BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting

  • Eun, Kiyoung (Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University) ;
  • Ham, Seok Won (Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University) ;
  • Kim, Hyunggee (Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University)
  • Received : 2016.12.08
  • Published : 2017.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Most of the cancers are still incurable human diseases. According to recent findings, especially targeting cancer stem cells (CSCs) is the most promising therapeutic strategy. CSCs take charge of a cancer hierarchy, harboring stem cell-like properties involving self-renewal and aberrant differentiation potential. Most of all, the presence of CSCs is closely associated with tumorigenesis and therapeutic resistance. Despite the numerous efforts to target CSCs, current anti-cancer therapies are still impeded by CSC-derived cancer malignancies; increased metastases, tumor recurrence, and even acquired resistance against the anti-CSC therapies developed in experimental models. One of the most forceful underlying reasons is a "cancer heterogeneity" due to "CSC plasticity". A comprehensive understanding of CSC-derived heterogeneity will provide novel insights into the establishment of efficient targeting strategies to eliminate CSCs. Here, we introduce findings on mechanisms of CSC reprogramming and CSC plasticity, which give rise to phenotypically varied CSCs. Also, we suggest concepts to improve CSC-targeted therapy in order to overcome therapeutic resistance caused by CSC plasticity and heterogeneity.

Keywords

References

  1. Kreso A and Dick JE (2014) Evolution of the cancer stem cell model. Cell Stem Cell 14, 275-291 https://doi.org/10.1016/j.stem.2014.02.006
  2. Bonnet D and Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3, 730-737 https://doi.org/10.1038/nm0797-730
  3. Lapidot T, Sirard C, Vormoor J et al (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645-648 https://doi.org/10.1038/367645a0
  4. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ and Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100, 3983-3988 https://doi.org/10.1073/pnas.0530291100
  5. Medema JP (2013) Cancer stem cells: The challenges ahead. Nat Cell Biol 15, 338-344 https://doi.org/10.1038/ncb2717
  6. Bao S, Wu Q, McLendon RE et al (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756-760 https://doi.org/10.1038/nature05236
  7. Jeon HM, Sohn YW, Oh SY et al (2011) ID4 imparts chemoresistance and cancer stemness to glioma cells by derepressing miR-9*-mediated suppression of SOX2. Cancer Res 71, 3410-3421 https://doi.org/10.1158/0008-5472.CAN-10-3340
  8. Brooks MD, Burness ML and Wicha MS (2015) Therapeutic Implications of Cellular Heterogeneity and Plasticity in Breast Cancer. Cell Stem Cell 17, 260-271 https://doi.org/10.1016/j.stem.2015.08.014
  9. Sun Y, Campisi J, Higano C et al (2012) Treatmentinduced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18, 1359-1368 https://doi.org/10.1038/nm.2890
  10. Plaks V, Kong N and Werb Z (2015) The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16, 225-238 https://doi.org/10.1016/j.stem.2015.02.015
  11. Ricci-Vitiani L, Pallini R, Biffoni M et al (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468, 824-828 https://doi.org/10.1038/nature09557
  12. Cheng L, Huang Z, Zhou W et al (2013) Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153, 139-152 https://doi.org/10.1016/j.cell.2013.02.021
  13. Petersen OW, Nielsen HL, Gudjonsson T et al (2003) Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 162, 391-402 https://doi.org/10.1016/S0002-9440(10)63834-5
  14. Hanahan D and Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144, 646-674 https://doi.org/10.1016/j.cell.2011.02.013
  15. Charafe-Jauffret E, Ginestier C, Iovino F et al (2009) Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 69, 1302-1313 https://doi.org/10.1158/0008-5472.CAN-08-2741
  16. Jiao X, Katiyar S, Willmarth NE et al (2010) c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion. J Biol Chem 285, 8218-8226 https://doi.org/10.1074/jbc.M110.100792
  17. Xin YH, Bian BS, Yang XJ et al (2013) POU5F1 enhances the invasiveness of cancer stem-like cells in lung adenocarcinoma by upregulation of MMP-2 expression. PLoS One 8, e83373 https://doi.org/10.1371/journal.pone.0083373
  18. Chen L, Fan J, Chen H et al (2014) The IL-8/CXCR1 axis is associated with cancer stem cell-like properties and correlates with clinical prognosis in human pancreatic cancer cases. Sci Rep 4, 5911
  19. Friedl P and Alexander S (2011) Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992-1009 https://doi.org/10.1016/j.cell.2011.11.016
  20. Eppert K, Takenaka K, Lechman ER et al (2011) Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 17, 1086-1093 https://doi.org/10.1038/nm.2415
  21. Piccirillo SG, Colman S, Potter NE et al (2015) Genetic and functional diversity of propagating cells in glioblastoma. Stem Cell Reports 4, 7-15 https://doi.org/10.1016/j.stemcr.2014.11.003
  22. Meacham CE and Morrison SJ (2013) Tumour heterogeneity and cancer cell plasticity. Nature 501, 328-337 https://doi.org/10.1038/nature12624
  23. Chen K, Huang Y-h and Chen J-l (2013) Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin 34, 732-740 https://doi.org/10.1038/aps.2013.27
  24. Sirko S, Behrendt G, Johansson PA et al (2013) Reactive glia in the injured brain acquire stem cell properties in response to sonic hedgehog. Cell Stem Cell 12, 426-439 https://doi.org/10.1016/j.stem.2013.01.019
  25. Yan G-N, Yang L, Lv Y-F et al (2014) Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway. J Pathol 234, 11-22 https://doi.org/10.1002/path.4349
  26. Hay ED (1995) An overview of epithelial-mesenchymal transformation. Acta Anat (Basel) 154, 8-20 https://doi.org/10.1159/000147748
  27. Mani SA, Guo W, Liao MJ et al (2008) The epithelialmesenchymal transition generates cells with properties of stem cells. Cell 133, 704-715 https://doi.org/10.1016/j.cell.2008.03.027
  28. Ouyang G, Wang Z, Fang X, Liu J and Yang CJ (2010) Molecular signaling of the epithelial to mesenchymal transition in generating and maintaining cancer stem cells. Cell Mol Life Sci 67, 2605-2618 https://doi.org/10.1007/s00018-010-0338-2
  29. Karin M and Greten FR (2005) NF-kappa B: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5, 749-759 https://doi.org/10.1038/nri1703
  30. Li CW, Xia W, Huo L et al (2012) Epithelial-mesenchymal transition induced by TNF-alpha requires NF-kappaB-mediated transcriptional upregulation of Twist1. Cancer Res 72, 1290-1300 https://doi.org/10.1158/0008-5472.CAN-11-3123
  31. Li Y, Li A, Glas M et al (2011) c-Met signaling induces a reprogramming network and supports the glioblastoma stem-like phenotype. Proc Natl Acad Sci U S A 108, 9951-9956 https://doi.org/10.1073/pnas.1016912108
  32. Takahashi K and Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663-676 https://doi.org/10.1016/j.cell.2006.07.024
  33. Suva ML, Rheinbay E, Gillespie SM et al (2014) Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157, 580-594 https://doi.org/10.1016/j.cell.2014.02.030
  34. Lee TK, Castilho A, Cheung VC, Tang KH, Ma S and Ng IO (2011) CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 9, 50-63 https://doi.org/10.1016/j.stem.2011.06.005
  35. Jeter CR, Liu B, Liu X et al (2011) NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene 30, 3833-3845 https://doi.org/10.1038/onc.2011.114
  36. Rudin CM, Durinck S, Stawiski EW et al (2012) Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44, 1111-1116 https://doi.org/10.1038/ng.2405
  37. Suva ML, Rheinbay E, Gillespie SM et al (2014) Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells. Cell 157, 580-594 https://doi.org/10.1016/j.cell.2014.02.030
  38. Li L and Xie T (2005) Stem cell niche: structure and function. Annu Rev Cell Dev Biol 21, 605-631 https://doi.org/10.1146/annurev.cellbio.21.012704.131525
  39. Plaks V, Kong N and Werb Z (2015) The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? Cell stem cell 16, 225-238 https://doi.org/10.1016/j.stem.2015.02.015
  40. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C and Morrison SJ (2005) SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109-1121 https://doi.org/10.1016/j.cell.2005.05.026
  41. Oh M and Nor JE (2015) The Perivascular Niche and Self-Renewal of Stem Cells. Front Physiol 6, 367
  42. Calabrese C, Poppleton H, Kocak M et al (2007) A Perivascular Niche for Brain Tumor Stem Cells. Cancer Cell 11, 69-82 https://doi.org/10.1016/j.ccr.2006.11.020
  43. Charles N, Ozawa T, Squatrito M et al (2010) Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells. Cell Stem Cell 6, 141-152 https://doi.org/10.1016/j.stem.2010.01.001
  44. Jeon HM, Kim SH, Jin X et al (2014) Crosstalk between glioma-initiating cells and endothelial cells drives tumor progression. Cancer Res 74, 4482-4492 https://doi.org/10.1158/0008-5472.CAN-13-1597
  45. Yan GN, Yang L, Lv YF et al (2014) Endothelial cells promote stem-like phenotype of glioma cells through activating the Hedgehog pathway. J Pathol 234, 11-22 https://doi.org/10.1002/path.4349
  46. Beck B, Driessens G, Goossens S et al (2011) A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478, 399-403 https://doi.org/10.1038/nature10525
  47. Zhang Z, Dong Z, Lauxen IS, Filho MS and Nor JE (2014) Endothelial cell-secreted EGF induces epithelial to mesenchymal transition and endows head and neck cancer cells with stem-like phenotype. Cancer Res 74, 2869-2881 https://doi.org/10.1158/0008-5472.CAN-13-2032
  48. Simon MC and Keith B (2008) The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9, 285-296 https://doi.org/10.1038/nrm2354
  49. Jogi A, Ora I, Nilsson H et al (2002) Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype. Proc Natl Acad Sci U S A 99, 7021-7026 https://doi.org/10.1073/pnas.102660199
  50. Lofstedt T, Jogi A, Sigvardsson M et al (2004) Induction of ID2 expression by hypoxia-inducible factor-1: a role in dedifferentiation of hypoxic neuroblastoma cells. J Biol Chem 279, 39223-39231 https://doi.org/10.1074/jbc.M402904200
  51. Zhang C, Samanta D, Lu H et al (2016) Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA. Proc Nat Acad Sci U S A 113, E2047-E2056 https://doi.org/10.1073/pnas.1602883113
  52. Yang MH, Wu MZ, Chiou SH et al (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10, 295-305 https://doi.org/10.1038/ncb1691
  53. Joseph JV, Conroy S, Pavlov K et al (2015) Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1alpha-ZEB1 axis. Cancer Lett 359, 107-116 https://doi.org/10.1016/j.canlet.2015.01.010
  54. Bao B, Azmi AS, Ali S et al (2012) The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness. Biochimica et biophysica acta 1826, 272-296
  55. Xing F, Okuda H, Watabe M et al (2011) Hypoxiainduced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells. Oncogene 30, 4075-4086 https://doi.org/10.1038/onc.2011.122
  56. Condeelis J and Pollard JW (2006) Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis. Cell 124, 263-266 https://doi.org/10.1016/j.cell.2006.01.007
  57. Sullivan NJ, Sasser AK, Axel AE et al (2009) Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28, 2940-2947 https://doi.org/10.1038/onc.2009.180
  58. Wu Y, Deng J, Rychahou PG, Qiu S, Evers BM and Zhou BP (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15, 416-428 https://doi.org/10.1016/j.ccr.2009.03.016
  59. Yu Y, Xiao CH, Tan LD, Wang QS, Li XQ and Feng YM (2014) Cancer-associated fibroblasts induce epithelialmesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br J Cancer 110, 724-732 https://doi.org/10.1038/bjc.2013.768
  60. Vermeulen L, De Sousa E Melo F, van der Heijden M et al (2010) Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 12, 468-476 https://doi.org/10.1038/ncb2048
  61. Hamada S, Masamune A, Takikawa T et al (2012) Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells. Biochem Biophys Res Commun 421, 349-354 https://doi.org/10.1016/j.bbrc.2012.04.014
  62. Lotti F, Jarrar AM, Pai RK et al (2013) Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med 210, 2851-2872 https://doi.org/10.1084/jem.20131195
  63. Orkin SH and Hochedlinger K (2011) Chromatin connections to pluripotency and cellular reprogramming. Cell 145, 835-850 https://doi.org/10.1016/j.cell.2011.05.019
  64. Liang G and Zhang Y (2013) Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective. Cell Res 23, 49-69 https://doi.org/10.1038/cr.2012.175
  65. Widschwendter M, Fiegl H, Egle D et al (2007) Epigenetic stem cell signature in cancer. Nat Genet 39, 157-158 https://doi.org/10.1038/ng1941
  66. Ohm JE, McGarvey KM, Yu X et al (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat Genet 39, 237-242 https://doi.org/10.1038/ng1972
  67. Easwaran H, Johnstone SE, Van Neste L et al (2012) A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res 22, 837-849 https://doi.org/10.1101/gr.131169.111
  68. Rizzo S, Hersey JM, Mellor P et al (2011) Ovarian cancer stem cell-like side populations are enriched following chemotherapy and overexpress EZH2. Mol Cancer Ther 10, 325-335 https://doi.org/10.1158/1535-7163.MCT-10-0788
  69. Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN and Struhl K (2010) Loss of miR-200 inhibition of Suz12 leads to Polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell 39, 761-772 https://doi.org/10.1016/j.molcel.2010.08.013
  70. Crea F, Hurt EM, Mathews LA et al (2011) Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer. Mol Cancer 10, 40 https://doi.org/10.1186/1476-4598-10-40
  71. Benoit YD, Witherspoon MS, Laursen KB et al (2013) Pharmacological inhibition of polycomb repressive complex-2 activity induces apoptosis in human colon cancer stem cells. Exp Cell Res 319, 1463-1470 https://doi.org/10.1016/j.yexcr.2013.04.006
  72. Yang J, Chai L, Liu F et al (2007) Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Nat Acad Sci U S A 104, 10494-10499 https://doi.org/10.1073/pnas.0704001104
  73. Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J and Bernier G (2009) BMI1 sustains human glioblastoma multiforme stem cell renewal. J Neurosci 29, 8884-8896 https://doi.org/10.1523/JNEUROSCI.0968-09.2009
  74. Pathania R, Ramachandran S, Elangovan S et al (2015) DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat Commun 6, 6910 https://doi.org/10.1038/ncomms7910
  75. Yang L, Rau R and Goodell MA (2015) DNMT3A in haematological malignancies. Nat Rev Cancer 15, 152-165 https://doi.org/10.1038/nrc3895
  76. Heddleston JM, Wu Q, Rivera M et al (2012) Hypoxiainduced mixed-lineage leukemia 1 regulates glioma stem cell tumorigenic potential. Cell Death Differ 19, 428-439 https://doi.org/10.1038/cdd.2011.109
  77. Roesch A, Fukunaga-Kalabis M, Schmidt EC et al (2010) A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141, 583-594 https://doi.org/10.1016/j.cell.2010.04.020
  78. Chaffer CL, Marjanovic ND, Lee T et al (2013) Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 154, 61-74 https://doi.org/10.1016/j.cell.2013.06.005
  79. Frank NY, Schatton T and Frank MH (2010) The therapeutic promise of the cancer stem cell concept. J Clin Invest 120, 41-50 https://doi.org/10.1172/JCI41004
  80. Schmohl JU and Vallera DA (2016) CD133, Selectively Targeting the Root of Cancer. Toxins (Basel) 8, 165 https://doi.org/10.3390/toxins8060165
  81. Gurney A, Axelrod F, Bond CJ et al (2012) Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci U S A 109, 11717-11722 https://doi.org/10.1073/pnas.1120068109
  82. Gavai AV, Quesnelle C, Norris D et al (2015) Discovery of Clinical Candidate BMS-906024: A Potent Pan-Notch Inhibitor for the Treatment of Leukemia and Solid Tumors. ACS Med Chem Lett 6, 523-527 https://doi.org/10.1021/acsmedchemlett.5b00001
  83. Justilien V and Fields AP (2015) Molecular pathways: novel approaches for improved therapeutic targeting of Hedgehog signaling in cancer stem cells. Clin Cancer Res 21, 505-513 https://doi.org/10.1158/1078-0432.CCR-14-0507
  84. Huang SD, Yuan Y, Tang H et al (2013) Tumor cells positive and negative for the common cancer stem cell markers are capable of initiating tumor growth and generating both progenies. PLoS One 8, e54579 https://doi.org/10.1371/journal.pone.0054579
  85. Kim J, Villadsen R, Sorlie T et al (2012) Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity. Proc Natl Acad Sci U S A 109, 6124-6129 https://doi.org/10.1073/pnas.1203203109
  86. Patel AP, Tirosh I, Trombetta JJ et al (2014) Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396-1401 https://doi.org/10.1126/science.1254257
  87. Meyer M, Reimand J, Lan X et al (2015) Single cellderived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc Natl Acad Sci U S A 112, 851-856 https://doi.org/10.1073/pnas.1320611111
  88. Liu S, Cong Y, Wang D et al (2014) Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2, 78-91 https://doi.org/10.1016/j.stemcr.2013.11.009
  89. Brennan CW, Verhaak RG, McKenna A et al (2013) The somatic genomic landscape of glioblastoma. Cell 155, 462-477 https://doi.org/10.1016/j.cell.2013.09.034
  90. Mao P, Joshi K, Li J et al (2013) Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci U S A 110, 8644-8649 https://doi.org/10.1073/pnas.1221478110
  91. Bhat KP, Balasubramaniyan V, Vaillant B et al (2013) Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell 24, 331-346 https://doi.org/10.1016/j.ccr.2013.08.001
  92. Das R, Gregory PA, Hollier BG, Tilley WD and Selth LA (2014) Epithelial plasticity in prostate cancer: principles and clinical perspectives. Trends Mol Med 20, 643-651 https://doi.org/10.1016/j.molmed.2014.09.004
  93. Banyard J, Chung I, Wilson AM et al (2013) Regulation of epithelial plasticity by miR-424 and miR-200 in a new prostate cancer metastasis model. Sci Rep 3, 3151 https://doi.org/10.1038/srep03151
  94. Ruscetti M, Dadashian EL, Guo W et al (2016) HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 35, 3781-3795 https://doi.org/10.1038/onc.2015.444
  95. Ebrahimi B (2015) Reprogramming barriers and enhancers: strategies to enhance the efficiency and kinetics of induced pluripotency. Cell Regen (Lond) 4, 10

Cited by

  1. Overview of Cancer Stem Cells and Stemness for Community Oncologists vol.12, pp.4, 2017, https://doi.org/10.1007/s11523-017-0508-3
  2. BRM270, a Compound from Natural Plant Extracts, Inhibits Glioblastoma Stem Cell Properties and Glioblastoma Recurrence vol.20, pp.9, 2017, https://doi.org/10.1089/jmf.2017.3929
  3. Drug Resistance Driven by Cancer Stem Cells and Their Niche vol.18, pp.12, 2017, https://doi.org/10.3390/ijms18122574
  4. Extremely Low-Frequency Magnetic Fields and Redox-Responsive Pathways Linked to Cancer Drug Resistance: Insights from Co-Exposure-Based In Vitro Studies vol.6, pp.2296-2565, 2018, https://doi.org/10.3389/fpubh.2018.00033
  5. Targeting melanoma stem cells with the Vitamin E derivative δ-tocotrienol vol.8, pp.1, 2018, https://doi.org/10.1038/s41598-017-19057-4
  6. Anticancer properties of tocotrienols: A review of cellular mechanisms and molecular targets vol.234, pp.2, 2018, https://doi.org/10.1002/jcp.27075
  7. Dynamism, Sensitivity, and Consequences of Mesenchymal and Stem-Like Phenotype of Cancer Cells vol.2018, pp.1687-9678, 2018, https://doi.org/10.1155/2018/4516454
  8. Demystifying the Differences Between Tumor-Initiating Cells and Cancer Stem Cells in Colon Cancer pp.1556-3804, 2018, https://doi.org/10.1007/s11888-018-0421-x
  9. The role of cancer stem cells and the therapeutic potential of TRX-E-002-1 in ovarian cancer vol.6, pp.8, 2018, https://doi.org/10.1080/21678707.2018.1508339
  10. Not Everyone Fits the Mold: Intratumor and Intertumor Heterogeneity and Innovative Cancer Drug Design and Development vol.22, pp.1, 2018, https://doi.org/10.1089/omi.2017.0174
  11. Uncoupling Warburg effect and stemness in CD133+ve cancer stem cells from Saos-2 (osteosarcoma) cell line under hypoxia pp.1573-4978, 2018, https://doi.org/10.1007/s11033-018-4309-2
  12. Chemoresistance to Cancer Treatment: Benzo-α-Pyrene as Friend or Foe? vol.23, pp.4, 2018, https://doi.org/10.3390/molecules23040930
  13. Dopamine receptor antagonists induce differentiation of PC-3 human prostate cancer cell-derived cancer stem cell-like cells pp.02704137, 2019, https://doi.org/10.1002/pros.23779
  14. Hyperthermia enhances photodynamic therapy by regulation of HCP1 and ABCG2 expressions via high level ROS generation vol.9, pp.1, 2019, https://doi.org/10.1038/s41598-018-38460-z