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Advances in ovarian tumor stem cells and therapy

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Abstract

Ovarian cancer is considered the most lethal among all gynecological malignancies due to its early metastatic dissemination, extensive spread, and malignant ascites. The current standard of care for advanced ovarian cancer involves a combination of cytoreductive surgery and chemotherapy utilizing platinum-based and taxane-based agents. Although initial treatment yields clinical remission in 70–80% of patients, the majority eventually develop treatment resistance and tumor recurrence. A growing body of evidence indicates the existence of cancer stem cells within diverse solid tumors, including ovarian cancer, which function as a subpopulation to propel tumor growth and disease advancement by means of drug resistance, recurrence, and metastasis. The presence of ovarian cancer stem cells is widely considered to be a significant contributor to the unfavorable clinical outcomes observed in patients with ovarian cancer, as they play a crucial role in mediating chemotherapy resistance, recurrence, and metastasis. Ovarian cancer stem cells possess the capacity to reassemble within the entirety of the tumor following conventional treatment, thereby instigating the recurrence of ovarian cancer and inducing resistance to treatment. Consequently, the creation of therapeutic approaches aimed at eliminating ovarian cancer stem cells holds great potential for the management of ovarian cancer. These cells are regarded as one of the most auspicious targets and mechanisms for the treatment of ovarian cancer. There is a pressing need for a comprehensive comprehension of the fundamental mechanisms of ovarian cancer’s recurrence, metastasis, and drug resistance, alongside the development of effective strategies to overcome chemoresistance, metastasis, and recurrence. The implementation of cancer stem cell therapies may potentially augment the tumor cells’ sensitivity to existing chemotherapy protocols, thereby mitigating the risks of tumor metastasis and recurrence, and ultimately improving the survival rates of ovarian cancer patients.

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References

  1. Shanmugasundaram, G., Sundaramoorthy, E., & Sudalaiandi, S., et al. (2015). Double pathology: Malignant epithelial ovarian tumor and germ cell tumor (choriocarcinoma), a rare coexistence. World Journal of Clinical Oncology, 6, 421–425.

    Article  Google Scholar 

  2. Siegel, R. L., Miller, K. D. & Jemal, A. (2020). Cancer statistics. CA: A Cancer Journal for Clinicians, 70, 7–30. https://doi.org/10.3322/caac.21590.

    Article  PubMed  Google Scholar 

  3. Karnezis, A. N., Cho, K. R., & Gilks, C. B., et al. (2017). The disparate origins of ovarian cancers: pathogenesis and prevention strategies. Nature Reviews Cancer, 17(1), 65–74. https://doi.org/10.1038/nrc.2016.113.

    Article  CAS  PubMed  Google Scholar 

  4. Chen, V. W., Ruiz, B., Killeen, J. L., Cote, T. R., Wu, X. C., & Correa, C. N. (2003). Pathology and classifification of ovarian tumors. Cancer, 97, 2631–2642.

    Article  PubMed  Google Scholar 

  5. Li, S. S., Ma, J., & Wong, A. S. T. (2018). Chemoresistance in ovarian cancer: exploiting cancer stem cell metabolism. Journal of Gynecologic Oncology, 29, e32 https://doi.org/10.3802/jgo.2018.29.e32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet-Tieulent, J., & Jemal, A. (2012). Global cancer statistics. CA: A Cancer Journal for Clinicians, 65, 87–108.

    Google Scholar 

  7. Bachmayr-Heyda, A., Auer, K., Sukhbaatar, N., Aust, S., Deycmar, S., Reiner, A. T., Polterauer, S., Dekan, S., & Pils, D. (2016). Small RNAs and the competing endogenous RNA network in high grade serous ovarian cancer tumor spread. Oncotarget, 7, 39640–39653.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Stewart, C., Ralyea, C., & Lockwood, S. (2019). Ovarian cancer: An integrated review. Seminars in Oncology Nursing, 35(2), 151–156. https://doi.org/10.1016/j.soncn.2019.02.001.

    Article  PubMed  Google Scholar 

  9. Torre L., Trabert B., DeSantis C., et al. (2018) Ovarian cancer statistics. CA. 68(4):284–296. https://doi.org/10.3322/caac.21456

  10. Vargas-Hern´ andez, V. M., Moreno-Eutimio, M. A., Acosta-Altamirano, G., & Vargas-Aguilar, V. M. (2014). Management of recurrent epithelial ovarian cancer. Gland Surgery, 3(3), 198–202.

    Google Scholar 

  11. Cornelison, R., Llaneza, D. C., & Landen, C. N. (2017). Emerging therapeutics to overcome chemoresistance in epithelial ovarian cancer: a mini-review. International Journal of Molecular Sciences, 18(10), 2171.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kim, J. Y., Cho, C. H., & Song, H. S. (2017). Targeted therapy of ovarian cancer including immune check point inhibitor. Korean Journal of Internal Medicine, 32(5), 798–804. https://doi.org/10.3904/kjim.2017.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ffrench, B., Gasch, C., O’Leary, J. J., & Gallagher, M. F. (2014). Develo** ovarian cancer stem cell models: Laying the pipeline from discovery to clinical intervention. Molecular Cancer, 13, 262 .

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bai, X., Chen, Y., Hou, X., Huang, M., & **, J. (2016). Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters. Drug Metabolism Reviews, 48, 541–567.

    Article  CAS  PubMed  Google Scholar 

  15. McGuire, W. P., Hoskins, W. J., & Brady, M. F., et al. (1996). Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. The New England Journal of Medicine, 334, 1–6.

    Article  CAS  PubMed  Google Scholar 

  16. Vergote, I., Tropé, C. G., & Amant, F., et al. (2010). Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. The New England Journal of Medicine, 363, 943–953.

    Article  CAS  PubMed  Google Scholar 

  17. Davis, A., Tinker, A. V., & Friedlander, M. (2014). Platinum resistant” ovarian cancer: What is it, who to treat and how to measure benefit? Gynecologic Oncology, 133, 624–631.

    Article  CAS  PubMed  Google Scholar 

  18. Foley, O. W., Rauh-Hain, J. A., & del Carmen, M. G. (2013). Recurrent epithelial ovarian cancer: an update on treatment. Oncology, 27(4), 288.

    PubMed  Google Scholar 

  19. Dao, F., Schlappe, B. A., & Tseng, J., et al. (2016). Characteristics of 10-year survivors of high-grade serous ovarian carcinoma. Gynecologic Oncology, 141(2), 260–263. https://doi.org/10.1016/j.ygyno.2016.03.010.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kim, S., Han, Y., Kim, S. I., Kim, H. S., Kim, S. J., & Song, Y. S. (2018). Tumor evolution and chemoresistance in ovarian cancer. NPJ Precision Oncology, 2, e20 .

    Article  Google Scholar 

  21. Rich, J. N. (2016). Cancer stem cells: Understanding tumor hierarchy and heterogeneity. Medicine, 95, S2–S7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Clarke, M. F., Dick, J. E., Dirks, P. B., Eaves, C. J., Jamieson, C. H. M., Jones, D. L., Visvader, J., Weissman, I. L., & Wahl, G. M. (2006). Cancer stem cells-perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Research, 66, 9339–9344.

    Article  CAS  PubMed  Google Scholar 

  23. Ajani, J. A., Song, S., Hochster, H. S., & Steinberg, I. B. (2015). Cancer stem cells: the promise and the potential. Seminars in Oncology, 42, S3–S17.

    Article  CAS  PubMed  Google Scholar 

  24. Nishi, M., Akutsu, H., Kudoh, A., Kimura, H., Yamamoto, N., Umezawa, A., Lee, S. W., & Ryo, A. (2014). Induced cancer stem-like cells as a model for biological screening and discovery of agents targeting phenotypic traits of cancer stem cell. Oncotarget, 5, 8665–8680.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Alison, M. R., Lim, S. M., & Nicholson, L. J. (2011). Cancer stem cells: Problems for therapy? The Journal of Pathology, 223, 147–161.

    Article  CAS  PubMed  Google Scholar 

  27. Bao, B., Ahmad, A., Azmi, A., Ali, S., & Sarkar, F. (2013). Overview of cancer stem cells (CSCs) and mechanisms of their regulation: Implications for cancer therapy. Current Protocols in Pharmacology, 61, 14 .

    Article  Google Scholar 

  28. Shibue, T., & Weinberg, R. A. (2017). EMT, CSCs, and drug resistance: The mechanistic link and clinical implications. Nature Reviews Clinical Oncology, 14, 611–629.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Batlle, E., & Clevers, H. (2017). Cancer stem cells revisited. Nature Medicine, 23, 1124–1134.

    Article  CAS  PubMed  Google Scholar 

  30. Chang, J. C. (2016). Cancer stem cells: Role in tumor growth, recurrence, metastasis, and treatment resistance. Medicine, 95, S20–S25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lytle, N. K., Barber, A. G., & Reya, T. (2018). Stem cell fate in cancer growth, progression and therapy resistance. Nature Reviews Cancer, 18, 669–680. https://doi.org/10.1038/s41568-018-0056-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen, D., Wu, M., Li, Y., Chang, I., Yuan, Q., & Ekimyan-Salvo, M., et al. (2017). Targeting BMI1(+) cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma. Cell Stem Cell, 20, 621–634.e626. https://doi.org/10.1016/j.stem.2017.02.003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Vinogradov, S., & Wei, X. (2012). Cancer stem cells and drug resistance: the potential of nanomedicine. Nanomed, 7, 597–615.

    Article  CAS  Google Scholar 

  34. Keyvani, V., Farshchian, M., Esmaeili, S.-A., Yari, H., Moghbeli, M., & Nezhad, S.-R. K., et al. (2019). Ovarian cancer stem cells and targeted therapy. Journal of Ovarian Research, 12(1), 1–11. https://doi.org/10.1186/s13048-019-0588-z.

    Article  Google Scholar 

  35. Liang, D. H., Choi, D. S., Ensor, J. E., Kaipparettu, B. A., Bass, B. L., & Chang, J. C. (2016). The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair. Cancer Letters, 376(2), 249–258. https://doi.org/10.1016/j.canlet.2016.04.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yamamoto, M., Suzuki, S., Togashi, K., Sanomachi, T., Seino, S., & Kitanaka, C., et al. (2019). AS602801 sensitizes ovarian cancer stem cells to paclitaxel by down-regulating MDR1. AntiCancer Research, 39(2), 609–617. https://doi.org/10.21873/anticanres.13154.

    Article  CAS  PubMed  Google Scholar 

  37. Nassar, D., & Blanpain, C. (2016). Cancer stem cells: basic concepts and therapeutic implications. Annual Review of Pathology, 11, 47–76. https://doi.org/10.1146/annurev-pathol-012615-044438.

    Article  CAS  PubMed  Google Scholar 

  38. Pal, D., Kolluru, V., Chandrasekaran, B., Baby, B. V., Aman, M., Suman, S., Sirimulla, S., Sanders, M. A., Alatassi, H., & Ankem, M. K., et al. (2017). Targeting aberrant expression of Notch-1 in ALDH (+) cancer stem cells in breast cancer. Molecular Carcinogenesis, 56, 1127–1136.

    Article  CAS  PubMed  Google Scholar 

  39. Li, C., Heidt, D. G., Dalerba, P., Burant, C. F., Zhang, L., Adsay, V., Wicha, M., Clarke, M. F., & Simeone, D. M. (2007). Identification of pancreatic cancer stem cells. Cancer Research, 67, 1030–1037.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. He Q. Z., Luo X. Z., Wang K., Zhou Q., Ao H., Yang Y., Li S. X., Li Y., Zhu H. T., Duan T., (2014) Cellular physiology and biochemistry. International Journal of Experimental Cellular Physiology, Biochemistry and Pharmacology 33,173–184.

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

    Article  CAS  PubMed  Google Scholar 

  44. Jordan, C. T., Guzman, M. L., & Noble, M. (2007). Cancer stem cells. The New England Journal of Medicine, 355, 1253–1261.

    Article  Google Scholar 

  45. Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414, 105–111.

    Article  CAS  PubMed  Google Scholar 

  46. Pardal, R., Clarke, M. F., & Morrison, S. J. (2003). Applying the principles of stem-cell biology to cancer. Nature Reviews Cancer, 3, 895–902.

    Article  CAS  PubMed  Google Scholar 

  47. Gkountela, S., & Aceto, N. (2016). Stem-like features of cancer cells on their way to metastasis. Biology Direct, 11, e33 .

    Article  Google Scholar 

  48. Maugeri-Sacca, M., Bartucci, M., & De Maria, R. (2012). DNA damage repair pathways in cancer stem cells. Molecular Cancer Therapeutics, 11, 1627–1636.

    Article  CAS  PubMed  Google Scholar 

  49. Phi, L. T. H., Sari, I. N., Yang, Y. G., Lee, S. H., Jun, N., Kim, K. S., Lee, Y. K., & Kwon, H. Y. (2018). Cancer Stem Cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells International, 2018, e5416923 .

    Article  Google Scholar 

  50. Chow, E. K. (2013). Implication of cancer stem cells in cancer drug development and drug delivery. Journal of Laboratory Automation, 18, 6–11.

    Article  CAS  PubMed  Google Scholar 

  51. Abdullah, L. N., & Chow, E. K. (2013). Mechanisms of chemoresistance in cancer stem cells. Clinical and Translational Medicine, 2, e3 .

    Article  Google Scholar 

  52. Deheeger, M., Lesniak, M. S., & Ahmed, A. U. (2014). Cellular plasticity regulated cancer stem cell niche: A possible new mechanism of chemoresistance. Cancer Cell Microenviron, 1, e295.

    PubMed  PubMed Central  Google Scholar 

  53. Doherty, M. R., Smigiel, J. M., Junk, D. J., & Jackson, M. W. (2016). Cancer stem cell plasticity drives therapeutic resistance. Cancers, 8, e8 .

    Article  Google Scholar 

  54. Brown, R., Curry, E., Magnani, L., Wilhelm-Benartzi, C. S., & Borley, J. (2014). Poised epigenetic states and acquired drug resistance in cancer. Nature Reviews Cancer, 14, 747–753.

    Article  CAS  PubMed  Google Scholar 

  55. 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.

    Article  CAS  PubMed  Google Scholar 

  56. 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, e29079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kuroda, T., Hirohashi, Y., Torigoe, T., Yasuda, K., Takahashi, A., Asanuma, H., Morita, R., Mariya, T., Asano, T., Mizuuchi, M., Saito, T., & Sato, N. (2013). ALDH1-high ovarian cancer stem-like cells can be isolated from serous and clear cell adenocarcinoma cells, and ALDH1 high expression is associated with poor prognosis. PLoS ONE, 8, e65158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Scaffiffiffidi, P., & Misteli, T. (2011). In vitro generation of human cells with cancer stem cell properties. Nature Cell Biology, 13, 1051–1061.

    Article  Google Scholar 

  59. Kao, C. Y., Oakley, C. S., Welsch, C. W., & Chang, C. C. (1997). Growth requirements and neoplastic transformation of two types of normal human breast epithelial cells derived from reduction mammoplasty. Cellular & Developmental Biology - Animal, 33, 282–288.

    Article  CAS  Google Scholar 

  60. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., & Clarke, M. F. (2003). Prospective identifification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 3983–3988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Singh, S. K., Clarke, I. D., Terasaki, M., Bonn, V. E., Hawkins, C., Squire, J., & Dirks, P. B. (2003). Identifification of a cancer stem cell in human brain tumors. Cancer Research, 63, 5821–5828.

    CAS  PubMed  Google Scholar 

  62. Charafe-Jauffffret, E., Ginestier, C., Iovino, F., Wicinski, J., Cervera, N., Finetti, P., Hur, M. H., Diebel, M. E., Monville, F., & Dutcher, J., et al. (2009). Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Research, 69, 1302–1313.

    Article  Google Scholar 

  63. Chang, Y., Wu, K., & Ding, D. (2021). The natural compound n-butylidenephthalide kills high-grade serous ovarian cancer stem cells by activating intrinsic apoptosis signaling pathways. Journal of Cancer, 12(11), 3126–3135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Cannistra, S. A., DeFranzo, B., Niloff, J., & Ottensmeir, C. (1995). Functional heterogeneity of CD44 molecules in ovarian cancer cell lines. Clinical Cancer Research, 1, 333–342.

    CAS  PubMed  Google Scholar 

  65. Ferrandina, G., Bonanno, G., Pierelli, L., Perillo, A., Procoli, A., & Mariotti, A., et al. (2008). Expression of CD133-1 and CD133-2 in ovarian cancer. International Journal of Gynecological Cancer, 18, 506–514.

    Article  CAS  PubMed  Google Scholar 

  66. 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, 4311–4320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 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, 2875–2883.

    Article  CAS  PubMed  Google Scholar 

  68. Gao, M. Q., Choi, Y. P., Kang, S., Youn, J. H., & Cho, N. H. (2010). CD24+ cells from hierarchically organized ovarian cancer are enriched in cancer stem cells. Oncogene, 29, 2672–2680.

    Article  CAS  PubMed  Google Scholar 

  69. Koren, E., & Fuchs, Y. (2016). The bad seed: Cancer stem cells in tumor development and resistance. Drug Resistance Updates, 28, 1–12.

    Article  PubMed  Google Scholar 

  70. Thakur, B., & Ray, P. (2017). Cisplatin triggers cancer stem cell enrichment in platinumresistant cells through NF-κB-TNFα-PIK3CA loop. Journal of Experimental & Clinical Cancer Research, 36(1), 164.

    Article  Google Scholar 

  71. Kaushik, N. K., Kaushik, N., Yoo, K. C., Uddin, N., Kim, J. S., Lee, S. J., & Choi, E. H. (2016). Low doses of PEG-coated gold nanoparticles sensitize solid tumors to cold plasma by blocking the PI3K/AKT-driven signaling axis to suppress cellular transformation by inhibiting growth and EMT. Biomaterials, 87, 118–130.

    Article  CAS  PubMed  Google Scholar 

  72. Mani, S. A., Guo, W., Liao, M.-J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., Brooks, M., Reinhard, F., Zhang, C. C., & Shipitsin, M., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133, 704–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gupta, P. B., Önder, T., Jiang, G., Tao, K., Kuperwasser, C., Weinberg, R. A., & Lander, E. S. (2009). Identifification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 138, 645–659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Li, N., & Zhan, X. (2019). Identification of clinical trait–related lncRNA and mRNA biomarkers with weighted gene co-expression network analysis as useful tool for personalized medicine in ovarian cancer. EPMA Journal, 10, 273–290.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Latifi, A., Luwor, R. B., Bilandzic, M., Nazaretian, S., Stenvers, K., Pyman, J., Zhu, H., Thompson, E. W., Quinn, M. A., Findlay, J. K., & Ahmed, N. (2012). Isolation and characterization of tumor cells from the ascites of ovarian cancer patients: molecular phenotype of chemoresistant ovarian tumors. PLoS ONE, 7(10), e46858 https://doi.org/10.1371/journal.pone.0046858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tan, D. S., Agarwal, R., & Kaye, S. B. (2006). Mechanisms of transcoelomic metastasis in ovarian cancer. The Lancet Oncology, 7(11), 925–934. https://doi.org/10.1016/S1470-2045(06)70939-1.

    Article  PubMed  Google Scholar 

  77. Kaku, T., Ogawa, S., Kawano, Y., Ohishi, Y., Kobayashi, H., Hirakawa, T., & Nakano, H. (2003). Histological classifification of ovarian cancer. Medical Electron Microscopy, 36, 9–17.

    Article  PubMed  Google Scholar 

  78. Baba, T., Convery, P. A., Matsumura, N., Whitaker, R. S., Kondoh, E., Perry, T., Huang, Z., Bentley, R. C., Mori, S., & Fujii, S., et al. (2009). Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene, 28, 209–218.

    Article  CAS  PubMed  Google Scholar 

  79. Yu, S., Mulero, M. C., Chen, W., Shang, X., Tian, S., Watanabe, J., Watanabe, A., Vorberg, T., Wong, C., & Gately, D., et al. (2021). Therapeutic targeting of tumor cells rich in LGR stem cell receptors. Bioconjugate Chemistry, 32, 376–384.

    Article  CAS  PubMed  Google Scholar 

  80. Landen, Jr, C. N., Goodman, B., Katre, A. A., Steg, A. D., Nick, A. M., Stone, R. L., Miller, L. D., Mejia, P. V., Jennings, N. B., & Gershenson, D. M., et al. (2010). Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Molecular Cancer Therapeutics, 9, 3186–3199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Avila-Carrasco, L., Majano, P., & Sánchez-Toméro, J. A., et al. (2019). Natural plants compounds as modulators of epithelial-to-mesenchymal transition. Frontiers in Pharmacology, 10, 715 https://doi.org/10.3389/fphar.2019.00715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Liu C. L., Chen Y. J., Fan M. H., et al. (2020) Characteristics of CD133-sustained chemoresistant cancer stem-like cells in human ovarian carcinoma. International Journal of Molecular Sciences, 21(18):6467.

  83. 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. https://doi.org/10.3892/ol.2019.10221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Fan, Q., Zhang, W., & Emerson, R. E., et al. (2020). ZIP4 Is a novel cancer stem cell marker in high-grade serous ovarian cancer. Cancers, 12(12), 3692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Salem, M. L., El-Badawy, A. S., & Li, Z. (2014). Immunobiology and signaling pathways of cancer stem cells: Implication for cancer therapy. Cytotechnology, 67, 749–759.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Takebe, N., Miele, L., Harris, P. J., Jeong, W., Bando, H., Kahn, M. G., Yang, S. X., & Ivy, S. P. (2015). Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: Clinical update. Nature Reviews Clinical Oncology, 12, 445–464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. **, X., **, X., & Kim, H. (2017). Cancer stem cells and differentiation therapy. Tumour Biology, 39, 1010428317729933.

    Article  PubMed  Google Scholar 

  88. Hanahan, D., & Coussens, L. M. (2012). Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell, 21, 309–322.

    Article  CAS  PubMed  Google Scholar 

  89. Fessler E., Dijkgraaf F. E., De Sousa E. M. F., Medema J. P., (2013) Cancer Letters. 341,97–104.

  90. Li, Y., & Laterra, J. (2012). Cancer stem cells: distinct entities or dynamically regulated phenotypes? Cancer Research, 72, 576–580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kim, D. K., Kim, Y. N., Kim, Y. E., Lee, S. Y., Shin, M. J., Do, E. K., Choi, K. U., Kim, S. C., Kim, K. H., Suh, D. S., Song, P., & Kim, J. H. (2021). TRIB2 stimulates cancer stem-like properties through activating the AKT-GSK3β-β-catenin signaling axis. Molecular Cell, 44(7), 481–492. https://doi.org/10.14348/molcells.2021.0030.

    Article  CAS  Google Scholar 

  92. Muñoz-Galván, S., Felipe-Abrio, B., García-Carrasco, M., Domínguez-Piñol, J., Suarez-Martinez, E., Verdugo-Sivianes, E. M., Espinosa-Sánchez, A., Navas, L. E., Otero-Albiol, D., Marin, J. J., Jiménez-García, M. P., García-Heredia, J. M., Quiroga, A. G., Estevez-Garcia, P., & Carnero, A. (2019). New markers for human ovarian cancer that link platinum resistance to the cancer stem cell phenotype and define new therapeutic combinations and diagnostic tools. Journal of Experimental & Clinical Cancer Research, 38(1), 234 https://doi.org/10.1186/s13046-019-1245-5.

    Article  CAS  Google Scholar 

  93. Cho, J. G., Kim, S. W., Lee, A., Jeong, H. N., Yun, E., Choi, J., Jeong, S. J., Chang, W., Oh, S., Yoo, K. H., Lee, J. B., Yoon, S., Lee, M. S., Park, J. H., Jung, M. H., Kim, S. W., Kim, K. H., Suh, D. S., Choi, K. U., Choi, J., Kim, J., & Kwon, B. S. (2022). MicroRNA-dependent inhibition of WEE1 controls cancer stem-like characteristics and malignant behavior in ovarian cancer. Molecular Therapy-Nucleic Acids, 29, 803–822. https://doi.org/10.1016/j.omtn.2022.08.028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Steg, A. D., Bevis, K. S., Katre, A. A., Ziebarth, A., Alvarez, R. D., & Zhang, K., et al. (2012). Stem cell pathway contribute to clinical chemoresistance in ovarian cancer. Clinical Cancer Research, 1, 869–881.

    Article  Google Scholar 

  95. The Cancer Genomic Atlas Research Network. (2011). Integrated genomic analysis of ovarian carcinoma. Nature, 474, 609–615.

    Article  Google Scholar 

  96. Eyvani, V., Farshchian, M., Esmaeili, S. A., Hadi, Y., Moghbeli, M., Nezhad, S.-R. K., & Abbaszadegan, M. R. (2019). Ovarian cancer stem cells and targeted therapy. Journal of Ovarian Research, 12, 120.

    Article  Google Scholar 

  97. Zhang, L., Ma, R., Gao, M., Zhao, Y., Lv, X., Zhu, W., Han, L., Su, P., Fan, Y., Yan, Y., Zhao, L., Ma, H., Wei, M., & He, M. (2020). SNORA72 Activates the Notch1/c-Myc pathway to promote stemness transformation of ovarian cancer cells. Frontiers in Cell and Developmental Biology, 8, 583087 https://doi.org/10.3389/fcell.2020.583087.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Islam, S. S., & Aboussekhra, A. (2019). Sequential combination of cisplatin with eugenol targets ovarian cancer stem cells through the Notch-Hes1 signalling pathway. Journal of Experimental, Clinical Cancer Research : CR, 38, 382.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Huang, M. Y., Wang, H. M., Chang, H. J., Hsiao, C. P., Wang, J. Y., & Lin, S. R. (2012). Overexpression of S100B, TM4SF4, and OLFM4 genes is correlated with liver metastasis in Taiwanese colorectal cancer patients. DNA and Cell Biology, 31, 43–49.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Yang, T., Cheng, J., Yang, Y., Qi, W., Zhao, Y., Long, H., **e, R., & Zhu, B. (2017). S100B mediates stemness of ovarian cancer stem-like cells through inhibiting p53. Stem Cells, 35, 325–336.

    Article  CAS  PubMed  Google Scholar 

  101. Yang, T., Cheng, J., You, J., Yan, B., Liu, H., & Li, F. (2018). S100B promotes chemoresistance in ovarian cancer stem cells by regulating p53. Oncology Reports, 40(3), 1574–1582. https://doi.org/10.3892/or.2018.6527.

    Article  CAS  PubMed  Google Scholar 

  102. Markowitz, J., & MacKerell, A. D. (2007). Jr and Weber DJ: A search for inhibitors of S100B, a member of the S100 family of calcium-binding proteins. Mini-Reviews in Medicinal Chemistry, 7, 609–616.

    Article  CAS  PubMed  Google Scholar 

  103. Wang H., Chirshev E., Hojo N., et al. (2021) The Epithelial-mesenchymal transcription factor SNAI1 represses transcription of the tumor suppressor miRNA let-7 in cancer. Cancers, 13(6):1469.

  104. Chen, Q., Dong, R., & Chen, P. (2019). Extracts of the medicinal plants Pao Pereira and Rauwolfia vomitoria inhibit ovarian cancer stem cells in vitro. The FASEB Journal, 33(S1), 15347354221123019.

    Google Scholar 

  105. Li, H., Zhang, W., Niu, C., Lin, C., Wu, X., Jian, Y., Li, Y., Ye, L., Dai, Y., Ouyang, Y., Chen, J., Qiu, J., Song, L., & Zhang, Y. (2019). Nuclear orphan receptor NR2F6 confers cisplatin resistance in epithelial ovarian cancer cells by activating the Notch3 signaling pathway. International Journal of Cancer, 145, 1921–1934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Guan, X. Y., Sham, J. S., Tang, T. C., Fang, Y., Huo, K. K., & Yang, J. M. (2001). Isolation of a novel candidate oncogene within a frequently amplified region at 3q26 in ovarian cancer. Cancer Research, 61, 3806–3809.

    CAS  PubMed  Google Scholar 

  107. Cao, T. T., Lin, S. H., Fu, L., Tang, Z., Che, C. M., & Guan, X. Y., et al. (2017). Eukaryotic translation initiation factor 5A2 promotes metabolic reprogramming in hepatocellular carcinoma cells. Carcinogenesis, 38, 94–104.

    Article  CAS  PubMed  Google Scholar 

  108. Wang, K., Wang, Y., & Wang, Y., et al. (2021). EIF5A2 enhances stemness of epithelial ovarian cancer cells via a E2F1/KLF4 axis[J]. Stem Cell Research & Therapy, 12(1), 186.

    Article  CAS  Google Scholar 

  109. Li, Y., Wang, D., & Liu, J., et al. (2020). BaicaliN Attenuates YAP activity to suppress ovarian cancer stemness. OncoTargets and Therapy, 13, 7151–7163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yan, Z., **, Z., & Sui, H., et al. (2022). Bruceine D sensitizes human ovarian cancer cells to paclitaxel through JNK and STAT3 signal regulation. Revista Brasileira de Farmacognosia, 32(2), 257–265.

    Article  CAS  Google Scholar 

  111. He, Y., Alejo, S., Venkata, P. P., Johnson, J. D., Loeffel, I., Pratap, U. P., Zou, Y., Lai, Z., Tekmal, R. R., Kost, E. R., & Sareddy, G. R. (2022). Therapeutic targeting of ovarian cancer stem cells using estrogen receptor beta agonist. International Journal of Molecular Sciences, 23(13), 7159 https://doi.org/10.3390/ijms23137159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Campbell, I. G., Russell, S. E., Choong, D. Y. H., Montgomery, K. G., Ciavarella, M. L., Hooi, C. S. F., Cristiano, B. E., Pearson, R. B., & Phillips, W. A. (2004). Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Research, 64, 7678–7681.

    Article  CAS  PubMed  Google Scholar 

  113. Ma, J., Kala, S., & Yung, S., et al. (2018). Blocking stemness and metastatic properties of ovarian cancer cells by targeting p70S6K with dendrimer nanovector-based siRNA delivery. Molecular Therapy, 26(1), 70–83.

    Article  CAS  PubMed  Google Scholar 

  114. Huang, R., Zhu, L., & Zhang, Y. (2020). XIST lost induces ovarian cancer stem cells to acquire taxol resistance via a KMT2C-dependent way. Cancer Cell Internationalernational, 20(1), 436.

    Article  CAS  Google Scholar 

  115. Holmberg, R., Robinson, M., Gilbert, S. F., Lujano-Olazaba, O., Waters, J. A., Kogan, E., Velasquez, C. L. R., Stevenson, D., Cruz, L. S., Alexander, L. J., Lara, J., Mu, E. M., Camillo, J. R., Bitler, B. G., Huxford, T., & House, C. D. (2023). TWEAK-Fn14-RelB signaling cascade promotes stem cell-like features that contribute to post-chemotherapy ovarian cancer relapse. Molecular Cancer Research, 21(2), 170–186. https://doi.org/10.1158/1541-7786.MCR-22-0486.

    Article  CAS  PubMed  Google Scholar 

  116. Srivastava, A. K., Rizvi, A., Cui, T., Han, C., Banerjee, A., Naseem, I., Zheng, Y., Wani, A. A., & Wang, Q. E. (2018). Depleting ovarian cancer stem cells with calcitriol. Oncotarget, 9(18), 14481–14491. https://doi.org/10.18632/oncotarget.24520.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Ji, M., Liu, L., Hou, Y., & Li, B. (2019). 1α,25-Dihydroxyvitamin D3 restrains stem cell-like properties of ovarian cancer cells by enhancing vitamin D receptor and suppressing CD44. Oncology Reports, 41(6), 3393–3403. https://doi.org/10.3892/or.2019.7116.

    Article  CAS  PubMed  Google Scholar 

  118. Chan, E., Luwor, R., Burns, C., Kannourakis, G., Findlay, J. K., & Ahmed, N. (2018). Momelotinib decreased cancer stem cell associated tumor burden and prolonged disease-free remission period in a mouse model of human ovarian cancer. Oncotarget, 9(24), 16599–16618. https://doi.org/10.18632/oncotarget.24615.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Yanai, K., Nagai, S., Wada, J., Yamanaka, N., Nakamura, M., & Torata, N., et al. (2007). Hedgehog signaling pathway is a possible therapeutic target for gastric cancer. Journal of Surgical Oncology, 95, 55–62.

    Article  CAS  PubMed  Google Scholar 

  120. Zhao, Y., He, M., Cui, L., Gao, M., Zhang, M., Yue, F., Shi, T., Yang, X., Pan, Y. & Zheng, X. et al.(2020). Chemotherapy exacerbates ovarian cancer cell migration and cancer stem cell-like characteristics through GLI1. British Journal of Cancer, 122, 1638–1648.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Leung, Y. K., Mak, P., Hassan, S., & Ho, S. M. (2006). Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. Proceedings of the National Academy of Sciences of the United States of America, 103(35), 13162–13167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bossard, C., Busson, M., Vindrieux, D., Gaudin, F., Machelon, V., Brigitte, M., Jacquard, C., Pillon, A., Balaguer, P., & Balabanian, K., et al. (2012). Potential role of estrogen receptor beta as a tumor suppressor of epithelial ovarian cancer. PLoS ONE, 7(9), e44787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chan, K. K. L., Siu, M. K. Y., Jiang, Y. X., Wang, J. J., Leung, T. H. Y., & Ngan, H. Y. S. (2018). Estrogen receptor modulators genistein, daidzein and ERB-041 inhibit cell migration, invasion, proliferation and sphere formation via modulation of FAK and PI3K/AKT signaling in ovarian cancer. Cancer Cell International, 18, 65 https://doi.org/10.1186/s12935-018-0559-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wen, H., Qian, M., He, J., Li, M., Yu, Q., & Leng, Z. (2020). Inhibiting of self-renewal, migration and invasion of ovarian cancer stem cells by blocking TGF-β pathway. PLoS ONE, 15(3), e0230230 https://doi.org/10.1371/journal.pone.0230230.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhang, Y., Chen, S., Wei, C., Rankin, G. O., Ye, X., & Chen, Y. C. (2018). Dietary compound proanthocyanidins from Chinese bayberry (Myrica rubra Sieb. et Zucc.) leaves attenuate chemotherapy-resistant ovarian cancer stem cell traits via targeting the Wnt/β-catenin signaling pathway and inducing G1 cell cycle arrest. Food & Function, 9(1), 525–533. https://doi.org/10.1039/c7fo01453h.

    Article  CAS  Google Scholar 

  126. Fang, C. H., Lin, Y. T., Liang, C. M., & Liang, S. M. (2020). A novel c-Kit/phospho-prohibitin axis enhances ovarian cancer stemness and chemoresistance via Notch3-PBX1 and β-catenin-ABCG2 signaling. Journal of Biomedical Science, 27(1), 42 https://doi.org/10.1186/s12929-020-00638-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Zhang, K., Ying, H., Zhao, R., Chen, Y., & Deng, Q. (2021). Capilliposide from Lysimachia capillipes promotes terminal differentiations and reverses paclitaxel resistance in A2780T cells of human ovarian cancer by regulating Fos/Jun pathway. Chinese Herbal Medicines, 14(1), 111–116. https://doi.org/10.1016/j.chmed.2021.09.009.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Jiang, Y. X., Siu, M. K. Y., Wang, J. J., Leung, T. H. Y., Chan, D. W., Cheung, A. N. Y., Ngan, H. Y. S., & Chan, K. K. L. (2022). PFKFB3 regulates chemoresistance, metastasis and stemness via IAP proteins and the NF-κB signaling pathway in ovarian cancer. Frontiers in Oncology, 12, 748403 https://doi.org/10.3389/fonc.2022.748403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Muñoz-Galván, S., Felipe-Abrio, B., Verdugo-Sivianes, E. M., Perez, M., Jiménez-García, M. P., Suarez-Martinez, E., Estevez-Garcia, P., & Carnero, A. (2020). Downregulation of MYPT1 increases tumor resistance in ovarian cancer by targeting the Hippo pathway and increasing the stemness. Molecular Cancer, 19(1), 7 https://doi.org/10.1186/s12943-020-1130-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Li, X., Wang, J., Wu, W., Gao, H., Liu, N., Zhan, G., Li, L., Han, L. & Guo, X. (2020). Myeloid-derived suppressor cells promote epithelial ovarian cancer cell stemness by inducing the CSF2/p-STAT3 signalling pathway. FEBS Journal, 287(23), 5218–5235. https://doi.org/10.1111/febs.15311.

    Article  CAS  PubMed  Google Scholar 

  131. Wang, S., Li, Z., Zhu, G., Hong, L., Hu, C., Wang, K., Cui, K., & Hao, C. (2021). RNA-binding protein IGF2BP2 enhances circ_0000745 abundancy and promotes aggressiveness and stemness of ovarian cancer cells via the microRNA-3187-3p/ERBB4/PI3K/AKT axis. Journal of Ovarian Research, 14(1), 154 https://doi.org/10.1186/s13048-021-00917-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. He, M., Wu, H., Jiang, Q., Liu, Y., Han, L., Yan, Y., Wei, B., Liu, F., Deng, X., Chen, H., Zhao, L., Wang, M., Wu, X., Yao, W., Zhao, H., Chen, J. & Wei, M. (2019). Hypoxia-inducible factor-2α directly promotes BCRP expression and mediates the resistance of ovarian cancer stem cells to adriamycin. Molecular Oncology, 13(2), 403–421. https://doi.org/10.1002/1878-0261.12419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Muralikrishnan, V., Hurley, T. D., & Nephew, K. P. (2020). Targeting aldehyde dehydrogenases to eliminate cancer stem cells in gynecologic malignancies. Cancers, 12, 961.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kaipio, K., Chen, P., Roering, P., Huhtinen, K., Mikkonen, P., Ostling, P., Lehtinen, L., Mansuri, N., Korpela, T., & Potdar, S., et al. (2020). ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors. The Journal of Pathology, 250, 159–169.

    Article  CAS  PubMed  Google Scholar 

  135. Liu, L., Cai, S., Han, C., Banerjee, A., Wu, D., Cui, T., **e, G., Zhang, J., Zhang, X., & McLaughlin, E., et al. (2020). ALDH1A1 Contributes to PARP inhibitor resistance via enhancing DNA repair in BRCA2(−/−) ovarian cancer cells. Molecular Cancer Therapeutics, 19, 199–210.

    Article  PubMed  Google Scholar 

  136. Nwani, N. G., Condello, S., Wang, Y., Swetzig, W. M., Barber, E., Hurley, T., & Matei, D. (2019). A novel ALDH1A1 inhibitor targets cells with stem cell characteristics in ovarian cancer. Cancers, 11(4), 502 https://doi.org/10.3390/cancers11040502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Cui, T., Srivastava, A. K., Han, C., Wu, D., Wani, N., Liu, L., Gao, Z., Qu, M., Zou, N., Zhang, X., Yi, P., Yu, J., Bell, E. H., Yang, S. M., Maloney, D. J., Zheng, Y., Wani, A. A., & Wang, Q. E. (2018). DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1. Cell Death & Disease, 9(5), 561 https://doi.org/10.1038/s41419-018-0585-y.

    Article  CAS  Google Scholar 

  138. Muralikrishnan, V., Fang, F., Given, T. C., Podicheti, R., Chtcherbinine, M., Metcalfe, T. X., Sriramkumar, S., O’Hagan, H. M., Hurley, T. D., & Nephew, K. P. (2022). A Novel ALDH1A1 inhibitor blocks platinum-induced senescence and stemness in ovarian cancer. Cancers, 14(14), 3437 https://doi.org/10.3390/cancers14143437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Fang, G. A., Zhi, Y. A., & Hk, A., et al. (2019). Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation. Biomedicine & Pharmacotherapy, 118, 109371–109371.

    Article  Google Scholar 

  140. Guo, F., Yang, Z., Sehouli, J., & Kaufmann, A. M. (2022). Blockade of ALDH in cisplatin-resistant ovarian cancer stem cells in vitro synergistically enhances chemotherapy-induced cell death. Current Oncology, 29(4), 2808–2822. https://doi.org/10.3390/curroncol29040229.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Whitworth, J. M., et al. (2012). The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells. Gynecologic Oncology, 125, 226–230.

    Article  CAS  PubMed  Google Scholar 

  142. Kim, D., Choi, B. H., Ryoo, I. G., & Kwak, M. K. (2018). High NRF2 level mediates cancer stem cell-like properties of aldehyde dehydrogenase (ALDH)-high ovarian cancer cells: inhibitory role of all-trans retinoic acid in ALDH/NRF2 signaling. Cell Death & Disease, 9(9), 896 https://doi.org/10.1038/s41419-018-0903-4.

    Article  CAS  Google Scholar 

  143. Lee, H., Kwon, O. B., & Lee, J. E., et al. (2021). Repositioning trimebutine maleate as a cancer treatment targeting ovarian cancer stem cells. Cells, 10(4), 918.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Lee H., Kim J. W., Lee D. S., et al. (2020) Combined poziotinib with manidipine treatment suppresses ovarian cancer stem-cell proliferation and stemness. International Journal of Molecular Sciences, 21(19):7379.

  145. Zhang, Q., Wang, J., Qiao, H., Huyan, L., Liu, B., Li, C., Jiang, J., Zhao, F., Wang, H. & Yan, J. (2021). ISG15 is downregulated by KLF12 and implicated in maintenance of cancer stem cell‐like features in cisplatin‐resistant ovarian cancer. Journal of Cellular and Molecular Medicine, 25(9), 4395–4407. https://doi.org/10.1111/jcmm.16503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Sohn, E. J. (2022). PIK3R3, a regulatory subunit of PI3K, modulates ovarian cancer stem cells and ovarian cancer development and progression by integrative analysis. BMC Cancer, 22(1), 708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lokman, N. A., Price, Z. K., & Hawkins, E. K., et al. (2019). 4-Methylumbelliferone inhibits cancer stem cell activation and overcomes chemoresistance in ovarian cancer. Cancers, 11(8), 1187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kristen, S., Linah, A. A., & Eavarone, D. A., et al. (2018). Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-nouveau. Oncotarget, 9(33), 23289.

    Article  Google Scholar 

  149. Shan, L., Song, P., & Zhao, Y., et al. (2022). miR-600 promotes ovarian cancer cells stemness, proliferation and metastasis via targeting KLF9. Journal of Ovarian Research, 15, 52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Chirshev, E., Suzuki, T., & Wang, H., et al. (2021). Let-7i reduces aggressive phenotype and induces BRCAness in ovarian cancer cells. Cancers, 13(18), 4617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wu, Y., Wang, T., **a, L., & Zhang, M. (2021). LncRNA WDFY3-AS2 promotes cisplatin resistance and the cancer stem cell in ovarian cancer by regulating hsa-miR-139-5p/SDC4 axis. Cancer Cell International, 21(1), 284 https://doi.org/10.1186/s12935-021-01993-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Cheng, F. H. C., Lin, H. Y., Hwang, T. W., Chen, Y. C., Huang, R. L., Chang, C. B., Yang, W., Lin, R. I., Lin, C. W., Chen, G. C. W., Mai, S. Y., Lin, J. M. J., Chuang, Y. M., Chou, J. L., Kuo, L. W., Li, C., Cheng, A. S. L., Lai, H. C., Wu, S. F., Tsai, J. C. & & Chan, M. W. Y. (2019). E2F6 functions as a competing endogenous RNA, and transcriptional repressor, to promote ovarian cancer stemness. Cancer Science, 110(3), 1085–1095. https://doi.org/10.1111/cas.13920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Khalil, A. M., Guttman, M., & Huarte, M., et al. (2009). Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proceedings of the National Academy of Sciences of the United States of America, 106, 11667–11672. https://doi.org/10.1073/pnas.0904715106.

    Article  PubMed  PubMed Central  Google Scholar 

  154. Zhan, F. L., Chen, C. F. & Yao, M. Z. (2020). LncRNA TUG1 facilitates proliferation, invasion and stemness of ovarian cancer cell via miR-186-5p/ZEB1 axis. Cell Biochemistry & Function, 38(8), 1069–1078. https://doi.org/10.1002/cbf.3544.

    Article  CAS  Google Scholar 

  155. Shanshan, Yongfang, & Yue, et al. (2018). STON2 negatively modulates stem-like properties in ovarian cancer cells via DNMT1/MUC1 pathway. Journal of Experimental & Clinical Cancer Research: CR, 37, 305.

    Article  Google Scholar 

  156. Piccirillo, S., Reynolds, B. A., Zanetti, N., Lamorte, G., Binda, E., & Broggi, G., et al. (2006). Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature, 444(7120), 761–765. https://doi.org/10.1038/nature05349.

    Article  CAS  PubMed  Google Scholar 

  157. Yan, Y., Li, Z., Xu, X., Chen, C., Wei, W., & Fan, M., et al. (2016). All-trans retinoic acids induce differentiation and sensitize a radioresistant breast cancer cells to chemotherapy. BMC Complementary and Alternative Medicine, 16(1), 1–11. https://doi.org/10.1186/s12906-016-1088-y.

    Article  CAS  Google Scholar 

  158. Yang, R., Liu, B., Yang, M., Xu, F., Wu, S., & Zhao, S. (2022). Lumiflavin reduces cisplatin resistance in cancer stem-like cells of OVCAR-3 cell line by inducing differentiation. Frontiers in Oncology, 12, 859275 https://doi.org/10.3389/fonc.2022.859275.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Chang, C., Lee, S. O., Yeh, S., & Chang, T. M. (2014). Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver. Oncogene, 33(25), 3225–3234.

    Article  CAS  PubMed  Google Scholar 

  160. Proverbs-Singh, T., Feldman, J. L., Morris, M. J., Autio, K. A., & Traina, T. A. (2015). Targeting the androgen receptor in prostate and breast cancer: several new agents in development. Endocrine-Related Cancer, 22(3), R87–r106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Gruessner, C., Gruessner, A., Glaser, K., AbuShahin, N., Zhou, Y., Laughren, C., Wright, H., Pinkerton, S., Yi, X., & Stoffer, J., et al. (2014). Flutamide and biomarkers in women at high risk for ovarian cancer: preclinical and clinical evidence. Cancer Prevention Research, 7(9), 896–905.

    Article  CAS  PubMed  Google Scholar 

  162. Zhu, H., Zhu, X., Zheng, L., Hu, X., Sun, L., & Zhu, X. (2017). The role of the androgen receptor in ovarian cancer carcinogenesis and its clinical implications. Oncotarget, 8(17), 29395–29405.

    Article  PubMed  Google Scholar 

  163. Jonsson, J. M., Skovbjerg Arildsen, N., Malander, S., Masback, A., Hartman, L., Nilbert, M., & Hedenfalk, I. (2015). Sex steroid hormone receptor expression affects ovarian Cancer survival. Translational Oncology, 8(5), 424–433.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Ling, K., Jiang, L., & Liang, S., et al. (2018). Nanog interaction with the androgen receptor signaling axis induce ovarian cancer stem cell regulation: studies based on the CRISPR/Cas9 system. Journal of Ovarian Research, 11(1), 1–16.

    Article  Google Scholar 

  165. Naujokat, C., Fuchs, D., & Opelz, G. J. (2010). Salinomycin in cancer: a new mission for an old agent. Molecular Medicine Reports, 3(4), 555–559. https://doi.org/10.3892/mmr_00000296.

    Article  CAS  PubMed  Google Scholar 

  166. An, H., Kim, J. Y., Lee, N., Cho, Y., Oh, E., & Seo, J. H. (2015). Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via an apoptosis-independent pathway. Biochemical and Biophysical Research Communications, 466(4), 696–703. https://doi.org/10.1016/j.bbrc.2015.09.108.

    Article  CAS  PubMed  Google Scholar 

  167. Lee, H. G., Shin, S. J., & Chung, H. W., et al. (2017). Salinomycin reduces stemness and induces apoptosis on human ovarian cancer stem cell. Journal Gynecologic Oncology, 28(2), e14 https://doi.org/10.3802/jgo.2017.28.e14.

    Article  CAS  Google Scholar 

  168. Mao, J., Fan, S., & Ma, W., et al. (2014). Roles of Wnt/beta-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. Cell Death & Disease, 5, e1039 https://doi.org/10.1038/cddis.2013.515.

    Article  CAS  Google Scholar 

  169. Zou, M., Yin, X., Zhou, X., Niu, X., Wang, Y., & Su, M. (2022). Salinomycin-loaded high-density lipoprotein exerts promising anti-ovarian cancer effects by inhibiting epithelial-mesenchymal transition. International Journal of Nanomedicine, 17, 4059–4071. https://doi.org/10.2147/IJN.S380598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Lee, Y. J., Kim, S. W., Jung, M. H., Kim, Y. S., Kim, K. S., Suh, D. S., Kim, K. H., Choi, E. H., Kim, J., & Kwon, B. S. (2022). Plasma-activated medium inhibits cancer stem cell-like properties and exhibits a synergistic effect in combination with cisplatin in ovarian cancer. Free Radical Biology & Medicine, 182, 276–288. https://doi.org/10.1016/j.freeradbiomed.2022.03.001.

    Article  CAS  Google Scholar 

  171. Coward, J. I., Barve, M. A., Kichenadasse, G., Moore, K. N., Harnett, P. R., Berg, D., Garner, J. S., & Dizon, D. S. (2021). Maximum tolerated dose and anti-tumor activity of intraperitoneal cantrixil (TRX-E-002-1) in patients with persistent or recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer: phase I study results. Cancers, 13(13), 3196 https://doi.org/10.3390/cancers13133196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Ohsawa, I., Ishikawa, M., & Takahashi, K., et al. (2007). Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nature Medicine, 13, 688–694.

    Article  CAS  PubMed  Google Scholar 

  173. Ohta, S. (2014). Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine. Pharmacology & Therapeutics, 144, 1–11.

    Article  CAS  Google Scholar 

  174. Lei, S., Fei, X., & Li, J., et al. (2018). Therapeutic potential of molecular hydrogen in ovarian cancer. Translational Cancer Research, 7(4), 988–995.

    Article  Google Scholar 

  175. Feng, X., Li, L., Wang, L., Luo, S., & Bai, X. (2019). Chromatin target of protein arginine methyltransferase regulates invasion, chemoresistance, and stemness in epithelial ovarian cancer. Bioscience Reports, 39(4), BSR20190016 https://doi.org/10.1042/BSR20190016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Lee, J. S., Choi, Y. D., Lee, J. H., Nam, J. H., Choi, C., & Lee, M. C., et al. (2006). Expression of cyclooxygenase-2 in epithelial ovarian tumors and its relation to vascular endothelial growth factor and p53 expression. International Journal of Gynecological Cancer, 16(Suppl 1), 247–253.

    Article  PubMed  Google Scholar 

  177. Wen, Z., Liu, H., Li, M., Li, B., Gao, W., & Shao, Q., et al. (2015). Increased metabolites of 5-lipoxygenase from hypoxic ovarian cancer cells promote tumorassociated macrophage infifiltration. Oncogene, 34, 1241–1252.

    Article  CAS  PubMed  Google Scholar 

  178. Hirst, J., Pathak, H. B., Hyter, S., Pessetto, Z. Y., Ly, T., Graw, S., Koestler, D. C., Krieg, A. J., Roby, K. F. & Godwin, A. K. (2018). Licofelone enhances the efficacy of paclitaxel in ovarian cancer by reversing drug resistance and tumor stem-like properties. Cancer Research, 78(15), 4370–4385. https://doi.org/10.1158/0008-5472.CAN-17-3993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Nacarelli, T., Fukumoto, T., Zundell, J. A., Fatkhutdinov, N., Jean, S., Cadungog, M. G., Borowsky, M. E., & Zhang, R. (2020). NAMPT Inhibition suppresses cancer stem-like cells associated with therapy-induced senescence in ovarian cancer. Cancer Research, 80(4), 890–900. https://doi.org/10.1158/0008-5472.CAN-19-2830.

    Article  CAS  PubMed  Google Scholar 

  180. Kapur, A., Mehta, P., Simmons, A. D., Ericksen, S. S., Mehta, G., Palecek, S. P., Felder, M., Stenerson, Z., Nayak, A., Dominguez, J. M. A., Patankar, M., & Barroilhet, L. M. (2022). Atovaquone: An inhibitor of oxidative phosphorylation as studied in gynecologic cancers. Cancers, 14(9), 2297 https://doi.org/10.3390/cancers14092297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Li, X., Liu, Y., & Wang, N., et al. (2019). Synthesis and discovery of 18β-glycyrrhetinic acid derivatives inhibiting cancer stem cell properties in ovarian cancer cells. RSC Advances, 9, 27294–27304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Lupia, M., & Cavallaro, U. (2017). Ovarian cancer stem cells: still an elusive entity? Molecular Cancer, 16(1), 64.

    Article  PubMed  PubMed Central  Google Scholar 

  183. Sriramkumar, S., Sood, R., Huntington, T. D., Ghobashi, A. H., Vuong, T. T., Metcalfe, T. X., Wang, W., Nephew, K. P., & O’Hagan, H. M. (2022). Platinum-induced mitochondrial OXPHOS contributes to cancer stem cell enrichment in ovarian cancer. Journal of Translational Medicine, 20(1), 246 https://doi.org/10.1186/s12967-022-03447-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Zhao, E., Maj, T., & Kryczek, I., et al. (2016). Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nature Immunology, 17(1), 95–103.

    Article  CAS  PubMed  Google Scholar 

  185. Wojtowicz, K., Sterzyńska, K., Świerczewska, M., Nowicki, M., Zabel, M., & Januchowski, R. (2021). Piperine targets different drug resistance mechanisms in human ovarian cancer cell lines leading to increased sensitivity to cytotoxic drugs. International Journal of Molecular Sciences, 22(8), 4243 https://doi.org/10.3390/ijms22084243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Simpkins, F., Hevia-Paez, P., Sun, J., Ullmer, W., Gilbert, C. A., & da Silva, T., et al. (2012). Src inhibition with saracatinib reverses fulvestrant resistance in ERpositive ovarian cancer models in vitro and in vivo. Clinical Cancer Research, 18, 5911–5923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Hew, K., Miller, P. C., El-Ashry, D., Sun, J., Besser, A., & Ince, T., et al. (2016). MAPK activation predicts poor outcome and the MEK inhibitor, selumetinib, reverses antiestrogen resistance in high-grade serous ovarian cancer. Clinical Cancer Research, 22, 935–947.

    Article  CAS  PubMed  Google Scholar 

  188. Simpkins, F., Jang, K., Yoon, H., Hew, K. E., Kim, M., Azzam, D. J., Sun, J., Zhao, D., Ince, T. A., Liu, W., Guo, W., Wei, Z., Zhang, G., Mills, G. B. & Slingerland, J. M. (2018). Dual Src and MEK inhibition decreases ovarian cancer growth and targets tumor initiating stem-like cells. Clinical Cancer Research, 24(19), 4874–4886. https://doi.org/10.1158/1078-0432.CCR-17-3697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Ma, J., Salamoun, J., & Wipf, P., et al. (2018). Combination of a thioxodihydroquinazolinone with cisplatin eliminates ovarian cancer stem cell-like cells (CSC-LCs) and shows preclinical potential. Oncotarget, 9(5), 6042–6054.

    Article  PubMed  Google Scholar 

  190. Keita, Togashi, & Masashi, et al. (2018). A Small-molecule Kinase Inhibitor, CEP-1347, Inhibits survivin expression and sensitizes ovarian cancer stem cells to paclitaxel. AntiCancer Research, 38(8), 4535–4542.

    Article  Google Scholar 

  191. Wu, Y. H., Chiu, W. T., Young, M. J., Chang, T. H., Huang, Y. F., & Chou, C. Y. (2015). Solanum incanum extract downregulates aldehyde dehydrogenase 1-mediated stemness and inhibits tumor formation in ovarian cancer cells. Journal Cancer, 6(10), 1011–1019.

    Article  CAS  Google Scholar 

  192. Young, M. J., Wu, Y. H., Chiu, W. T., Weng, T. Y., Huang, Y. F., & Chou, C. Y. (2015). All-trans retinoic acid downregulates ALDH1-mediated stemness and inhibits tumour formation in ovarian cancer cells. Carcinogenesis, 36(4), 498–507. https://doi.org/10.1093/carcin/bgv018.

    Article  CAS  PubMed  Google Scholar 

  193. Campos, B., Wan, F., Farhadi, M., Ernst, A., Zeppernick, F., & Tagscherer, K. E., et al. (2010). Differentiation therapy exerts antitumor effects on stem-like glioma cells. Clinical Cancer Research, 16(10), 2715–2728. https://doi.org/10.1158/1078-0432.CCR-09-1800.

    Article  CAS  PubMed  Google Scholar 

  194. Mal, A., Bukhari, A. B., Singh, R. K., Kapoor, A., & Barai, A., et al. (2020). EpCAM-mediated cellular plasticity promotes radiation resistance and metastasis in breast cancer. Frontiers in Cell and Developmental Biology, 8, 597673.

    Article  PubMed  Google Scholar 

  195. Yang, L., Shi, P., Zhao, G., Xu, J., & Peng, W., et al. (2020). Targeting cancer stem cell pathways for cancer therapy. Signal Transduction and Target Therapy, 5, 8.

    Article  Google Scholar 

  196. Fu, Z., Ma, K., Dong, B., Zhao, C., Che, C., Dong, C., Zhang, R., Wang, H., Wang, X., & Liang, R. (2019). The synergistic antitumor effffect of Huaier combined with 5-Florouracil in human cholangiocarcinoma cells. BMC Complementary and Alternative Medicine, 19, 203 .

    Article  PubMed  PubMed Central  Google Scholar 

  197. Pokhriyal, R., Hariprasad, R., Kumar, L., & Hariprasad, G. (2019). Chemotherapy resistance in advanced ovarian cancer patients. Biomark Cancer, 11, 1179299X19860815 .

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Patch, A. M., Christie, E. L., Etemadmoghadam, D., Garsed, D. W., George, J., Fereday, S., Nones, K., Cowin, P., Alsop, K., & Bailey, P., et al. (2015). Whole-genome characterization of chemoresistant ovarian cancer. Nature, 521, 489–494.

    Article  CAS  PubMed  Google Scholar 

  200. Lee, H., Kim, J. W., & Kim, D. K., et al. (2020). Calcium channels as novel therapeutic targets for ovarian cancer stem cells. International Journal of Molecular Sciences, 21(7), 2327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Biqing Chen assumed the responsibility of composing and organizing the initial draft, Jiaqi Liu undertook the responsibility of graphic editing and table structuring.

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Chen, B., Liu, J. Advances in ovarian tumor stem cells and therapy. Cell Biochem Biophys (2024). https://doi.org/10.1007/s12013-024-01385-8

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