 129.
    Saga, Y., Ohwada, M., Suzuki, M., et al. (2008). Glutathione peroxidase 3 is a candidate mechanism of anticancer drug resistance of ovarian clear cell adenocarcinoma. Oncology Reports, 20, 1299–1303.PubMedGoogle Scholar
  130. 130.
    Bast, R. C., Jr., Hennessy, B., & Mills, G. B. (2009). The biology of ovarian cancer: new opportunities for translation. Nature Reviews. Cancer, 9, 415–428.PubMedCrossRefGoogle Scholar
  131. 131.
    Frumovitz, M., Schmeler, K. M., Malpica, A., Sood, A. K., & Gershenson, D. M. (2010). Unmasking the complexities of mucinous ovarian carcinoma. Gynecologic Oncology, 117, 491–496.PubMedCrossRefGoogle Scholar
  132. 132.
    Gilks, C. B., & Prat, J. (2009). Ovarian carcinoma pathology and genetics: recent advances. Human Pathology, 40, 1213–1223.PubMedCrossRefGoogle Scholar
  133. 133.
    Storey, D. J., Rush, R., Stewart, M., et al. (2008). Endometrioid epithelial ovarian cancer: 20 years of prospectively collected data from a single center. Cancer, 112, 2211–2220.PubMedCrossRefGoogle Scholar
  134. 134.
    Auersperg, N., Wong, A. S., Choi, K. C., Kang, S. K., & Leung, P. C. (2001). Ovarian surface epithelium: biology, endocrinology, and pathology. Endocrine Reviews, 22, 255–288.PubMedCrossRefGoogle Scholar
  135. 135.
    O’Brien, C. A., Pollett, A., Gallinger, S., & Dick, J. E. (2007). A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature, 445, 106–110.PubMedCrossRefGoogle Scholar
  136. 136.
    Yin, S., Li, J., Hu, C., et al. (2007). CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity. International Journal of Cancer, 120, 1444–1450.CrossRefGoogle Scholar
  137. 137.
    Rappa, G., Fodstad, O., & Lorico, A. (2008). The stem cell-associated antigen CD133 (Prominin-1) is a molecular therapeutic target for metastatic melanoma. Stem Cells, 26, 3008–3017.PubMedCrossRefGoogle Scholar
  138. 138.
    Angelastro, J. M., & Lame, M. W. (2010). Overexpression of CD133 promotes drug resistance in C6 glioma cells. Molecular Cancer Research, 8, 1105–1115.PubMedCrossRefGoogle Scholar
  139. 139.
    Saigusa, S., Tanaka, K., Toiyama, Y., et al. (2010). Immunohistochemical features of CD133 expression: association with resistance to chemoradiotherapy in rectal cancer. Oncology Reports, 24, 345–350.PubMedCrossRefGoogle Scholar
  140. 140.
    Afify, A. M., Ferguson, A. W., Davila, R. M., & Werness, B. A. (2001). Expression of CD44S and CD44v5 is more common in stage III than in stage I serous ovarian carcinomas. Applied Immunohistochemistry & Molecular Morphology, 9, 309–314.CrossRefGoogle Scholar
  141. 141.
    Sillanpaa, S., Anttila, M. A., Voutilainen, K., et al. (2003). CD44 expression indicates favorable prognosis in epithelial ovarian cancer. Clinical Cancer Research, 9, 5318–5324.PubMedGoogle Scholar
  142. 142.
    Hong, S. P., Wen, J., Bang, S., Park, S., & Song, S. Y. (2009). CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. International Journal of Cancer, 125, 2323–2331.CrossRefGoogle Scholar
  143. 143.
    Horst, D., Kriegl, L., Engel, J., Kirchner, T., & Jung, A. (2009). Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer. Cancer Investigation, 27, 844–850.PubMedCrossRefGoogle Scholar
  144. 144.
    Takaishi, S., Okumura, T., Tu, S., et al. (2009). Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells, 27, 1006–1020.PubMedCrossRefGoogle Scholar
  145. 145.
    Oliveras-Ferraros, C., Vazquez-Martin, A., Martin-Castillo, B., et al. (2010). Dynamic emergence of the mesenchymal CD44(pos)CD24(neg/low) phenotype in HER2-gene amplified breast cancer cells with de novo resistance to trastuzumab (Herceptin). Biochemical and Biophysical Research Communications, 397, 27–33.PubMedCrossRefGoogle Scholar
  146. 146.
    Sviatoha, V., Tani, E., Kleina, R., Sperga, M., & Skoog, L. (2010). Immunohistochemical analysis of the S100A1, S100B, CD44 and Bcl-2 antigens and the rate of cell proliferation assessed by Ki-67 antibody in benign and malignant melanocytic tumours. Melanoma Research, 20, 118–125.PubMedCrossRefGoogle Scholar
  147. 147.
    Abeysinghe, H. R., Cao, Q., Xu, J., et al. (2003). THY1 expression is associated with tumor suppression of human ovarian cancer. Cancer Genetics and Cytogenetics, 143, 125–132.PubMedCrossRefGoogle Scholar
  148. 148.
    Lung, H. L., Bangarusamy, D. K., Xie, D., et al. (2005). THY1 is a candidate tumour suppressor gene with decreased expression in metastatic nasopharyngeal carcinoma. Oncogene, 24, 6525–6532.PubMedGoogle Scholar
  149. 149.
    Yang, Z. F., Ho, D. W., Ng, M. N., et al. (2008). Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell, 13, 153–166.PubMedCrossRefGoogle Scholar
  150. 150.
    Kristiansen, G., Denkert, C., Schluns, K., Dahl, E., Pilarsky, C., & Hauptmann, S. (2002). CD24 is expressed in ovarian cancer and is a new independent prognostic marker of patient survival. American Journal of Pathology, 161, 1215–1221.PubMedCrossRefGoogle Scholar
  151. 151.
    Lee, H. J., Kim, D. I., Kwak, C., Ku, J. H., & Moon, K. C. (2008). Expression of CD24 in clear cell renal cell carcinoma and its prognostic significance. Urology, 72, 603–607.PubMedCrossRefGoogle Scholar
  152. 152.
    Nagy, B., Szendroi, A., & Romics, I. (2009). Overexpression of CD24, c-myc and phospholipase 2A in prostate cancer tissue samples obtained by needle biopsy. Pathology Oncology Research, 15, 279–283.PubMedCrossRefGoogle Scholar
  153. 153.
    Yang, X. R., Xu, Y., Yu, B., et al. (2009). CD24 is a novel predictor for poor prognosis of hepatocellular carcinoma after surgery. Clinical Cancer Research, 15, 5518–5527.PubMedCrossRefGoogle Scholar
  154. 154.
    Kajiyama, H., Shibata, K., Ino, K., Mizutani, S., Nawa, A., & Kikkawa, F. (2010). The expression of dipeptidyl peptidase IV (DPPIV/CD26) is associated with enhanced chemosensitivity to paclitaxel in epithelial ovarian carcinoma cells. Cancer Science, 101, 347–354.PubMedCrossRefGoogle Scholar
  155. 155.
    Pang, R., Law, W. L., Chu, A. C., et al. (2010). A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell, 6, 603–615.PubMedCrossRefGoogle Scholar
  156. 156.
    Wei, H., Wang, C., & Chen, L. (2006). Proliferating cell nuclear antigen, survivin, and CD34 expressions in pancreatic cancer and their correlation with hypoxia-inducible factor 1alpha. Pancreas, 32, 159–163.PubMedCrossRefGoogle Scholar
  157. 157.
    Shin, S. J., Jeung, H. C., Ahn, J. B., et al. (2008). Mobilized CD34+ cells as a biomarker candidate for the efficacy of combined maximal tolerance dose and continuous infusional chemotherapy and G-CSF surge in gastric cancer. Cancer Letters, 270, 269–276.PubMedCrossRefGoogle Scholar
  158. 158.
    Jiang, X., Forrest, D., Nicolini, F., et al. (2010). Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate. Blood, 116, 2112–2121.PubMedCrossRefGoogle Scholar
  159. 159.
    Liu, L., Chen, R., Huang, S., et al. (2010). Knockdown of SOD1 sensitizes the CD34+ CML cells to imatinib therapy. Med Oncol.Google Scholar
  160. 160.
    Salnikov, A. V., Groth, A., Apel, A., et al. (2009). Targeting of cancer stem cell marker EpCAM by bispecific antibody EpCAMxCD3 inhibits pancreatic carcinoma. Journal of Cellular and Molecular Medicine, 13, 4023–4033.PubMedCrossRefGoogle Scholar
  161. 161.
    Yamashita, T., Ji, J., Budhu, A., et al. (2009). EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology, 136, 1012–1024.PubMedCrossRefGoogle Scholar
  162. 162.
    Terris, B., Cavard, C., & Perret, C. (2010). EpCAM, a new marker for cancer stem cells in hepatocellular carcinoma. Journal of Hepatology, 52, 280–281.PubMedCrossRefGoogle Scholar
  163. 163.
    Colvin, M., Russo, J. E., Hilton, J., Dulik, D. M., & Fenselau, C. (1988). Enzymatic mechanisms of resistance to alkylating agents in tumor cells and normal tissues. Advances in Enzyme Regulation, 27, 211–221.PubMedCrossRefGoogle Scholar
  164. 164.
    Eastman, A., & Schulte, N. (1988). Enhanced DNA repair as a mechanism of resistance to cis-diamminedichloroplatinum(II). Biochemistry, 27, 4730–4734.PubMedCrossRefGoogle Scholar
  165. 165.
    Bunting, K. D., Lindahl, R., & Townsend, A. J. (1994). Oxazaphosphorine-specific resistance in human MCF-7 breast carcinoma cell lines expressing transfected rat class 3 aldehyde dehydrogenase. Journal of Biological Chemistry, 269, 23197–23203.PubMedGoogle Scholar
  166. 166.
    Carpentino, J. E., Hynes, M. J., Appelman, H. D., et al. (2009). Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Research, 69, 8208–8215.PubMedCrossRefGoogle Scholar
  167. 167.
    Chen, Y. C., Chen, Y. W., Hsu, H. S., et al. (2009). Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochemical and Biophysical Research Communications, 385, 307–313.PubMedCrossRefGoogle Scholar
  168. 168.
    Morimoto, K., Kim, S. J., Tanei, T., et al. (2009). Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression. Cancer Science, 100, 1062–1068.PubMedCrossRefGoogle Scholar
  169. 169.
    Li, T., Su, Y., Mei, Y., et al. (2010). ALDH1A1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients’ outcome. Laboratory Investigation, 90, 234–244.PubMedCrossRefGoogle Scholar
  170. 170.
    Bleau, A. M., Huse, J. T., & Holland, E. C. (2009). The ABCG2 resistance network of glioblastoma. Cell Cycle, 8, 2936–2944.PubMedCrossRefGoogle Scholar
  171. 171.
    Hegedus, C., Ozvegy-Laczka, C., Apati, A., et al. (2009). Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. British Journal of Pharmacology, 158, 1153–1164.PubMedCrossRefGoogle Scholar
  172. 172.
    Agarwal, S., Sane, R., Gallardo, J. L., Ohlfest, J. R., & Elmquist, W. F. (2010). Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. Journal of Pharmacology and Experimental Therapeutics, 334, 147–155.PubMedCrossRefGoogle Scholar
  173. 173.
    Ding, X. W., Wu, J. H., & Jiang, C. P. (2010). ABCG2: a potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sciences, 86, 631–637.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Cristóbal Aguilar-Gallardo
    • 1
  • Emily Cecilia Rutledge
    • 1
  • Ana M. Martínez-Arroyo
    • 1
  • Juan José Hidalgo
    • 3
  • Santiago Domingo
    • 3
  • Carlos Simón
    • 1
    • 2
  1. 1.Valencia Node of the Spanish Stem Cell Bank, Prince Felipe Research Centre (CIPF)ValenciaSpain
  2. 2.Fundación IVI-Instituto Universitario IVIValencia UniversityValenciaSpain
  3. 3.University Hospital “La Fe”ValenciaSpain

Personalised recommendations