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Ovarian Cancer Stem Cells: Characterization and Role in Tumorigenesis

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Ovarian Cancer: Molecular & Diagnostic Imaging and Treatment Strategies

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1330))

Abstract

Ovarian cancer is a heterogenous disease with variable clinicopathological and molecular mechanisms being responsible for tumorigenesis. Despite substantial technological improvement, lack of early diagnosis contributes to its highest mortality. Ovarian cancer is considered to be the most lethal female gynaecological cancer across the world. Conventional treatment modules with platinum- and Taxane-based chemotherapy can cause an initial satisfactory improvement in ovarian cancer patients. However, approximately 75–80% patients of advanced stage ovarian cancer, experience relapse and nearly 40% have overall poor survival rate. It has been observed that a subpopulation of cells referred as cancer stem cells (CSCs), having self renewal property, escape the conventional chemotherapy because of their quiescent nature. Later, these CSCs following its interaction with microenvironment and release of various inflammatory cytokines, chemokines and matrix metalloproteinases, induce invasion and propagation to distant organs of the body mainly peritoneal cavity. These CSCs can be enriched by their specific surface markers such as CD44, CD117, CD133 and intracellular enzyme such as aldehyde dehydrogenase. This tumorigenicity is further aggravated by the epithelial to mesenchymal transition of CSCs and neovascularisation via epigenetic reprogramming and over-expression of various signalling cascades such as Wnt/β-catenin, NOTCH, Hedgehog, etc. to name a few. Hence, a comprehensive understanding of various cellular events involving interaction between cancer cells and cancer stem cells as well as its surrounding micro environmental components would be of unmet need to achieve the ultimate goal of better management of ovarian cancer patients. This chapter deals with the impact of ovarian cancer stem cells in tumorigenesis which would help in the implementation of basic research into the clinical field in the form of translational research in order to reduce the morbidity and mortality in ovarian cancer patients through amelioration of diagnosis and impoverishment of therapeutic resistance.

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References

  1. Lheureux, S., Gourley, C., Vergote, I., & Oza, A. M. (2019). Epithelial ovarian cancer. The Lancet, 393(10177), 1240–1253.

    Article  Google Scholar 

  2. World ovarian cancer coalition. (2020). Retrieved from https://worldovariancancercoalition.org/.

  3. Key Statistics for Ovarian Cancer. American Cancer Society. (2020). Retrieved from https://www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html.

  4. Motohara, T., & Katabuchi, H. (2019). Ovarian cancer stemness: Biological and clinical implications for metastasis and chemotherapy resistance. Cancers, 11(7), 907.

    Article  CAS  PubMed Central  Google Scholar 

  5. Stewart, C., Ralyea, C., & Lockwood, S. (2019). Ovarian cancer: An integrated review. Seminars in Oncology Nursing, 35(2), 151–156.

    Article  PubMed  Google Scholar 

  6. Ayob, A. Z., & Ramasamy, T. S. (2018). Cancer stem cells as key drivers of tumour progression. Journal of Biomedical Science, 25(1), 1–18.

    Article  CAS  Google Scholar 

  7. Zuber, E., Schweitzer, D., Allen, D., Parte, S., & Kakar, S. S. (2020). Stem cells in ovarian cancer and potential therapies. Proceedings of Stem Cell Research and Oncogenesis, 8, e1001.

    PubMed  PubMed Central  Google Scholar 

  8. Pieterse, Z., Amaya-Padilla, M. A., Singomat, T., Binju, M., Madjid, B. D., Yu, Y., et al. (2019). Ovarian cancer stem cells and their role in drug resistance. The International Journal of Biochemistry & Cell Biology, 106, 117–126.

    Article  CAS  Google Scholar 

  9. Zhang, Y., Roos, M., Himburg, H., Termini, C. M., Quarmyne, M., Li, M., et al. (2019). PTPσ inhibitors promote hematopoietic stem cell regeneration. Nature Communications, 10(1), 1–15.

    CAS  Google Scholar 

  10. Prasetyanti, P. R., & Medema, J. P. (2017). Intra-tumor heterogeneity from a cancer stem cell perspective. Molecular Cancer, 16(1), 1–9.

    Article  CAS  Google Scholar 

  11. Meacham, C. E., & Morrison, S. J. (2013). Tumour heterogeneity and cancer cell plasticity. Nature, 501(7467), 328–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Melo, F. D. S. E., Vermeulen, L., Fessler, E., & Medema, J. P. (2013). Cancer heterogeneity—A multifaceted view. EMBO Reports, 14(8), 686–695.

    Article  CAS  PubMed Central  Google Scholar 

  13. Sasaki, R., Narisawa-Saito, M., Yugawa, T., Fujita, M., Tashiro, H., Katabuchi, H., et al. (2009). Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes. Carcinogenesis, 30(3), 423–431.

    Article  CAS  PubMed  Google Scholar 

  14. Kakar, S., & Jennes, L. (1999). Molecular cloning and characterization of the tumor transforming gene (TUTR1): A novel gene in human tumorigenesis. Cytogenetic and Genome Research, 84(3–4), 211–216.

    Article  CAS  Google Scholar 

  15. Puri, R., Tousson, A., Chen, L., & Kakar, S. S. (2001). Molecular cloning of pituitary tumor transforming gene 1 from ovarian tumors and its expression in tumors. Cancer Letters, 163(1), 131–139.

    Article  CAS  PubMed  Google Scholar 

  16. Hamid, T., Malik, M. T., & Kakar, S. S. (2005). Ectopic expression of PTTG1/securin promotes tumorigenesis in human embryonic kidney cells. Molecular Cancer, 4(1), 3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Parte, S., Virant-Klun, I., Patankar, M., Batra, S. K., Straughn, A., & Kakar, S. S. (2019). PTTG1: A unique regulator of stem/cancer stem cells in the ovary and ovarian cancer. Stem Cell Reviews and Reports, 15(6), 866–879.

    Article  CAS  PubMed  Google Scholar 

  18. Berebichez-Fridman, R., & Montero-Olvera, P. R. (2018). Sources and clinical applications of mesenchymal stem cells: State-of-the-art review. Sultan Qaboos University Medical Journal, 18(3), e264.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819), 154–156.

    Article  CAS  PubMed  Google Scholar 

  20. Martin, G. R. (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proceedings of the National Academy of Sciences, 78(12), 7634–7638.

    Article  CAS  Google Scholar 

  21. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145–1147.

    Article  CAS  PubMed  Google Scholar 

  22. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.

    Article  CAS  PubMed  Google Scholar 

  23. Shibata, M., & Hoque, M. O. (2019). Targeting cancer stem cells: A strategy for effective eradication of cancer. Cancers, 11(5), 732.

    Article  CAS  PubMed Central  Google Scholar 

  24. Konrad, C. V., Murali, R., Varghese, B. A., & Nair, R. (2017). The role of cancer stem cells in tumor heterogeneity and resistance to therapy. Canadian Journal of Physiology and Pharmacology, 95(1), 1–15.

    Article  CAS  PubMed  Google Scholar 

  25. Miranda-Lorenzo, I., Dorado, J., Lonardo, E., Alcala, S., Serrano, A. G., Clausell-Tormos, J., et al. (2014). Intracellular autofluorescence: A biomarker for epithelial cancer stem cells. Nature Methods, 11(11), 1161.

    Article  CAS  PubMed  Google Scholar 

  26. Szotek, P. P., Chang, H. L., Brennand, K., Fujino, A., Pieretti-Vanmarcke, R., Celso, C. L., et al. (2008). Normal ovarian surface epithelial label-retaining cells exhibit stem/progenitor cell characteristics. Proceedings of the National Academy of Sciences, 105(34), 12469–12473.

    Article  CAS  Google Scholar 

  27. Hu, L., McArthur, C., & Jaffe, R. (2010). Ovarian cancer stem-like side-population cells are tumourigenic and chemoresistant. British Journal of Cancer, 102(8), 1276–1283.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Choi, Y.-L., Kim, S.-H., Shin, Y. K., Hong, Y.-C., Lee, S.-J., Kang, S. Y., et al. (2005). Cytoplasmic CD24 expression in advanced ovarian serous borderline tumors. Gynecologic Oncology, 97(2), 379–386.

    Article  CAS  PubMed  Google Scholar 

  29. Nakamura, K., Terai, Y., Tanabe, A., Ono, Y. J., Hayashi, M., Maeda, K., et al. (2017). CD24 expression is a marker for predicting clinical outcome and regulates the epithelial-mesenchymal transition in ovarian cancer via both the Akt and ERK pathways. Oncology Reports, 37(6), 3189–3200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Meng, E., Long, B., Sullivan, P., McClellan, S., Finan, M. A., Reed, E., et al. (2012). CD44+/CD24− ovarian cancer cells demonstrate cancer stem cell properties and correlate to survival. Clinical & Experimental Metastasis, 29(8), 939–948.

    Article  CAS  Google Scholar 

  31. Raspollini, M., Amunni, G., Villanucci, A., Baroni, G., Taddei, A., & Taddei, G. (2004). c-KIT expression and correlation with chemotherapy resistance in ovarian carcinoma: An immunocytochemical study. Annals of Oncology, 15(4), 594–597.

    Article  CAS  PubMed  Google Scholar 

  32. Baba, T., Convery, P., Matsumura, N., Whitaker, R., Kondoh, E., Perry, T., et al. (2009). Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene, 28(2), 209–218.

    Article  CAS  PubMed  Google Scholar 

  33. Landen, C. N., Goodman, B., Katre, A. A., Steg, A. D., Nick, A. M., Stone, R. L., et al. (2010). Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Molecular Cancer Therapeutics, 9(12), 3186–3199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang, S., Balch, C., Chan, M. W., Lai, H.-C., Matei, D., Schilder, J. M., et al. (2008). Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Research, 68(11), 4311–4320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kusumbe, A. P., & Bapat, S. A. (2009). Cancer stem cells and aneuploid populations within developing tumors are the major determinants of tumor dormancy. Cancer Research, 69(24), 9245–9253.

    Article  CAS  PubMed  Google Scholar 

  36. Alvero, A. B., Chen, R., Fu, H.-H., Montagna, M., Schwartz, P. E., Rutherford, T., et al. (2009). Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance. Cell Cycle, 8(1), 158–166.

    Article  CAS  PubMed  Google Scholar 

  37. Alvero, A. B., Fu, H. H., Holmberg, J., Visintin, I., Mor, L., Marquina, C. C., et al. (2009). Stem-like ovarian cancer cells can serve as tumor vascular progenitors. Stem Cells, 27(10), 2405–2413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang, J., Yuan, B., Zhang, H., & Li, H. (2019). Human epithelial ovarian cancer cells expressing CD105, CD44 and CD106 surface markers exhibit increased invasive capacity and drug resistance. Oncology Letters, 17(6), 5351–5360.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Tayama, S., Motohara, T., Narantuya, D., Li, C., Fujimoto, K., Sakaguchi, I., et al. (2017). The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer. Oncotarget, 8(27), 44312.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zheng, J., Zhao, S., Yu, X., Huang, S., & Liu, H. Y. (2017). Simultaneous targeting of CD44 and EpCAM with a bispecific aptamer effectively inhibits intraperitoneal ovarian cancer growth. Theranostics, 7(5), 1373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wen, Y., Hou, Y., Huang, Z., Cai, J., & Wang, Z. (2017). SOX 2 is required to maintain cancer stem cells in ovarian cancer. Cancer Science, 108(4), 719–731.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang, H., Qiu, J., Ye, C., Yang, D., Gao, L., Su, Y., et al. (2014). ROR1 expression correlated with poor clinical outcome in human ovarian cancer. Scientific Reports, 4, 5811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lee, M., Nam, E. J., Kim, S. W., Kim, S., Kim, J. H., & Kim, Y. T. (2012). Prognostic impact of the cancer stem cell–related marker NANOG in ovarian serous carcinoma. International Journal of Gynecologic Cancer, 22(9), 1489–1496.

    Article  Google Scholar 

  44. Ruan, Z., Yang, X., & Cheng, W. (2019). OCT4 accelerates tumorigenesis through activating JAK/STAT signaling in ovarian cancer side population cells. Cancer Management and Research, 11, 389.

    Article  CAS  PubMed  Google Scholar 

  45. Ning, Y.-X., Luo, X., Xu, M., Feng, X., & Wang, J. (2017). Let-7d increases ovarian cancer cell sensitivity to a genistein analog by targeting c-Myc. Oncotarget, 8(43), 74836.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Dou, J., Jiang, C., Wang, J., Zhang, X., Zhao, F., Hu, W., et al. (2011). Using ABCG2-molecule-expressing side population cells to identify cancer stem-like cells in a human ovarian cell line. Cell Biology International, 35(3), 227–234.

    Article  CAS  PubMed  Google Scholar 

  47. Schindler, A. J., Watanabe, A., & Howell, S. B. (2018). LGR5 and LGR6 in stem cell biology and ovarian cancer. Oncotarget, 9(1), 1346.

    Article  PubMed  Google Scholar 

  48. Ng, A., Tan, S., Singh, G., Rizk, P., Swathi, Y., Tan, T. Z., et al. (2014). Lgr5 marks stem/progenitor cells in ovary and tubal epithelia. Nature Cell Biology, 16(8), 745–757.

    Article  CAS  PubMed  Google Scholar 

  49. Hashimoto, H., Sudo, T., Mikami, Y., Otani, M., Takano, M., Tsuda, H., et al. (2008). Germ cell specific protein VASA is over-expressed in epithelial ovarian cancer and disrupts DNA damage-induced G2 checkpoint. Gynecologic Oncology, 111(2), 312–319.

    Article  CAS  PubMed  Google Scholar 

  50. Virant-Klun, I., Kenda-Suster, N., & Smrkolj, S. (2016). Small putative NANOG, SOX2, and SSEA-4-positive stem cells resembling very small embryonic-like stem cells in sections of ovarian tissue in patients with ovarian cancer. Journal of Ovarian Research, 9(1), 12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Bapat, S. A. (2010). Human ovarian cancer stem cells. Reproduction (Cambridge, England), 140(1), 33.

    Article  CAS  Google Scholar 

  52. Padilla, M. A. A., Binju, M., Wan, G., Rahmanto, Y. S., Kaur, P., & Yu, Y. (2019). Relationship between ovarian cancer stem cells, epithelial mesenchymal transition and tumour recurrence. Cancer Drug Resistance, 2, 1127–1135.

    PubMed  PubMed Central  Google Scholar 

  53. Nimmakayala, R. K., Batra, S. K., & Ponnusamy, M. P. (2019). Unraveling the journey of cancer stem cells from origin to metastasis. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1871(1), 50–63.

    Article  CAS  Google Scholar 

  54. Tirino, V., Desiderio, V., Paino, F., De Rosa, A., Papaccio, F., Fazioli, F., et al. (2011). Human primary bone sarcomas contain CD133+ cancer stem cells displaying high tumorigenicity in vivo. The FASEB Journal, 25(6), 2022–2030.

    Article  CAS  PubMed  Google Scholar 

  55. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: THE next generation. Cell, 144(5), 646–674.

    Article  CAS  PubMed  Google Scholar 

  56. Moharil, R. B., Dive, A., Khandekar, S., & Bodhade, A. (2017). Cancer stem cells: An insight. Journal of Oral and Maxillofacial Pathology, 21(3), 463.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Abildgaard, C., Do Canto, L. M., Steffensen, K. D., & Rogatto, S. R. (2019). Long non-coding RNAs involved in resistance to chemotherapy in ovarian cancer. Frontiers in Oncology, 9, 1549.

    Article  PubMed  Google Scholar 

  58. Papaccio, F., Paino, F., Regad, T., Papaccio, G., Desiderio, V., & Tirino, V. (2017). Concise review: Cancer cells, cancer stem cells, and mesenchymal stem cells: Influence in cancer development. Stem Cells Translational Medicine, 6(12), 2115–2125.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F., & Kirchner, T. (2005). Migrating cancer stem cells—An integrated concept of malignant tumour progression. Nature Reviews. Cancer, 5(9), 744–749.

    Article  CAS  PubMed  Google Scholar 

  60. Diaz-Cano, S. J. (2012). Tumor heterogeneity: Mechanisms and bases for a reliable application of molecular marker design. International Journal of Molecular Sciences, 13(2), 1951–2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Koźlik, M., & Wójcicki, P. (2014). The use of stem cells in plastic and reconstructive surgery. Advances in Clinical and Experimental Medicine, 23(6), 1011–1017.

    Article  PubMed  Google Scholar 

  62. Giuseppe Longo, U., Rizzello, G., Berton, A., Ciuffreda, M., Migliorini, F., Khan, W. S., et al. (2013). Potential of adipose derived stem cells in orthopaedic surgery. Current Stem Cell Research & Therapy, 8(6), 418–421.

    Article  Google Scholar 

  63. Gimble, J. M., Bunnell, B. A., & Guilak, F. (2012). Human adipose-derived cells: An update on the transition to clinical translation. Regenerative Medicine, 7(2), 225–235.

    Article  CAS  PubMed  Google Scholar 

  64. Pan, Y., Ma, S., Cao, K., Zhou, S., Zhao, A., Li, M., et al. (2018). Therapeutic approaches targeting cancer stem cells. Journal of Cancer Research and Therapeutics, 14(7), 1469.

    Article  CAS  PubMed  Google Scholar 

  65. Rahman, M., Deleyrolle, L., Vedam-Mai, V., Azari, H., Abd-El-Barr, M., & Reynolds, B. A. (2011). The cancer stem cell hypothesis: Failures and pitfalls. Neurosurgery, 68(2), 531–545.

    Article  PubMed  Google Scholar 

  66. O’Flaherty, J. D., Barr, M., Fennell, D., Richard, D., Reynolds, J., O’Leary, J., 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(12), 1880–1890.

    Article  PubMed  CAS  Google Scholar 

  67. Ponnusamy, M. P., & Batra, S. K. (2008). Ovarian cancer: Emerging concept on cancer stem cells. Journal of Ovarian Research, 1(1), 4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Nelson, H. D., Westhoff, C., Piepert, J., & Berg, A. (2004). Screening for ovarian cancer: Brief evidence update. Agency for Healthcare Research and Quality: Rockville, MD.

    Google Scholar 

  69. Roett, M. A., & Evans, P. (2009). Ovarian cancer: An overview. American Family Physician, 80(6), 609–616.

    PubMed  Google Scholar 

  70. Pal, T., Permuth-Wey, J., Betts, J. A., Krischer, J. P., Fiorica, J., Arango, H., et al. (2005). BRCA1 and BRCA2 mutations account for a large proportion of ovarian carcinoma cases. Cancer: Interdisciplinary International Journal of the American Cancer Society, 104(12), 2807–2816.

    Article  CAS  Google Scholar 

  71. Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., et al. (1995). Identification of the breast cancer susceptibility gene BRCA2. Nature, 378(6559), 789–792.

    Article  CAS  PubMed  Google Scholar 

  72. Struewing, J. P., Hartge, P., Wacholder, S., Baker, S. M., Berlin, M., McAdams, M., et al. (1997). The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England Journal of Medicine, 336(20), 1401–1408.

    Article  CAS  PubMed  Google Scholar 

  73. Moslehi, R., Chu, W., Karlan, B., Fishman, D., Risch, H., Fields, A., et al. (2000). BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer. The American Journal of Human Genetics, 66(4), 1259–1272.

    Article  CAS  PubMed  Google Scholar 

  74. Risch, H. A., McLaughlin, J. R., Cole, D. E., Rosen, B., Bradley, L., Kwan, E., et al. (2001). Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. The American Journal of Human Genetics, 68(3), 700–710.

    Article  CAS  PubMed  Google Scholar 

  75. Chen, S., & Parmigiani, G. (2007). Meta-analysis of BRCA1 and BRCA2 penetrance. Journal of Clinical Oncology, 25(11), 1329.

    Article  PubMed  Google Scholar 

  76. Evans, D., Young, K., Bulman, M., Shenton, A., Wallace, A., & Lalloo, F. (2008). Probability of BRCA1/2 mutation varies with ovarian histology: Results from screening 442 ovarian cancer families. Clinical Genetics, 73(4), 338–345.

    Article  CAS  PubMed  Google Scholar 

  77. Bolton, K. L., Chenevix-Trench, G., Goh, C., Sadetzki, S., Ramus, S. J., Karlan, B. Y., et al. (2012). Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. Journal of the American Medical Association, 307(4), 382–389.

    Article  CAS  PubMed  Google Scholar 

  78. Ben David, Y., Chetrit, A., Hirsh-Yechezkel, G., Friedman, E., Beck, B., Beller, U., et al. (2002). Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. Journal of Clinical Oncology, 20(2), 463–466.

    Article  CAS  PubMed  Google Scholar 

  79. Cass, I., Baldwin, R. L., Varkey, T., Moslehi, R., Narod, S. A., & Karlan, B. Y. (2003). Improved survival in women with BRCA-associated ovarian carcinoma. Cancer: Interdisciplinary International Journal of the American Cancer Society, 97(9), 2187–2195.

    Article  CAS  Google Scholar 

  80. Meindl, A., Hellebrand, H., Wiek, C., Erven, V., Wappenschmidt, B., Niederacher, D., et al. (2010). Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nature Genetics, 42(5), 410–414.

    Article  CAS  PubMed  Google Scholar 

  81. Osorio, A., Endt, D., Fernández, F., Eirich, K., de la Hoya, M., Schmutzler, R., et al. (2012). Predominance of pathogenic missense variants in the RAD51C gene occurring in breast and ovarian cancer families. Human Molecular Genetics, 21(13), 2889–2898.

    Article  CAS  PubMed  Google Scholar 

  82. Pelttari, L. M., Heikkinen, T., Thompson, D., Kallioniemi, A., Schleutker, J., Holli, K., et al. (2011). RAD51C is a susceptibility gene for ovarian cancer. Human Molecular Genetics, 20(16), 3278–3288.

    Article  CAS  PubMed  Google Scholar 

  83. Loveday, C., Turnbull, C., Ramsay, E., Hughes, D., Ruark, E., Frankum, J. R., et al. (2011). Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nature Genetics, 43(9), 879–882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ahmed, N., Kadife, E., Raza, A., Short, M., Jubinsky, P. T., & Kannourakis, G. (2020). Ovarian cancer, Cancer stem cells and current treatment strategies: A potential role of magmas in the current treatment methods. Cell, 9(3), 719.

    Article  CAS  Google Scholar 

  85. Virant-Klun, I., & Stimpfel, M. (2016). Novel population of small tumour-initiating stem cells in the ovaries of women with borderline ovarian cancer. Scientific Reports, 6, 34730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Visvader, J. E., & Lindeman, G. J. (2008). Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nature Reviews. Cancer, 8(10), 755–768.

    Article  CAS  PubMed  Google Scholar 

  87. Agro, L., & O’Brien, C. (2015). In vitro and in vivo limiting dilution assay for colorectal cancer. Bio-Protocol, 5(22), 1.

    Article  CAS  PubMed  Google Scholar 

  88. 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(8), 3025–3029.

    Article  CAS  PubMed  Google Scholar 

  89. Luo, L., Zeng, J., Liang, B., Zhao, Z., Sun, L., Cao, D., et al. (2011). Ovarian cancer cells with the CD117 phenotype are highly tumorigenic and are related to chemotherapy outcome. Experimental and Molecular Pathology, 91(2), 596–602.

    Article  CAS  PubMed  Google Scholar 

  90. Štemberger-Papić, S., Vrdoljak-Mozetič, D., Verša Ostojić, D., Rubeša-Mihaljević, R., Krištofić, I., Brnčić-Fischer, A., et al. (2015). Expression of CD133 and CD117 in 64 serous ovarian cancer cases. Collegium Antropologicum, 39(3), 745–753.

    PubMed  Google Scholar 

  91. Conic, I., Stanojevic, Z., Jankovic Velickovic, L., Stojnev, S., Ristic Petrovic, A., Krstic, M., et al. (2015). Epithelial ovarian cancer with CD117 phenotype is highly aggressive and resistant to chemotherapy. Journal of Obstetrics and Gynaecology Research, 41(10), 1630–1637.

    Article  CAS  PubMed  Google Scholar 

  92. Curley, M. D., Therrien, V. A., Cummings, C. L., Sergent, P. A., Koulouris, C. R., Friel, A. M., et al. (2009). CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells, 27(12), 2875–2883.

    Article  CAS  PubMed  Google Scholar 

  93. Skubitz, A. P., Taras, E. P., Boylan, K. L., Waldron, N. N., Oh, S., Panoskaltsis-Mortari, A., et al. (2013). Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression. Gynecologic Oncology, 130(3), 579–587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang, J., Guo, X., Chang, D. Y., Rosen, D. G., Mercado-Uribe, I., & Liu, J. (2012). CD133 expression associated with poor prognosis in ovarian cancer. Modern Pathology, 25(3), 456–464.

    Article  CAS  PubMed  Google Scholar 

  95. Burgos-Ojeda, D., Rueda, B. R., & Buckanovich, R. J. (2012). Ovarian cancer stem cell markers: Prognostic and therapeutic implications. Cancer Letters, 322(1), 1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jaggupilli, A., & Elkord, E. (2012). Significance of CD44 and CD24 as cancer stem cell markers: An enduring ambiguity. Clinical and Developmental Immunology, 2012, 708036.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Wang, Y., Shao, F., & Chen, L. (2018). ALDH1A2 suppresses epithelial ovarian cancer cell proliferation and migration by downregulating STAT3. OncoTargets and Therapy, 11, 599.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Wang, Y.-C., Yo, Y.-T., Lee, H.-Y., Liao, Y.-P., Chao, T.-K., Su, P.-H., et al. (2012). ALDH1-bright epithelial ovarian cancer cells are associated with CD44 expression, drug resistance, and poor clinical outcome. The American Journal of Pathology, 180(3), 1159–1169.

    Article  CAS  PubMed  Google Scholar 

  99. Januchowski, R., Wojtowicz, K., Sterzyſska, K., Sosiſska, P., Andrzejewska, M., Zawierucha, P., et al. (2016). Inhibition of ALDH1A1 activity decreases expression of drug transporters and reduces chemotherapy resistance in ovarian cancer cell lines. The International Journal of Biochemistry & Cell Biology, 78, 248–259.

    Article  CAS  Google Scholar 

  100. Ng, P. M.-L., & Lufkin, T. (2011). Embryonic stem cells: Protein interaction networks. Biomolecular Concepts, 2(1–2), 13–25.

    CAS  PubMed  Google Scholar 

  101. Szotek, P. P., Pieretti-Vanmarcke, R., Masiakos, P. T., Dinulescu, D. M., Connolly, D., Foster, R., 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, 103(30), 11154–11159.

    Article  CAS  Google Scholar 

  102. Vathipadiekal, V., Saxena, D., Mok, S. C., Hauschka, P. V., Ozbun, L., & Birrer, M. J. (2012). Identification of a potential ovarian cancer stem cell gene expression profile from advanced stage papillary serous ovarian cancer. PLoS One, 7(1), e29079.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Parte, S. C., Smolenkov, A., Batra, S. K., Ratajczak, M. Z., & Kakar, S. S. (2017). Ovarian cancer stem cells: Unraveling a germline connection. Stem Cells and Development, 26(24), 1781–1803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Parte, S. C., Batra, S. K., & Kakar, S. S. (2018). Characterization of stem cell and cancer stem cell populations in ovary and ovarian tumors. Journal of Ovarian Research, 11(1), 69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Udoh, K., Parte, S., Carter, K., Mack, A., & Kakar, S. S. (2019). Targeting of lung cancer stem cell self-renewal pathway by a small molecule verrucarin. Journal of Stem Cell Reviews and Reports, 15(4), 601–611.

    Article  CAS  PubMed  Google Scholar 

  106. Carter, K., Rameshwar, P., Ratajczak, M. Z., & Kakar, S. S. (2017). Verrucarin J inhibits ovarian cancer and targets cancer stem cells. Oncotarget, 8(54), 92743.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Kakar, S. S., Parte, S., Kelsey Carter, I. G. J., Worth, C., Rameshwar, P., & Ratajczak, M. Z. (2017). Withaferin A (WFA) inhibits tumor growth and metastasis by targeting ovarian cancer stem cells. Oncotarget, 8(43), 74494.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Kakar, S. S., Worth, C. A., Wang, Z., Carter, K., Ratajczak, M., & Gunjal, P. (2016). DOXIL when combined with Withaferin A (WFA) targets ALDH1 positive cancer stem cells in ovarian cancer. Journal of Cancer Stem Cell Research, 4, e1002.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kakar, S. S., Ratajczak, M. Z., Powell, K. S., Moghadamfalahi, M., Miller, D. M., Batra, S. K., et al. (2014). Withaferin a alone and in combination with cisplatin suppresses growth and metastasis of ovarian cancer by targeting putative cancer stem cells. PLoS One, 9(9), e107596.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Yang, Y., Yang, Y., Yang, J., Zhao, X., & Wei, X. (2020). Tumor microenvironment in ovarian cancer: Function and therapeutic strategy. Frontiers in Cell and Developmental Biology, 8, 758.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Yu, Y., Xiao, C., Tan, L., Wang, Q., Li, X., & Feng, Y. (2014). Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF-β signalling. British Journal of Cancer, 110(3), 724–732.

    Article  CAS  PubMed  Google Scholar 

  112. Barrett, R., & Puré, E. (2020). Cancer-associated fibroblasts: Key determinants of tumor immunity and immunotherapy. Current Opinion in Immunology, 64, 80–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Givel, A.-M., Kieffer, Y., Scholer-Dahirel, A., Sirven, P., Cardon, M., Pelon, F., et al. (2018). miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers. Nature Communications, 9(1), 1–20.

    Article  CAS  Google Scholar 

  114. Ahmed, Z., & Bicknell, R. (2009). Angiogenic signalling pathways. In C. Murray & S. Martin (Eds.), Angiogenesis protocols (pp. 3–24). New York: Springer.

    Chapter  Google Scholar 

  115. Apte, R. S., Chen, D. S., & Ferrara, N. (2019). VEGF in signaling and disease: Beyond discovery and development. Cell, 176(6), 1248–1264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ghosn, E. E. B., Cassado, A. A., Govoni, G. R., Fukuhara, T., Yang, Y., Monack, D. M., et al. (2010). Two physically, functionally, and developmentally distinct peritoneal macrophage subsets. Proceedings of the National Academy of Sciences, 107(6), 2568–2573.

    Article  CAS  Google Scholar 

  117. Atretkhany, K.-S., & Drutskaya, M. (2016). Myeloid-derived suppressor cells and proinflammatory cytokines as targets for cancer therapy. Biochemistry (Moscow), 81(11), 1274–1283.

    Article  CAS  Google Scholar 

  118. Bruno, A., Mortara, L., Baci, D., Noonan, D. M., & Albini, A. (2019). Myeloid derived suppressor cells interactions with natural killer cells and pro-angiogenic activities: Roles in tumor progression. Frontiers in Immunology, 10, 771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cheng, L., Wu, S., Zhang, K., & Xu, T. (2017). A comprehensive overview of exosomes in ovarian cancer: Emerging biomarkers and therapeutic strategies. Journal of Ovarian Research, 10(1), 1–9.

    Article  CAS  Google Scholar 

  120. Dongre, A., & Weinberg, R. A. (2019). New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nature Reviews. Molecular Cell Biology, 20(2), 69–84.

    Article  CAS  PubMed  Google Scholar 

  121. Goossens, S., Vandamme, N., Van Vlierberghe, P., & Berx, G. (2017). EMT transcription factors in cancer development re-evaluated: Beyond EMT and MET. Biochimica et Biophysica Acta (BBA)-Reviews on Cancer, 1868(2), 584–591.

    Article  CAS  Google Scholar 

  122. Loret, N., Denys, H., Tummers, P., & Berx, G. (2019). The role of epithelial-to-mesenchymal plasticity in ovarian cancer progression and therapy resistance. Cancers, 11(6), 838.

    Article  CAS  PubMed Central  Google Scholar 

  123. Saxena, M., Stephens, M. A., Pathak, H., & Rangarajan, A. (2011). Transcription factors that mediate epithelial–mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death & Disease, 2(7), e179.

    Article  CAS  Google Scholar 

  124. Bae, J. S., Noh, S. J., Kim, K. M., Park, S.-H., Hussein, U. K., Park, H. S., et al. (2018). SIRT6 is involved in the progression of ovarian carcinomas via β-catenin-mediated epithelial to mesenchymal transition. Frontiers in Oncology, 8, 538.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Mezencev, R., & Wartell, R. (2018). Cisplatin binds to pre-miR-200b and impairs its processing to mature microRNA. Neoplasma, 65(2), 222–227.

    Article  CAS  PubMed  Google Scholar 

  126. Liu, Y., Han, S., Li, Y., Liu, Y., Zhang, D., Li, Y., et al. (2017). MicroRNA-20a contributes to cisplatin-resistance and migration of OVCAR3 ovarian cancer cell line. Oncology Letters, 14(2), 1780–1786.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Alsuliman, A., Colak, D., Al-Harazi, O., Fitwi, H., Tulbah, A., Al-Tweigeri, T., et al. (2015). Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: Significance in claudin-low breast cancer cells. Molecular Cancer, 14(1), 149.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Zhang, L., Chen, Y., Li, F., Bao, L., & Liu, W. (2019). Atezolizumab and bevacizumab attenuate cisplatin resistant ovarian cancer cells progression synergistically via suppressing epithelial-mesenchymal transition. Frontiers in Immunology, 10, 867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Shahin, S. A., Wang, R., Simargi, S. I., Contreras, A., Echavarria, L. P., Qu, L., et al. (2018). Hyaluronic acid conjugated nanoparticle delivery of siRNA against TWIST reduces tumor burden and enhances sensitivity to cisplatin in ovarian cancer. Nanomedicine: Nanotechnology, Biology and Medicine, 14(4), 1381–1394.

    Article  CAS  Google Scholar 

  130. Ramesh, V., Brabletz, T., & Ceppi, P. (2020). Targeting EMT in cancer with repurposed metabolic inhibitors. Trends in Cancer, 6(11), 942–950.

    Article  CAS  PubMed  Google Scholar 

  131. Liang, R., Chen, X., Chen, L., Wan, F., Chen, K., Sun, Y., et al. (2020). STAT3 signaling in ovarian cancer: A potential therapeutic target. Journal of Cancer, 11(4), 837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Zong, X., & Nephew, K. P. (2019). Ovarian cancer stem cells: Role in metastasis and opportunity for therapeutic targeting. Cancers, 11(7), 934.

    Article  CAS  PubMed Central  Google Scholar 

  133. Paik, E. S., Kim, T.-H., Cho, Y. J., Ryu, J., Choi, J.-J., Lee, Y.-Y., et al. (2020). Preclinical assessment of the VeGfR inhibitor axitinib as a therapeutic agent for epithelial ovarian cancer. Scientific Reports, 10(1), 1–9.

    Article  CAS  Google Scholar 

  134. Burger, R. A., Brady, M. F., Bookman, M. A., Fleming, G. F., Monk, B. J., Huang, H., et al. (2011). Incorporation of bevacizumab in the primary treatment of ovarian cancer. New England Journal of Medicine, 365(26), 2473–2483.

    Article  CAS  PubMed  Google Scholar 

  135. Oza, A. M., Cook, A. D., Pfisterer, J., Embleton, A., Ledermann, J. A., Pujade-Lauraine, E., et al. (2015). Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial. The Lancet Oncology, 16(8), 928–936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Aghajanian, C., Blank, S. V., Goff, B. A., Judson, P. L., Teneriello, M. G., Husain, A., et al. (2012). OCEANS: A randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. Journal of Clinical Oncology, 30(17), 2039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Pujade-Lauraine, E., Hilpert, F., Weber, B., Reuss, A., Poveda, A., Kristensen, G., et al. (2014). Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. Obstetrical & Gynecological Survey, 69(7), 402–404.

    Article  Google Scholar 

  138. Monk, B. J., Poveda, A., Vergote, I., Raspagliesi, F., Fujiwara, K., Bae, D.-S., et al. (2015). Impact of trebananib plus weekly paclitaxel on overall survival (OS) in patients (pts) with recurrent ovarian cancer and ascites: Results from the phase III TRINOVA-1 study. Journal of Clinical Oncology, 33(15).

    Google Scholar 

  139. Diab, Y., & Muallem, M. Z. (2017). Targeted therapy in ovarian cancer. A comprehensive systematic review of literature. Anticancer Research, 37(6), 2809–2815.

    CAS  PubMed  Google Scholar 

  140. Franzese, E., Diana, A., Centonze, S., Pignata, S., De Vita, F., Ciardiello, F., et al. (2020). PARP inhibitors in first-line therapy of ovarian cancer: Are there any doubts? Frontiers in Oncology, 10. https://doi.org/10.3389/fonc.2020.00782.

  141. Pujade-Lauraine, E., Ledermann, J. A., Selle, F., Gebski, V., Penson, R. T., Oza, A. M., et al. (2017). Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial. The Lancet Oncology, 18(9), 1274–1284.

    Article  CAS  PubMed  Google Scholar 

  142. Jimeno, A., Gordon, M., Chugh, R., Messersmith, W., Mendelson, D., Dupont, J., et al. (2017). A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP-54F28), a decoy receptor for Wnt ligands, in patients with advanced solid tumors. Clinical Cancer Research, 23(24), 7490–7497.

    Article  CAS  PubMed  Google Scholar 

  143. Chiorean, E. G., LoRusso, P., Strother, R. M., Diamond, J. R., Younger, A., Messersmith, W. A., et al. (2015). A phase I first-in-human study of enoticumab (REGN421), a fully human delta-like ligand 4 (Dll4) monoclonal antibody in patients with advanced solid tumors. Clinical Cancer Research, 21(12), 2695–2703.

    Article  CAS  PubMed  Google Scholar 

  144. Borella, F., Ghisoni, E., Giannone, G., Cosma, S., Benedetto, C., Valabrega, G., et al. (2020). Immune checkpoint inhibitors in epithelial ovarian cancer: An overview on efficacy and future perspectives. Diagnostics, 10(3), 146.

    Article  CAS  PubMed Central  Google Scholar 

  145. Wang, Y., Cardenas, H., Fang, F., Condello, S., Taverna, P., Segar, M., et al. (2014). Epigenetic targeting of ovarian cancer stem cells. Cancer Research, 74(17), 4922–4936.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Lin, P.-C., Hsieh, H.-Y., Chu, P.-C., & Chen, C. S. (2018). Therapeutic opportunities of targeting histone deacetylase isoforms to eradicate cancer stem cells. International Journal of Molecular Sciences, 19(7), 1939.

    Article  PubMed Central  CAS  Google Scholar 

  147. Stathis, A., & Bertoni, F. (2018). BET proteins as targets for anticancer treatment. Cancer Discovery, 8(1), 24–36.

    Article  CAS  PubMed  Google Scholar 

  148. Gening, S., Dolgova, D., Abakumova, T., Rizvanov, A., & Antoneeva, I. (2019). 29P Expression profiles of serum long non-coding RNA in ovarian cancer patients receiving platinum-containing chemotherapy. Annals of Oncology, 30(Suppl_11), mdz447.027.

    Google Scholar 

  149. Chen, P., Fang, X., Xia, B., Zhao, Y., Li, Q., & Wu, X. (2018). Long noncoding RNA LINC00152 promotes cell proliferation through competitively binding endogenous miR-125b with MCL-1 by regulating mitochondrial apoptosis pathways in ovarian cancer. Cancer Medicine, 7(9), 4530–4541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Li, F., Xu, Y., Xu, X., Ge, S., Zhang, F., Zhang, H., et al. (2020). lncRNA HotairM1 depletion promotes self-renewal of cancer stem cells through HOXA1-Nanog regulation loop. Molecular Therapy-Nucleic Acids, 22, 456–470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Saha, S., Parte, S., Roy, P., Kakar, S.S. (2021). Ovarian Cancer Stem Cells: Characterization and Role in Tumorigenesis. In: Schatten, H. (eds) Ovarian Cancer: Molecular & Diagnostic Imaging and Treatment Strategies. Advances in Experimental Medicine and Biology, vol 1330. Springer, Cham. https://doi.org/10.1007/978-3-030-73359-9_10

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