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Extirpating the cancer stem cell hydra: Differentiation therapy and Hyperthermia therapy for targeting the cancer stem cell hierarchy

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Abstract

Ever since the discovery of cancer stem cells (CSCs), they have progressively attracted more attention as a therapeutic target. Like the mythical hydra, this subpopulation of cells seems to contribute to cancer immortality, spawning more cells each time that some components of the cancer cell hierarchy are destroyed. Traditional modalities focusing on cancer treatment have emphasized apoptosis as a route to eliminate the tumor burden. A major problem is that cancer cells are often in varying degrees of dedifferentiation contributing to what is known as the CSCs hierarchy and cells which are known to be resistant to conventional therapy. Differentiation therapy is an experimental therapeutic modality aimed at the conversion of malignant phenotype to a more benign one. Hyperthermia therapy (HT) is a modality exploiting the changes induced in cells by the application of heat produced to aid in cancer therapy. While differentiation therapy has been successfully employed in the treatment of acute myeloid leukemia, it has not been hugely successful for other cancer types. Mounting evidence suggests that hyperthermia therapy may greatly augment the effects of differentiation therapy while simultaneously overcoming many of the hard-to-treat facets of recurrent tumors. This review summarizes the progress made so far in integrating hyperthermia therapy with existing modules of differentiation therapy. The focus is on studies related to the successful application of both hyperthermia and differentiation therapy when used alone or in conjunction for hard-to-treat cancer cell niche with emphasis on combined approaches to target the CSCs hierarchy.

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References

  1. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11. https://doi.org/10.1038/35102167.

    Article  CAS  PubMed  Google Scholar 

  2. Sadhukha T, Niu L, Wiedmann TS, Panyam J. Effective elimination of cancer stem cells by magnetic hyperthermia. Mol Pharm. 2013;10:1432–41. https://doi.org/10.1021/mp400015b.

    Article  CAS  PubMed  Google Scholar 

  3. Moise S, Byrne JM, El Haj AJ, Telling ND. The potential of magnetic hyperthermia for triggering the differentiation of cancer cells. Nanoscale. 2018;10:20519–25. https://doi.org/10.1039/C8NR05946B.

    Article  CAS  PubMed  Google Scholar 

  4. Ebert PS, Salcman M. Differentiation therapy is potentiated by chemotherapy and hyperthermia in human and canine brain tumor cells in vitro. Neurosurgery. 1994;34:657–64. https://doi.org/10.1227/00006123-199404000-00013.

    Article  CAS  PubMed  Google Scholar 

  5. Périgo EA, Hemery G, Sandre O, et al. Fundamentals and advances in magnetic hyperthermia. Appl Phys Rev. 2015;2:41302. https://doi.org/10.48550/arXiv.1510.06383.

    Article  Google Scholar 

  6. Bañobre-López M, Teijeiro A, Rivas J. Magnetic nanoparticle-based hyperthermia for cancer treatment. Reports Pract Oncol Radiother. 2013;18:397–400. https://doi.org/10.1016/j.rpor.2013.09.011.

    Article  Google Scholar 

  7. Beik J, Abed Z, Ghoreishi FS, et al. Nanotechnology in hyperthermia cancer therapy: from fundamental principles to advanced applications. J Control Release. 2016;235:205–21. https://doi.org/10.1016/j.jconrel.2016.05.062.

    Article  CAS  PubMed  Google Scholar 

  8. Nowak D, Stewart D, Koeffler HP. Differentiation therapy of leukemia: 3 decades of development. Blood. 2009;113(16):3655–65. https://doi.org/10.1182/blood-2009-01-198911.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sell S. Cancer stem cells and differentiation therapy. Tumor Biol. 2006;27:59–70. https://doi.org/10.1159/000092323.

    Article  Google Scholar 

  10. Leszczyniecka M, Roberts T, Dent P, Grant S, Fisher PB. Differentiation therapy of human cancer: basic science and clinical applications. Pharmacol Ther. 2001;90:105–56. https://doi.org/10.1016/s0163-7258(01)00132-2.

    Article  CAS  PubMed  Google Scholar 

  11. Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol. 2004;51:1–28. https://doi.org/10.1016/j.critrevonc.2004.04.007.

    Article  PubMed  Google Scholar 

  12. Récamier JCA. Recherches sur the Traitement du Cancer: par la Compression Methodique Simple ou Combinee, et sur l’Histoire General de la Meme Maladie. Paris: Gabon; 1829.

    Google Scholar 

  13. Cohnheim J. Congenitales, quergestreiftes muskelsarkom der nieren. Arch für Pathol Anat und Physiol und für Klin Med. 1875;65:64–9.

    Google Scholar 

  14. Kahroba H, Shirmohamadi M, Hejazi MS, Samadi N. The Role of Nrf2 signaling in cancer stem cells: From stemness and self-renewal to tumorigenesis and chemoresistance. Life Sci. 2019;239:116986. https://doi.org/10.1016/j.lfs.2019.116986.

    Article  CAS  PubMed  Google Scholar 

  15. Calabrese EJ. Hormesis and bone marrow stem cells: Enhancing cell proliferation, differentiation and resilience to inflammatory stress. Chem Biol Interact. 2022;351:109730. https://doi.org/10.1016/j.cbi.2021.109730.

    Article  CAS  PubMed  Google Scholar 

  16. Steinbichler TB, Savic D, Dudás J, et al. Cancer stem cells and their unique role in metastatic spread. Semin Cancer Biol. 2020;60:148–56. https://doi.org/10.1016/j.semcancer.2019.09.007.

    Article  CAS  PubMed  Google Scholar 

  17. Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 2006;66:9339–44. https://doi.org/10.1158/0008-5472.CAN-06-3126.

    Article  CAS  PubMed  Google Scholar 

  18. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci. 2003;100:3983–8. https://doi.org/10.1073/pnas.0530291100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63(18):5821–8.

    CAS  PubMed  Google Scholar 

  20. Zhang Q, Han Z, Zhu Y, Chen J, Li W. The role and specific mechanism of OCT4 in cancer stem cells: a review. Int J Stem Cells. 2020;13:312–25. https://doi.org/10.15283/ijsc20097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen S, Guttridge DC, You Z, et al. Wnt-1 signaling inhibits apoptosis by activating β-catenin/T cell factor–mediated transcription. J Cell Biol. 2001;152:87–96. https://doi.org/10.1083/jcb.152.1.87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ueda Y, Hijikata M, Takagi S, et al. Wnt/β-catenin signaling suppresses apoptosis in low serum medium and induces morphologic change in rodent fibroblasts. Int J cancer. 2002;99:681–8. https://doi.org/10.1002/ijc.10418.

    Article  CAS  PubMed  Google Scholar 

  23. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–50. https://doi.org/10.1038/nature03319.

    Article  CAS  PubMed  Google Scholar 

  24. Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer. 2008;8:387–98. https://doi.org/10.1038/nrc2389.

    Article  CAS  PubMed  Google Scholar 

  25. Shibata T, Chuma M, Kokubu A, Sakamoto M, Hirohashi S. EBP50, a β-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma. Hepatology. 2003;38:178–86. https://doi.org/10.1053/jhep.2003.50270.

    Article  CAS  PubMed  Google Scholar 

  26. Zhang Z, Bu X, Chen H, Wang Q, Sha W. Bmi-1 promotes the invasion and migration of colon cancer stem cells through the downregulation of E-cadherin. Int J Mol Med. 2016;38:1199–207. https://doi.org/10.3892/ijmm.2016.2730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yu X, Jiang X, Li H, Guo L, Jiang W, Lu S-H. miR-203 inhibits the proliferation and self-renewal of esophageal cancer stem-like cells by suppressing stem renewal factor Bmi-1. Stem Cells Dev. 2014;23:576–85. https://doi.org/10.1089/scd.2013.0308.

    Article  CAS  PubMed  Google Scholar 

  28. Wang Y, Zhe H, Ding Z, Gao P, Zhang N, Li G. Cancer stem cell marker Bmi-1 expression is associated with basal-like phenotype and poor survival in breast cancer. World J Surg. 2012;36:1189–94. https://doi.org/10.1007/s00268-012-1514-3.

    Article  PubMed  Google Scholar 

  29. Mueller M, Hermann PC, Witthauer J, et al. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology. 2009;137:1102–13. https://doi.org/10.1053/j.gastro.2009.05.053.

    Article  CAS  PubMed  Google Scholar 

  30. Athar M, Li C, Kim AL, Spiegelman VS, Bickers DR. Sonic hedgehog signaling in Basal cell nevus syndrome. Cancer Res. 2014;74:4967–75. https://doi.org/10.1158/0008-5472.CAN-14-1666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Han J-B, Sang F, Chang J, et al. Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli. OncoTargets Ther. 2013;6:1129-38. https://doi.org/10.2147/OTT.S49148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Venkatesh V, Nataraj R, Thangaraj GS, et al. Targeting Notch signalling pathway of cancer stem cells. Stem cell Investig. 2018;5:5. https://doi.org/10.21037/sci.2018.02.02.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lewis J. Notch signalling and the control of cell fate choices in vertebrates. Semin Cell Dev Biol. 1998. https://doi.org/10.1006/scdb.1998.0266.

    Article  PubMed  Google Scholar 

  34. Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast cancer Res. 2004;6:1–11. https://doi.org/10.1186/bcr920.

    Article  CAS  Google Scholar 

  35. Siekmann AF, Lawson ND. Notch signalling and the regulation of angiogenesis. Cell Adh Migr. 2007;1:104–5. https://doi.org/10.4161/cam.1.2.4488.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Apelqvist Å, Li H, Sommer L, et al. Notch signalling controls pancreatic cell differentiation. Nature. 1999;400:877–81. https://doi.org/10.1038/23716.

    Article  CAS  PubMed  Google Scholar 

  37. Hassan KA, Wang L, Korkaya H, et al. Notch pathway activity identifies cells with cancer stem cell–like properties and correlates with worse survival in lung adenocarcinoma. Clin cancer Res. 2013;19:1972–80. https://doi.org/10.1158/1078-0432.CCR-12-0370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ponnurangam S, Dandawate PR, Dhar A, et al. Quinomycin a targets Notch signaling pathway in pancreatic cancer stem cells. Oncotarget. 2016;7:3217–32. https://doi.org/10.18632/oncotarget.6560.

    Article  PubMed  Google Scholar 

  39. Hovinga KE, Shimizu F, Wang R, et al. Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells. 2010;28:1019–29. https://doi.org/10.1002/stem.429.

    Article  CAS  PubMed  Google Scholar 

  40. Suman S, Das TP, Damodaran C. Silencing NOTCH signaling causes growth arrest in both breast cancer stem cells and breast cancer cells. Br J Cancer. 2013;109:2587–96. https://doi.org/10.1038/bjc.2013.642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cai Y, Yu X, Hu S, Yu J. A brief review on the mechanisms of miRNA regulation. Genoms Proteoms Bioinform. 2009;7:147–54. https://doi.org/10.1016/S1672-0229(08)60044-3.

    Article  CAS  Google Scholar 

  42. Yi R, Poy MN, Stoffel M, Fuchs E. A skin microRNA promotes differentiation by repressing ‘stemness.’ Nature. 2008;452:225–9. https://doi.org/10.1038/nature06642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bloomston M, Frankel WL, Petrocca F, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297:1901–8. https://doi.org/10.1001/jama.297.17.1901.

    Article  CAS  PubMed  Google Scholar 

  44. Shimono Y, Zabala M, Cho RW, et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell. 2009;138:592–603. https://doi.org/10.1016/j.cell.2009.07.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Medema JP. Cancer stem cells: the challenges ahead. Nat Cell Biol. 2013;15:338–44. https://doi.org/10.1038/ncb2717.

    Article  CAS  PubMed  Google Scholar 

  46. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift. Cancer Res. 2006;66:1883–90. https://doi.org/10.1158/0008-5472.CAN-05-3153.

    Article  CAS  PubMed  Google Scholar 

  47. Wilson GS, Hu Z, Duan W, et al. Efficacy of using cancer stem cell markers in isolating and characterizing liver cancer stem cells. Stem Cells Dev. 2013;22:2655–64. https://doi.org/10.1089/scd.2012.0703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Raghav PK, Mann Z. Cancer stem cells targets and combined therapies to prevent cancer recurrence. Life Sci. 2021;277:119465. https://doi.org/10.1016/j.lfs.2021.119465.

    Article  CAS  PubMed  Google Scholar 

  49. Wu Y, Wu PY. CD133 as a marker for cancer stem cells: progresses and concerns. Stem Cells Dev. 2009;18:1127–34. https://doi.org/10.1089/scd.2008.0338.

    Article  CAS  PubMed  Google Scholar 

  50. Karsten U, Goletz S. What makes cancer stem cell markers different? Springerplus. 2013;2:301. https://doi.org/10.1186/2193-1801-2-301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem cell Rev reports. 2011;7:292–306. https://doi.org/10.1007/s12015-010-9208-4.

    Article  CAS  Google Scholar 

  52. Bach P, Abel T, Hoffmann C, et al. Specific elimination of CD133+ tumor cells with targeted oncolytic measles virus. Cancer Res. 2013;73:865–74. https://doi.org/10.1158/0008-5472.CAN-12-2221.

    Article  CAS  PubMed  Google Scholar 

  53. Buishand FO, Arkesteijn GJA, Feenstra LR, et al. Identification of CD90 as putative cancer stem cell marker and therapeutic target in insulinomas. Stem Cells Dev. 2016;25:826–35. https://doi.org/10.1089/scd.2016.0032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Boiko AD, Razorenova OV, van de Rijn M, et al. Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature. 2010;466:133–7. https://doi.org/10.1038/nature09161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Vassilopoulos A, Chisholm C, Lahusen T, Zheng H, Deng C-X. A critical role of CD29 and CD49f in mediating metastasis for cancer-initiating cells isolated from a Brca1-associated mouse model of breast cancer. Oncogene. 2014;33:5477–82. https://doi.org/10.1038/onc.2013.516.

    Article  CAS  PubMed  Google Scholar 

  56. Thapa R, Wilson GD. The Importance of CD44 as a stem cell biomarker and therapeutic target in cancer. Stem Cells Int. 2016. https://doi.org/10.1155/2016/2087204.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Yamazaki H, Wilson XuC, Naito M, et al. Regulation of cancer stem cell properties by CD9 in human B-acute lymphoblastic leukemia. Biochem Biophys Res Commun. 2011;409:14–21. https://doi.org/10.1016/j.bbrc.2011.04.098.

    Article  CAS  PubMed  Google Scholar 

  58. Kim YJ, Yu JM, Joo HJ, et al. Role of CD9 in proliferation and proangiogenic action of human adipose-derived mesenchymal stem cells. Pflügers Arch Eur J Physiol. 2007;455:283–96. https://doi.org/10.1007/s00424-007-0285-4.

    Article  CAS  Google Scholar 

  59. Carpenter MK, Rosler ES, Fisk GJ, et al. Properties of four human embryonic stem cell lines maintained in a feeder-free culture system. Dev Dyn. 2004;229:243–58. https://doi.org/10.1002/dvdy.10431.

    Article  CAS  PubMed  Google Scholar 

  60. Dvorak P, Dvorakova D, Hampl A. Fibroblast growth factor signaling in embryonic and cancer stem cells. FEBS Lett. 2006;580:2869–74. https://doi.org/10.1016/j.febslet.2006.01.095.

    Article  CAS  PubMed  Google Scholar 

  61. Thomas ML, Coyle KM, Sultan M, Vaghar-Kashani A, Marcato P. Chemoresistance in cancer stem cells and strategies to overcome resistance. Chemotherapy. 2014;3:1. https://doi.org/10.4172/2167-7700.1000125.

    Article  CAS  Google Scholar 

  62. An Y, Ongkeko WM. ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol. 2009;5:1529–42. https://doi.org/10.1517/17425250903228834.

    Article  CAS  PubMed  Google Scholar 

  63. Zhao J. Cancer stem cells and chemoresistance: the smartest survives the raid. Pharmacol Ther. 2016;160:145–58. https://doi.org/10.1016/j.pharmthera.2016.02.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Abdullah LN, Chow EK-H. Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med. 2013;2:3. https://doi.org/10.1186/2001-1326-2-3.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer. 2008;8:545–54. https://doi.org/10.1038/nrc2419.

    Article  CAS  PubMed  Google Scholar 

  66. Diehn M, Cho RW, Lobo NA, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458:780–3. https://doi.org/10.1038/nature07733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rycaj K, Tang DG. Cancer stem cells and radioresistance. Int J Radiat Biol. 2014;90:615–21. https://doi.org/10.3109/09553002.2014.892227.

    Article  CAS  PubMed  Google Scholar 

  68. Pajonk F, Vlashi E, McBride WH. Radiation resistance of cancer stem cells: the 4 R’s of radiobiology revisited. Stem Cells. 2010;28:639–48. https://doi.org/10.1002/stem.318.

    Article  CAS  PubMed  Google Scholar 

  69. Lagadec C, Vlashi E, Della Donna L, Dekmezian C, Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells. 2012;30:833–44. https://doi.org/10.1002/stem.1058.

    Article  CAS  PubMed  Google Scholar 

  70. Li F, Zhou K, Gao L, et al. Radiation induces the generation of cancer stem cells: a novel mechanism for cancer radioresistance. Oncol Lett. 2016;12:3059–65. https://doi.org/10.3892/ol.2016.5124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Beier D, Schulz JB, Beier CP. Chemoresistance of glioblastoma cancer stem cells-much more complex than expected. Mol Cancer. 2011;10:1–11. https://doi.org/10.1186/1476-4598-10-128.

    Article  CAS  Google Scholar 

  72. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med. 2017;23:1124–34. https://doi.org/10.1038/nm.4409.

    Article  CAS  PubMed  Google Scholar 

  73. Afify SM, Seno M. Conversion of stem cells to cancer stem cells: undercurrent of cancer initiation. Cancers (Basel). 2019;11(3):345. https://doi.org/10.3390/cancers11030345.

    Article  CAS  PubMed  Google Scholar 

  74. Zhang DY, Monteiro MJ, Liu JP, Gu WY. Mechanisms of cancer stem cell senescence: current understanding and future perspectives. Clin Exp Pharmacol Physiol. 2021;48(9):1185–202. https://doi.org/10.1111/1440-1681.13528.

    Article  CAS  PubMed  Google Scholar 

  75. Gailhouste L, Liew LC, Yasukawa K, et al. differentiation therapy by epigenetic reconditioning exerts antitumor effects on liver cancer Cells. Mol Ther. 2018;26(7):1840–54. https://doi.org/10.1016/j.ymthe.2018.04.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Schlumberger M, Leboulleux S. Current practice in patients with differentiated thyroid cancer. Nat Rev Endocrinol. 2021;17(3):176–88. https://doi.org/10.1038/s41574-020-00448-z.

    Article  CAS  PubMed  Google Scholar 

  77. Greaves M. Leukaemia, “firsts” in cancer research and treatment. Nat Rev Cancer. 2016;16(3):163–72. https://doi.org/10.1038/nrc.2016.3.

    Article  CAS  PubMed  Google Scholar 

  78. Jin X, Jin X, Kim H. Cancer stem cells and differentiation therapy. Tumor Biol. 2017. https://doi.org/10.1177/1010428317729933.

    Article  Google Scholar 

  79. Arima Y, Nobusue H, Saya H. Targeting of cancer stem cells by differentiation therapy. Cancer Sci. 2020;111(8):2689–95. https://doi.org/10.1111/cas.14504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Spira AI, Carducci MA. Differentiation therapy. Curr Opin Pharmacol. 2003;3:338–43. https://doi.org/10.1016/s1471-4892(03)00081-x.

    Article  CAS  PubMed  Google Scholar 

  81. Newmark HL, Young CW. Butyrate and phenylacetate as differentiating agents: practical problems and opportunities. J Cell Biochem. 1995;59:247–53. https://doi.org/10.1002/jcb.240590831.

    Article  Google Scholar 

  82. Ramya D, Siddikuzzaman MA, Berlin Grace VM. Chemoprotective effect of all-trans retinoic acid (ATRA) on oxidative stress and lung metastasis induced by benzo (a) pyrene. Immunopharmacol Immunotoxicol. 2012;34:317–25. https://doi.org/10.3109/08923973.2011.604087.

    Article  CAS  PubMed  Google Scholar 

  83. Hansen LA, Sigman CC, Andreola F, Ross SA, Kelloff GJ, De Luca LM. Retinoids in chemoprevention and differentiation therapy. Carcinogenesis. 2000;21:1271–9.

    Article  CAS  PubMed  Google Scholar 

  84. Castaigne S, Chomienne C, Daniel MT, et al. All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I Clinical Results. 1990;76(9):1704–9.

    CAS  Google Scholar 

  85. Warrell RP Jr, Frankel SR, Miller WH Jr, et al. Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991;324:1385–93. https://doi.org/10.1056/nejm199105163242002.

    Article  PubMed  Google Scholar 

  86. Reynolds CP. Differentiating agents in pediatric malignancies: Retinoids in neuroblastoma. Curr Oncol Rep. 2000;2:511–8. https://doi.org/10.1007/s11912-000-0104-y.

    Article  CAS  PubMed  Google Scholar 

  87. Waxman S. Differentiation therapy in acute myelogenous leukemia (non-APL). Leukemia. 2000;14:491–6. https://doi.org/10.1038/sj.leu.2401714.

    Article  CAS  PubMed  Google Scholar 

  88. Warrell RP Jr, de The H, Wang Z-Y, Degos L. Acute promyelocytic leukemia. N Engl J Med. 1993;329:177–89. https://doi.org/10.1056/nejm199307153290307.

    Article  CAS  PubMed  Google Scholar 

  89. Wang Z-Y, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111:2505–15. https://doi.org/10.1182/blood-2007-07-102798.

    Article  CAS  PubMed  Google Scholar 

  90. de Thé H, Chomienne C, Lanotte M, Degos L, Dejean A. The t (15; 17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor α gene to a novel transcribed locus. Nature. 1990;347:558–61. https://doi.org/10.1038/347558a0.

    Article  PubMed  Google Scholar 

  91. de Thé H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A. The PML-RARα fusion mRNA generated by the t (15; 17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991;66:675–84. https://doi.org/10.1016/0092-8674(91)90113-d.

    Article  PubMed  Google Scholar 

  92. Lawson ND, Berliner N. Neutrophil maturation and the role of retinoic acid. Exp Hematol. 1999;27:1355–67. https://doi.org/10.1016/s0301-472x(99)00085-5.

    Article  CAS  PubMed  Google Scholar 

  93. Huang ME, Ye YC, Chen SR, et al. All-trans retinoic acid with or without low dose cytosine arabinoside in acute promyelocytic leukemia: report of 6 cases. Chin Med J (Engl). 1987;100:949–53. https://doi.org/10.5555/cmj.0366-6999.100.12.p949.01.

    Article  CAS  PubMed  Google Scholar 

  94. Sun R, Liu Y, Li S-Y, et al. Co-delivery of all-trans-retinoic acid and doxorubicin for cancer therapy with synergistic inhibition of cancer stem cells. Biomaterials. 2015;37:405–14. https://doi.org/10.1016/j.biomaterials.2014.10.018.

    Article  CAS  PubMed  Google Scholar 

  95. Najafzadeh N, Mazani M, Abbasi A, Farassati F, Amani M. Low-dose all-trans retinoic acid enhances cytotoxicity of cisplatin and 5-fluorouracil on CD44+ cancer stem cells. Biomed Pharmacother. 2015;74:243–51. https://doi.org/10.1016/j.biopha.2015.08.019.

    Article  CAS  PubMed  Google Scholar 

  96. Karsy M, Albert L, Tobias ME, Murali R, Jhanwar-Uniyal M. All-trans retinoic acid modulates cancer stem cells of glioblastoma multiforme in an MAPK-dependent manner. Anticancer Res. 2010;30:4915–20.

    CAS  PubMed  Google Scholar 

  97. Nguyen PH, Giraud J, Staedel C, et al. All-trans retinoic acid targets gastric cancer stem cells and inhibits patient-derived gastric carcinoma tumor growth. Oncogene. 2016;35:5619–28. https://doi.org/10.1038/onc.2016.87.

    Article  CAS  PubMed  Google Scholar 

  98. Li R-J, Ying X, Zhang Y, et al. All-trans retinoic acid stealth liposomes prevent the relapse of breast cancer arising from the cancer stem cells. J Control release. 2011;149:281–91. https://doi.org/10.1016/j.jconrel.2010.10.019.

    Article  CAS  PubMed  Google Scholar 

  99. Whitworth JM, Londoño-Joshi AI, Sellers JC, et al. The impact of novel retinoids in combination with platinum chemotherapy on ovarian cancer stem cells. Gynecol Oncol. 2012;125:226–30. https://doi.org/10.1016/j.ygyno.2011.12.425.

    Article  CAS  PubMed  Google Scholar 

  100. Velázquez OC, Lederer HM, Rombeau JL. Butyrate and the colonocyte. Dig Dis Sci. 1996;41:727–39. https://doi.org/10.1007/BF02213129.

    Article  PubMed  Google Scholar 

  101. Carducci MA, Nelson JB, Chan-Tack KM, et al. Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. Clin Cancer Res. 1996;2:379–87.

    CAS  PubMed  Google Scholar 

  102. Marks PA, Richon VM, Rifkind RA. Histone deacetylase inhibitors: inducers of differentiation or apoptosis of transformed cells. J Natl Cancer Inst. 2000;92:1210–6. https://doi.org/10.1093/jnci/92.15.1210.

    Article  CAS  PubMed  Google Scholar 

  103. Witt O, Schulze S, Kanbach K, Roth C, Pekrun A. Tumor cell differentiation by butyrate and environmental stress. Cancer Lett. 2001;171(2):173–82. https://doi.org/10.1016/s0304-3835(01)00628-0.

    Article  CAS  PubMed  Google Scholar 

  104. Goh M, Chen F, Paulsen MT, Yeager AM, Dyer ES, Ljungman M. Phenylbutyrate attenuates the expression of Bcl-XL, DNA-PK, Caveolin-1, and VEGF in prostate cancer cells. Neoplasia. 2001;3:331–8. https://doi.org/10.1038/sj.neo.7900165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Barnard JA, Warwick G. Butyrate rapidly induces growth inhibition and differentiation in HT-29 cells. Cell growth Differ. 1993;4:495.

    CAS  PubMed  Google Scholar 

  106. Newmark HL, Lupton JR, Young CW. Butyrate as a differentiating agent:pharmacokinetics, analogues and current status. Cancer Lett. 1994;78:1–5. https://doi.org/10.1016/0304-3835(94)90023-x.

    Article  CAS  PubMed  Google Scholar 

  107. Davison K, Mann KK, Miller WH Jr. Arsenic trioxide: mechanisms of action. Semin Hematol. 2002. https://doi.org/10.1053/shem.2002.33610.

    Article  PubMed  Google Scholar 

  108. Giannı̀KokenChelbialix MMHMMK, et al. Combined arsenic and retinoic acid treatment enhances differentiation and apoptosis in arsenic-resistant NB4 cells. Blood. 1998;91:4300–10. https://doi.org/10.1182/blood.V91.11.4300.

    Article  Google Scholar 

  109. Ghavamzadeh A, Alimoghaddam K, Ghaffari SH, et al. Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy. Ann Oncol. 2006;17:131–4. https://doi.org/10.1093/annonc/mdj019.

    Article  CAS  PubMed  Google Scholar 

  110. de Ruijter AJM, van Gennip AH, Caron HN, Kemp S, van Kuilenburg ABP. Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2003;370:737–49. https://doi.org/10.1042/bj20021321.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Botrugno OA, Santoro F, Minucci S. Histone deacetylase inhibitors as a new weapon in the arsenal of differentiation therapies of cancer. Cancer Lett. 2009;280:134–44. https://doi.org/10.1016/j.canlet.2009.02.027.

    Article  CAS  PubMed  Google Scholar 

  112. He L-Z, Tolentino T, Grayson P, et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest. 2001;108:1321–30. https://doi.org/10.1172/jci11537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Göttlicher M, Minucci S, Zhu P, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. 2001;20:6969–78. https://doi.org/10.1093/emboj/20.24.6969.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Lim YC, Kang HJ, Kim YS, Choi EC. All-trans-retinoic acid inhibits growth of head and neck cancer stem cells by suppression of Wnt/β-catenin pathway. Eur J Cancer. 2012;48:3310–8. https://doi.org/10.1016/j.ejca.2012.04.013.

    Article  CAS  PubMed  Google Scholar 

  115. Ying M, Zhou X, Zhong L, et al. Bortezomib sensitizes human acute myeloid leukemia cells to all-trans-retinoic acid-induced differentiation by modifying the RARα/STAT1 axis. Mol Cancer Ther. 2013;12:195–206. https://doi.org/10.1158/1535-7163.mct-12-0433.

    Article  CAS  PubMed  Google Scholar 

  116. Zhao Q, Tao J, Zhu Q, et al. Rapid induction of cAMP/PKA pathway during retinoic acid-induced acute promyelocytic leukemia cell differentiation. Leukemia. 2004;18:285–92. https://doi.org/10.1038/sj.leu.2403226.

    Article  CAS  PubMed  Google Scholar 

  117. Zito G, Naselli F, Saieva L, et al. Retinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition. Sci Rep. 2017;7:4770. https://doi.org/10.1038/s41598-017-05047-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Busch AM, Galimberti F, Nehls KE, et al. All-trans-retinoic acid antagonizes the hedgehog pathway by inducing patched. Cancer Biol Ther. 2014;15:463–72. https://doi.org/10.4161/cbt.27821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Orfali N, O’Donovan TR, Cahill MR, et al. All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL). Eur J Haematol. 2020;104:236–50. https://doi.org/10.1111/ejh.13367.

    Article  CAS  PubMed  Google Scholar 

  120. Witt O, Sand K, Pekrun A. Butyrate-induced erythroid differentiation of human K562 leukemia cells involves inhibition of ERK and activation of p38 MAP kinase pathways. Blood. 2000;95:2391–6. https://doi.org/10.1182/blood.V95.7.2391.

    Article  CAS  PubMed  Google Scholar 

  121. Bai Z, Zhang Z, Ye Y, Wang S. Sodium butyrate induces differentiation of gastric cancer cells to intestinal cells via the PTEN/phosphoinositide 3-kinase pathway. Cell Biol Int. 2010;34:1141–5. https://doi.org/10.1042/CBI20090481.

    Article  CAS  PubMed  Google Scholar 

  122. Lévy P, Robin H, Bertrand F, Kornprobst M, Capeau J. Butyrate-treated colonic Caco-2 cells exhibit defective integrin-mediated signaling together with increased apoptosis and differentiation. J Cell Physiol. 2003;197:336–47. https://doi.org/10.1002/jcp.10345.

    Article  CAS  PubMed  Google Scholar 

  123. Orchel A, Dzierżewicz Z, Parfiniewicz B, Weglarz L, Wilczok T. Butyrate-induced differentiation of colon cancer cells is PKC and JNK dependent. Dig Dis Sci. 2005;50:490–8. https://doi.org/10.1007/s10620-005-2463-6.

    Article  CAS  PubMed  Google Scholar 

  124. Zhang X, Hu B, Sun Y-F, et al. Arsenic trioxide induces differentiation of cancer stem cells in hepatocellular carcinoma through inhibition of LIF/JAK1/STAT3 and NF-kB signaling pathways synergistically. Clin Transl Med. 2021;11:e335. https://doi.org/10.1002/ctm2.335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lallemand-Breitenbach V, Jeanne M, Benhenda S, et al. Arsenic degrades PML or PML–RARα through a SUMO-triggered RNF4/ubiquitin-mediated pathway. Nat Cell Biol. 2008;10:547–55. https://doi.org/10.1038/ncb1717.

    Article  CAS  PubMed  Google Scholar 

  126. Zhang K-Z, Zhang Q-B, Zhang Q-B, et al. Arsenic trioxide induces differentiation of CD133+ hepatocellular carcinoma cells and prolongs posthepatectomy survival by targeting GLI1 expression in a mouse model. J Hematol Oncol. 2014;7:28. https://doi.org/10.1186/1756-8722-7-28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Huang H, Reed CP, Zhang J-S, Shridhar V, Wang L, Smith DI. Carboxypeptidase A3 (CPA3): a novel gene highly induced by histone deacetylase inhibitors during differentiation of prostate epithelial cancer cells1. Cancer Res. 1999;59:2981–8.

    CAS  PubMed  Google Scholar 

  128. Stockhausen M-T, Sjölund J, Manetopoulos C, Axelson H. Effects of the histone deacetylase inhibitor valproic acid on Notch signalling in human neuroblastoma cells. Br J Cancer. 2005;92:751–9. https://doi.org/10.1038/sj.bjc.6602309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Condorelli F, Gnemmi I, Vallario A, Genazzani AA, Canonico PL. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br J Pharmacol. 2008;153:657–68. https://doi.org/10.1038/sj.bjp.0707608.

    Article  CAS  PubMed  Google Scholar 

  130. Taulli R, Bersani F, Foglizzo V, et al. The muscle-specific microRNA miR-206 blocks human rhabdomyosarcoma growth in xenotransplanted mice by promoting myogenic differentiation. J Clin Invest. 2009;119:2366–78. https://doi.org/10.1172/JCI38075.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev cancer. 2006;6:857–66. https://doi.org/10.1038/nrc1997.

    Article  CAS  PubMed  Google Scholar 

  132. Hammond SM. MicroRNAs as oncogenes. Curr Opin Genet Dev. 2006;16:4–9. https://doi.org/10.1016/j.gde.2005.12.005.

    Article  CAS  PubMed  Google Scholar 

  133. Mishra PJ, Merlino G. MicroRNA reexpression as differentiation therapy in cancer. J Clin Invest. 2009;119:2119–23. https://doi.org/10.1172/jci40107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Silber J, Lim DA, Petritsch C, et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 2008;6:1–17. https://doi.org/10.1186/1741-7015-6-14.

    Article  CAS  Google Scholar 

  135. Muller F, Ramiro G, Amelia C, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci. 2007;104:15805–10. https://doi.org/10.1073/pnas.0707628104.

    Article  Google Scholar 

  136. Wang H, Garzon R, Sun H, et al. NF-κB–YY1–miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell. 2008;14:369–81. https://doi.org/10.1016/j.ccr.2008.10.006.

    Article  CAS  PubMed  Google Scholar 

  137. Liu C, Kelnar K, Liu B, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17:211–5. https://doi.org/10.1038/nm.2284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ji Q, Hao X, Zhang M, et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One. 2009;4:e6816. https://doi.org/10.1371/journal.pone.0006816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Huang H, Hu M, Li P, Lu C, Li M. Mir-152 inhibits cell proliferation and colony formation of CD133+ liver cancer stem cells by targeting KIT. Tumor Biol. 2015;36:921–8. https://doi.org/10.1007/s13277-014-2719-x.

    Article  CAS  Google Scholar 

  140. Fang Y, Gu X, Li Z, Xiang J, Chen Z. miR-449b inhibits the proliferation of SW1116 colon cancer stem cells through downregulation of CCND1 and E2F3 expression. Oncol Rep. 2013;30:399–406. https://doi.org/10.3892/or.2013.2465.

    Article  CAS  PubMed  Google Scholar 

  141. Ji Q, Hao X, Meng Y, et al. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer. 2008;8:266. https://doi.org/10.1186/1471-2407-8-266.

    Article  CAS  PubMed  Google Scholar 

  142. Jung KH, Zhang J, Zhou C, et al. Differentiation therapy for hepatocellular carcinoma: multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis. Hepatology. 2016;63:864–79. https://doi.org/10.1002/hep.28367.

    Article  CAS  PubMed  Google Scholar 

  143. Zhao Z, Ma X, Sung D, et al. microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest. RNA Biol. 2015;12:538–54. https://doi.org/10.1080/15476286.2015.1023495.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Tsai W-C, Hsu S-D, Hsu C-S, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012;122:2884–97. https://doi.org/10.1172/jci63455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Skrzypek K, Nieszporek A, Badyra B, Lasota M, Majka M. Enhancement of myogenic differentiation and inhibition of rhabdomyosarcoma progression by miR-28-3p and miR-193a-5p regulated by SNAIL. Mol Ther Acids. 2021;24:888–904. https://doi.org/10.1016/j.omtn.2021.04.013.

    Article  CAS  Google Scholar 

  146. Misso G, Di Martino MT, De Rosa G, et al. Mir-34: a new weapon against cancer? Mol Ther acids. 2014;3:e195. https://doi.org/10.1038/mtna.2014.47.

    Article  CAS  Google Scholar 

  147. Ngalame NNO, Makia NL, Waalkes MP, Tokar EJ. Mitigation of arsenic-induced acquired cancer phenotype in prostate cancer stem cells by miR-143 restoration. Toxicol Appl Pharmacol. 2016;312:11–8. https://doi.org/10.1016/j.taap.2015.12.013.

    Article  CAS  PubMed  Google Scholar 

  148. Chang Y-L, Zhou P-J, Wei L, et al. MicroRNA-7 inhibits the stemness of prostate cancer stem-like cells and tumorigenesis by repressing KLF4/PI3K/Akt/p21 pathway. Oncotarget. 2015. https://doi.org/10.18632/oncotarget.4447.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Song X-L, Huang B, Zhou B-W, et al. miR-1301-3p promotes prostate cancer stem cell expansion by targeting SFRP1 and GSK3β. Biomed Pharmacother. 2018;99:369–74. https://doi.org/10.1016/j.biopha.2018.01.086.

    Article  CAS  PubMed  Google Scholar 

  150. Nalls D, Tang S-N, Rodova M, Srivastava RK, Shankar S. Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS ONE. 2011;6:e24099. https://doi.org/10.1371/journal.pone.0024099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Jang E, Kim E, Son H-Y, et al. Nanovesicle-mediated systemic delivery of microRNA-34a for CD44 overexpressing gastric cancer stem cell therapy. Biomaterials. 2016;105:12–24. https://doi.org/10.1016/j.biomaterials.2016.07.036.

    Article  CAS  PubMed  Google Scholar 

  152. Wu K, Ma L, Zhu J. miR-483-5p promotes growth, invasion and self-renewal of gastric cancer stem cells by Wnt/β-catenin signaling. Mol Med Rep. 2016;14:3421–8. https://doi.org/10.3892/mmr.2016.5603.

    Article  CAS  PubMed  Google Scholar 

  153. Zhang L, Guo X, Zhang D, et al. Upregulated miR-132 in Lgr5+ gastric cancer stem cell-like cells contributes to cisplatin-resistance via SIRT1/CREB/ABCG2 signaling pathway. Mol Carcinog. 2017;56:2022–34. https://doi.org/10.1002/mc.22656.

    Article  CAS  PubMed  Google Scholar 

  154. Chen C, Yang Q, Wang D, et al. MicroRNA-191, regulated by HIF-2α, is involved in EMT and acquisition of a stem cell-like phenotype in arsenite-transformed human liver epithelial cells. Toxicol Vitr. 2018;48:128–36. https://doi.org/10.1016/j.tiv.2017.12.016.

    Article  CAS  Google Scholar 

  155. Jiang C, Yu M, Xie X, et al. miR-217 targeting DKK1 promotes cancer stem cell properties via activation of the Wnt signaling pathway in hepatocellular carcinoma. Oncol Rep. 2017;38:2351–9. https://doi.org/10.3892/or.2017.5924.

    Article  CAS  PubMed  Google Scholar 

  156. Xie Y, Du J, Liu Z, Zhang D, Yao X, Yang Y. MiR-6875-3p promotes the proliferation, invasion and metastasis of hepatocellular carcinoma via BTG2/FAK/Akt pathway. J Exp Clin Cancer Res. 2019;38:7. https://doi.org/10.1186/s13046-018-1020-z.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Mayoral-Varo V, Calcabrini A, Sánchez-Bailón MP, Martín-Pérez J. miR205 inhibits stem cell renewal in SUM159PT breast cancer cells. PLoS ONE. 2017;12:e0188637. https://doi.org/10.1371/journal.pone.0188637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Lv C, Li F, Li X, et al. MiR-31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists. Nat Commun. 2017;8:1036. https://doi.org/10.1038/s41467-017-01059-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Li B, Lu Y, Yu L, et al. miR-221/222 promote cancer stem-like cell properties and tumor growth of breast cancer via targeting PTEN and sustained Akt/NF-κB/COX-2 activation. Chem Biol Interact. 2017;277:33–42. https://doi.org/10.1016/j.cbi.2017.08.014.

    Article  CAS  PubMed  Google Scholar 

  160. Cheng S, Huang Y, Lou C, He Y, Zhang Y, Zhang Q. FSTL1 enhances chemoresistance and maintains stemness in breast cancer cells via integrin β3/Wnt signaling under miR-137 regulation. Cancer Biol Ther. 2019;20:328–37. https://doi.org/10.1080/15384047.2018.1529101.

    Article  CAS  PubMed  Google Scholar 

  161. Luo X, Dong Z, Chen Y, Yang L, Lai D. Enrichment of ovarian cancer stem-like cells is associated with epithelial to mesenchymal transition through an miRNA-activated AKT pathway. Cell Prolif. 2013;46:436–46. https://doi.org/10.1111/cpr.12038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Man J, Shoemake JD, Ma T, et al. Hyperthermia sensitizes glioma stem-like cells to radiation by inhibiting AKT signaling. Cancer Res. 2015;75:1760–9. https://doi.org/10.1158/0008-5472.CAN-14-3621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Shi L, Xi J, Xu X, Peng B, Zhang B. MiR-148a suppressed cell invasion and migration via targeting WNT10b and modulating β-catenin signaling in cisplatin-resistant colorectal cancer cells. Biomed Pharmacother. 2019;109:902–9. https://doi.org/10.1016/j.biopha.2018.10.080.

    Article  CAS  PubMed  Google Scholar 

  164. Mamoori A, Gopalan V, Smith RA, Lam AKY. Modulatory roles of microRNAs in the regulation of different signalling pathways in large bowel cancer stem cells. Biol Cell. 2016;108:51–64. https://doi.org/10.1111/boc.201500062.

    Article  CAS  PubMed  Google Scholar 

  165. Jones MF, Hara T, Francis P, et al. The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation. Proc Natl Acad Sci. 2015;112:E1550–8. https://doi.org/10.1073/pnas.1503370112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Bu P, Chen K-Y, Chen JH, et al. A microRNA miR-34a-regulated bimodal switch targets notch in colon cancer stem cells. Cell Stem Cell. 2013;12:602–15. https://doi.org/10.1016/j.stem.2013.03.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Farzin A, Etesami SA, Quint J, Memic A, Tamayol A. Magnetic nanoparticles in cancer therapy and diagnosis. Adv Healthc Mater. 2020;9(9):e1901058. https://doi.org/10.1002/adhm.201901058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Nuzhina JV, Shtil AA, Prilepskii AY, Vinogradov VV. Preclinical evaluation and clinical translation of magnetite-based nanomedicines. J Drug Deliv Sci Technol. 2019;12(11):1807. https://doi.org/10.1016/j.jddst.2019.101282.

    Article  CAS  Google Scholar 

  169. Ito A, Matsuoka F, Honda H, Kobayashi T. Heat shock protein 70 gene therapy combined with hyperthermia using magnetic nanoparticles. Cancer Gene Ther. 2003;10:918–25. https://doi.org/10.1038/sj.cgt.7700648.

    Article  CAS  PubMed  Google Scholar 

  170. Kumar CSSR, Mohammad F. Magnetic nanomaterials for hyperthermia-based therapy and controlled drug delivery. Adv Drug Deliv Rev. 2011;63:789–808. https://doi.org/10.1016/j.addr.2011.03.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Laurent S, Dutz S, Häfeli UO, Mahmoudi M. Magnetic fluid hyperthermia: focus on superparamagnetic iron oxide nanoparticles. Adv Colloid Interface Sci. 2011;166:8–23. https://doi.org/10.1016/j.cis.2011.04.003.

    Article  CAS  PubMed  Google Scholar 

  172. Prasad NK, Rathinasamy K, Panda D, Bahadur D. Mechanism of cell death induced by magnetic hyperthermia with nanoparticles of γ-Mn x Fe2–x O3 synthesized by a single step process. J Mater Chem. 2007;17:5042–51. https://doi.org/10.1039/B708156A.

    Article  CAS  Google Scholar 

  173. Harima Y, Ohguri T, Imada H, et al. A multicentre randomised clinical trial of chemoradiotherapy plus hyperthermia versus chemoradiotherapy alone in patients with locally advanced cervical cancer. Int J Hyperth. 2016;32:801–8. https://doi.org/10.1080/02656736.2016.1213430.

    Article  CAS  Google Scholar 

  174. Cihoric N, Tsikkinis A, van Rhoon G, et al. Hyperthermia-related clinical trials on cancer treatment within the clinicaltrials. gov registry. Int J Hyperth. 2015;31:609–14. https://doi.org/10.3109/02656736.2015.1040471.

    Article  CAS  Google Scholar 

  175. Wessalowski R, Schneider DT, Mils O, et al. Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single-institution, phase 2 study. Lancet Oncol. 2013;14:843–52. https://doi.org/10.1016/s1470-2045(13)70271-7.

    Article  PubMed  Google Scholar 

  176. Overgaard J, Bentzen SM, Gonzalez DG, et al. Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma. Lancet. 1995;345:540–3. https://doi.org/10.1016/s0140-6736(95)90463-8.

    Article  CAS  PubMed  Google Scholar 

  177. Issels RD, Lindner LH, Verweij J, et al. Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 2010;11:561–70. https://doi.org/10.1016/s1470-2045(10)70071-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Colombo R, Salonia A, Da Pozzo LF, et al. Combination of intravesical chemotherapy and hyperthermia for the treatment of superficial bladder cancer: preliminary clinical experience. Crit Rev Oncol Hematol. 2003;47:127–39. https://doi.org/10.1016/s1040-8428(03)00076-3.

    Article  CAS  PubMed  Google Scholar 

  179. Zee J, González D, Rhoon GC, Dijk JDP, Putten WLJ, Hart AAM. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Lancet. 2000;355:1119–25. https://doi.org/10.1016/s0140-6736(00)02059-6.

    Article  PubMed  Google Scholar 

  180. LaRue SM, Vujaskovic Z. Combining radiation therapy with other treatment modalities. Semin Vet Med Surg Small Anim. 1995;10:197–204.

    CAS  PubMed  Google Scholar 

  181. Winslow TB, Eranki A, Ullas S, Singh AK, Repasky EA, Sen A. A pilot study of the effects of mild systemic heating on human head and neck tumour xenografts: analysis of tumour perfusion, interstitial fluid pressure, hypoxia and efficacy of radiation therapy. Int J Hyperth. 2015;31:693–701. https://doi.org/10.3109/02656736.2015.1037800.

    Article  CAS  Google Scholar 

  182. Horsman MR. Realistic biological approaches for improving thermoradiotherapy. Int J Hyperth. 2016;32:14–22. https://doi.org/10.3109/02656736.2015.1099169.

    Article  CAS  Google Scholar 

  183. Sen A, Capitano ML, Spernyak JA, et al. Mild elevation of body temperature reduces tumor interstitial fluid pressure and hypoxia and enhances efficacy of radiotherapy in murine tumor models. Cancer Res. 2011;71:3872–80. https://doi.org/10.1158/0008-5472.can-10-4482.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Vujaskovic Z, Poulson JM, Gaskin AA, et al. Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment. Int J Radiat Oncol Biol Phys. 2000;46:179–85. https://doi.org/10.1016/s0360-3016(99)00362-4.

    Article  CAS  PubMed  Google Scholar 

  185. Vaupel PW, Kelleher DK. Pathophysiological and vascular characteristics of tumours and their importance for hyperthermia: heterogeneity is the key issue. Int J Hyperth. 2010;26:211–23. https://doi.org/10.3109/02656731003596259.

    Article  CAS  Google Scholar 

  186. Wike-Hooley JL, Zee J, Rhoon GC, Berg AP, Reinhold HS. Human tumour pH changes following hyperthermia and radiation therapy. Eur J Cancer Clin Oncol. 1984;20:619–23. https://doi.org/10.1016/0277-5379(84)90006-3.

    Article  CAS  PubMed  Google Scholar 

  187. Song CW, Kang MS, Rhee JG, Levitt SH. The effect of hyperthermia on vascular function, pH, and cell survival. Radiology. 1980;137:795–803. https://doi.org/10.1148/radiology.137.3.7444064.

    Article  CAS  PubMed  Google Scholar 

  188. Kampinga HH, Dikomey E. Hyperthermic radiosensitization: mode of action and clinical relevance. Int J Radiat Biol. 2001;77:399–408. https://doi.org/10.1080/09553000010024687.

    Article  CAS  PubMed  Google Scholar 

  189. Elming PB, Sørensen BS, Oei AL, et al. Hyperthermia: the optimal treatment to overcome radiation resistant hypoxia. Cancers. 2019;11:60. https://doi.org/10.3390/cancers11010060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Horsman MR, Overgaard J. Hyperthermia: a potent enhancer of radiotherapy. Clin Oncol. 2007;19:418–26. https://doi.org/10.1016/j.clon.2007.03.015.

    Article  CAS  Google Scholar 

  191. Kaushik S, Thomas J, Panwar V, et al. In situ biosynthesized superparamagnetic iron oxide nanoparticles (SPIONS) induce efficient hyperthermia in cancer cells. ACS Appl Bio Mater. 2020;3:779–88. https://doi.org/10.1021/acsabm.9b00720.

    Article  CAS  PubMed  Google Scholar 

  192. Maity D, Kandasamy G, Sudame A. Superparamagnetic iron oxide nanoparticles for cancer theranostic applications. In: Rai M, Jamil B, editors. Nanotheranostics. Cham: Springer; 2019. p. 245–76. https://doi.org/10.1007/978-3-030-29768-8_12.

    Chapter  Google Scholar 

  193. Kok HP, Cressman ENK, Ceelen W, et al. Heating technology for malignant tumors: a review. Int J Hyperth. 2020. https://doi.org/10.1080/02656736.2020.1779357.

    Article  Google Scholar 

  194. Fatima H, Charinpanitkul T, Kim KS. Fundamentals to apply magnetic nanoparticles for hyperthermia therapy. Nanomaterials. 2021;11(5):1203. https://doi.org/10.3390/nano11051203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Mulens-Arias V, Nicolás-Boluda A, Pinto A, et al. Tumor-selective immune-active mild hyperthermia associated with chemotherapy in colon peritoneal metastasis by photoactivation of fluorouracil-gold nanoparticle complexes. ACS Nano. 2021;15:3330–48. https://doi.org/10.1021/acsnano.0c10276.

    Article  CAS  PubMed  Google Scholar 

  196. Nejati K, Dadashpour M, Gharibi T, Mellatyar H, Akbarzadeh A. Biomedical applications of functionalized gold nanoparticles: a review. J Clust Sci. 2022;33:1–16. https://doi.org/10.1007/s10876-020-01955-9.

    Article  CAS  Google Scholar 

  197. Encarnación C, Jimenez de Aberasturi D, Liz-Marzán LM. Multifunctional plasmonic-magnetic nanoparticles for bioimaging and hyperthermia. Adv Drug Deliv Rev. 2022;189:114484. https://doi.org/10.1016/j.addr.2022.114484.

    Article  CAS  PubMed  Google Scholar 

  198. Sharma A, Cressman E, Attaluri A, Kraitchman DL, Ivkov R. Current challenges in image-guided magnetic hyperthermia therapy for liver cancer. Nanomaterials. 2022;12(16):2768. https://doi.org/10.3390/nano12162768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Yang Z, Gao D, Zhao J, et al. Thermal immuno-nanomedicine in cancer. Nat Rev Clin Oncol. 2023;20:116–34. https://doi.org/10.1038/s41571-022-00717-y.

    Article  PubMed  Google Scholar 

  200. Attaluri A, Jackowski J, Sharma A, et al. Design and construction of a Maxwell-type induction coil for magnetic nanoparticle hyperthermia. Int J Hyperth. 2020;37:1–14. https://doi.org/10.1080/02656736.2019.1704448.

    Article  CAS  Google Scholar 

  201. Raspe C, Piso P, Wiesenack C, Bucher M. Anesthetic management in patients undergoing hyperthermic chemotherapy. Curr Opin Anesthesiol. 2012;25(3):348–55. https://doi.org/10.1097/ACO.0b013e32835347b2.

    Article  CAS  Google Scholar 

  202. International Commission on Non-Ionizing Radiation Protection (ICNIRP). Medical magnetic resonance (MR) procedures: protection of patients. Health Phys. 2004;87(2):197–216. https://doi.org/10.1097/00004032-200408000-00008.

    Article  Google Scholar 

  203. Datta NR, Marder D, Datta S, et al. Quantification of thermal dose in moderate clinical hyperthermia with radiotherapy: a relook using temperature–time area under the curve (AUC). Int J Hyperth. 2021;38:296–307. https://doi.org/10.1080/02656736.2021.1875060.

    Article  CAS  Google Scholar 

  204. Muramatsu K, Nagasawa H, Takeuchi I, et al. An analysis of patients with a chief complaint of difficulty moving. J Rural Med. 2023;18:36–41. https://doi.org/10.2185/jrm.2022-016.

    Article  PubMed  PubMed Central  Google Scholar 

  205. Shen S, Xia JX, Wang J. Nanomedicine-mediated cancer stem cell therapy. Biomaterials. 2016;74:1–18. https://doi.org/10.1016/j.biomaterials.2015.09.037.

    Article  CAS  PubMed  Google Scholar 

  206. Kwon Y-S, Sim K, Seo T, Lee J-K, Kwon Y, Yoon T-J. Optimization of magnetic hyperthermia effect for breast cancer stem cell therapy. RSC Adv. 2016;6:107298–304. https://doi.org/10.1039/C6RA22382F.

    Article  CAS  Google Scholar 

  207. Yang R, An LY, Miao QF, et al. Effective elimination of liver cancer stem-like cells by CD90 antibody targeted thermosensitive magnetoliposomes. Oncotarget. 2016;7(24):35894–916. https://doi.org/10.18632/oncotarget.9116.

    Article  PubMed  PubMed Central  Google Scholar 

  208. Yang R, Tang Q, Miao F, et al. Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice. Int J Nanomedicine. 2015;10:7345–58. https://doi.org/10.2147/IJN.S93758.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Velthoven CTJ, Rando TA. Stem cell quiescence: dynamism, restraint, and cellular idling. Cell Stem Cell. 2019;24(2):213–25. https://doi.org/10.1016/j.stem.2019.01.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Turdo A, Gaggianesi M, Chinnici A, Stassi G, Todaro M. Cancer stem cells: from birth to death. In: Maccalli C, Todaro M, Ferrone S, editors. Cancer stem cell resistance to targeted therapy. Resistance to targeted anti-cancer therapeutics, vol. 19. Cham: Springer; 2019. https://doi.org/10.1007/978-3-030-16624-3_1.

    Chapter  Google Scholar 

  211. Santos-de-Frutos K, Djouder N. When dormancy fuels tumour relapse. Commun Biol. 2021;4:747. https://doi.org/10.1038/s42003-021-02257-0.

    Article  PubMed  PubMed Central  Google Scholar 

  212. Lee H, Park HJ, Park C-S, et al. Response of breast cancer cells and cancer stem cells to metformin and hyperthermia alone or combined. PLoS One. 2014;9:e87979. https://doi.org/10.1371/journal.pone.0087979.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Burke AR, Singh RN, Carroll DL, et al. The resistance of breast cancer stem cells to conventional hyperthermia and their sensitivity to nanoparticle-mediated photothermal therapy. Biomaterials. 2012;33:2961–70. https://doi.org/10.1016/j.biomaterials.2011.12.052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Liu D, Hong Y, Li Y, et al. Targeted destruction of cancer stem cells using multifunctional magnetic nanoparticles that enable combined hyperthermia and chemotherapy. Theranostics. 2020;10:1181–96. https://doi.org/10.7150/thno.38989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. García-Santos EP, Padilla-Valverde D, Villarejo-Campos P, et al. The utility of hyperthermic intra-abdominal chemotherapy with gemcitabine for the inhibition of tumor progression in an experimental model of pancreatic peritoneal carcinomatosis, in relation to their behavior with pancreatic cancer stem cells CD133+ CXCR+. Pancreatology. 2016;16:632–9. https://doi.org/10.1016/j.pan.2016.04.031.

    Article  CAS  PubMed  Google Scholar 

  216. Paholak HJ, Stevers NO, Chen H, et al. Elimination of epithelial-like and mesenchymal-like breast cancer stem cells to inhibit metastasis following nanoparticle-mediated photothermal therapy. Biomaterials. 2016;104:145–57. https://doi.org/10.1016/j.biomaterials.2016.06.045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Xu Y, Wang J, Li X, et al. Selective inhibition of breast cancer stem cells by gold nanorods mediated plasmonic hyperthermia. Biomaterials. 2014;35:4667–77. https://doi.org/10.1016/j.biomaterials.2014.02.035.

    Article  CAS  PubMed  Google Scholar 

  218. Fernandes S, Fernandez T, Metze S, et al. Magnetic nanoparticle-based hyperthermia mediates drug delivery and impairs the tumorigenic capacity of quiescent colorectal cancer stem cells. ACS Appl Mater Interfaces. 2021;13:15959–72. https://doi.org/10.1021/acsami.0c21349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Tang J, Zhou H, Liu J, et al. Dual-mode imaging-guided synergistic chemo- and magnetohyperthermia therapy in a versatile nanoplatform to eliminate cancer stem cells. ACS Appl Mater Interfaces. 2017;9:23497–507. https://doi.org/10.1021/acsami.7b06393.

    Article  CAS  PubMed  Google Scholar 

  220. Sontag D, Miles DA, Uhanova J, Van Iderstine MG, Yang J, Minuk GY. The effects of hyperthermia on human hepatocellular carcinoma stem and mature cancer cells. Ann Hepatol. 2020;19:265–8. https://doi.org/10.1016/j.aohep.2019.12.006.

    Article  CAS  PubMed  Google Scholar 

  221. Wu C-C, Hsu Y-T, Chang C-L. Hyperthermic intraperitoneal chemotherapy enhances antitumor effects on ovarian cancer through immune-mediated cancer stem cell targeting. Int J Hyperth. 2021;38:1013–22. https://doi.org/10.1080/02656736.2021.1945688.

    Article  CAS  Google Scholar 

  222. Rajaee Z, Khoei S, Mahdavi SR, Ebrahimi M, Shirvalilou S, Mahdavian A. Evaluation of the effect of hyperthermia and electron radiation on prostate cancer stem cells. Radiat Environ Biophys. 2018;57:133–42. https://doi.org/10.1007/s00411-018-0733-x.

    Article  PubMed  Google Scholar 

  223. Atkinson RL, Zhang M, Diagaradjane P, et al. Thermal enhancement with optically activated gold nanoshells sensitizes breast cancer stem cells to radiation therapy. Sci Transl Med. 2010;2(55):55ra79. https://doi.org/10.1126/scitranslmed.3001447.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Atkinson R, Zhang M, Diagaradjane P, et al. Hyperthermia sensitizes breast cancer stem cells to radiation therapy. Cancer Res. 2009;69:506. https://doi.org/10.1158/0008-5472.SABCS-09-506.

    Article  Google Scholar 

  225. Fu Q, Huang T, Wang X, et al. Association of elevated reactive oxygen species and hyperthermia induced radiosensitivity in cancer stem-like cells. Oncotarget. 2017;8:101560–71. https://doi.org/10.18632/oncotarget.21678.

    Article  PubMed  PubMed Central  Google Scholar 

  226. Thapa R, Galoforo S, Kandel SM, et al. Radiosensitizing and hyperthermic properties of hyaluronan conjugated, dextran-coated ferric oxide nanoparticles: implications for cancer stem cell therapy. J Nanomater. 2015;2015:840594. https://doi.org/10.1155/2015/840594.

    Article  CAS  Google Scholar 

  227. Trieb K, Sztankay A, Amberger A, Lechner H, Grubeck-Loebenstein B. Hyperthermia inhibits proliferation and stimulates the expression of differentiation markers in cultured thyroid carcinoma cells. Cancer Lett. 1994;87:65–71. https://doi.org/10.1016/0304-3835(94)90410-3.

    Article  CAS  PubMed  Google Scholar 

  228. Kanamori M, Ohmori K, Yasuda T, Yudoh K. Effects of hyperthermia and differentiation on cultured Dunn osteosarcoma cells. Cancer Detect Prev. 2003;27:76–81. https://doi.org/10.1016/s0361-090x(02)00178-2.

    Article  PubMed  Google Scholar 

  229. Goliaei B, Deizadji A. Effects of hyperthermia and granulocyte-macrophage colony-stimulating factor on the differentiation of human leukemic cell line U937. Leuk Res. 1998;22:705–10. https://doi.org/10.1016/s0145-2126(98)00061-7.

    Article  CAS  PubMed  Google Scholar 

  230. Goliaei B, Rafiei M, Soheili Z. Effects of hyperthermia on the differentiation and growth of K562 erythroleukemic cell line. Leuk Res. 2004;28:1323–8. https://doi.org/10.1016/j.leukres.2004.04.012.

    Article  CAS  PubMed  Google Scholar 

  231. Sharif-Khatibi L, Kariminia A, Khoei S, Goliaei B. Hyperthermia induces differentiation without apoptosis in permissive temperatures in human erythroleukaemia cells. Int J Hyperth. 2007;23:645–55. https://doi.org/10.1080/02656730701769833.

    Article  CAS  Google Scholar 

  232. Deizaji AK, Goliaei B. The effect of hyperthermia on the differentiation of leukemic cell lines. Med J Islam Repub Iran. 1996;10:211–7.

    Google Scholar 

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The authors wish to thank the Institute of Nanoscience and Technology for their support in successful completion of this review.

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    Amit B. Tewari, Anamika Saini & Deepika Sharma

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ABT contributed to the conception and design, literature search and the drafting of the manuscript. AS designed the figures and graphs and played role in editing. DS contributed toward drafting and the final editing of the manuscript.

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Tewari, A.B., Saini, A. & Sharma, D. Extirpating the cancer stem cell hydra: Differentiation therapy and Hyperthermia therapy for targeting the cancer stem cell hierarchy. Clin Exp Med 23, 3125–3145 (2023). https://doi.org/10.1007/s10238-023-01066-5

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