Cancer Stem Cells and Autophagy: Present Knowledge and Future Perspectives

  • Bakiye Goker Bagca
  • Cigir Biray Avci
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)


Macroautophagy, commonly referred to as autophagy, is a recycling process involving lysosomal degradation of the cell components such as proteins and organelles. This process prevents damage to the cell through the degradation of nonfunctional cellular components and provides raw material and energy which are required to realize biosynthesis reactions. Since autophagy has evolutionarily conserved complex molecular mechanisms, the relationship between autophagy and cancer is multifaceted. There are some insights in which autophagy, also referred to as type 2 cell death, has been suggested as an alternative approach to kill cancer cells have defected apoptosis mechanism. On the other hand, it has also been shown in recent studies that autophagy mechanism, especially in cancer stem cells, may be responsible for obtaining epithelial–mesenchymal transition, invasion, metastasis, drug resistance and recurrence. This chapter focuses on the role of autophagy mechanisms on cancer stem cells and its place in future treatment approaches.


Autophagy Cancer stem cell 


  1. 1.
    The Nobel Prize in Physiology or Medicine 2016. Nobel Media AB 2014. Web. 16 Dec 2017.
  2. 2.
    De Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F. Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J. 1955;60(4):604–17.CrossRefPubMedGoogle Scholar
  3. 3.
    de Duve C, Wattiaux R. Functions of lysosomes. Annu Rev Physiol. 1966;28(1):435–92.CrossRefGoogle Scholar
  4. 4.
    Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011;147(4):728–41.CrossRefPubMedGoogle Scholar
  5. 5.
    Mijaljica D, Prescott M, Devenish RJ. Microautophagy in mammalian cells: revisiting a 40-year-old conundrum. Autophagy. 2011;7(7):673–82.CrossRefPubMedGoogle Scholar
  6. 6.
    Catarino S, Pereira P, Girão H. Molecular control of chaperone-mediated autophagy. Essays Biochem. 2017;61(6):663–74.CrossRefGoogle Scholar
  7. 7.
    Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 2011;27:107–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Lemasters JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 2005;8(1):3–5.CrossRefGoogle Scholar
  9. 9.
    Wang CW, Kim J, Huang WP, Abeliovich H, Stromhaug PE, Dunn WA Jr, Klionsky DJ. Apg2 is a novel protein required for the cytoplasm to vacuole targeting, autophagy, and pexophagy pathways. J Biol Chem. 2001;276(32):30442–51.CrossRefPubMedGoogle Scholar
  10. 10.
    Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal. 2014;20(3):460–73.CrossRefPubMedGoogle Scholar
  11. 11.
    Suzuki K, Kirisako T, Kamada Y, Mizushima N, Noda T, Ohsumi Y. The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation. EMBO J. 2001;20(21):5971–81.CrossRefPubMedGoogle Scholar
  12. 12.
    Suzuki K, Noda T, Ohsumi Y. Interrelationships among Atg proteins during autophagy in Saccharomyces cerevisiae. Yeast. 2004;21(12):1057–65.CrossRefGoogle Scholar
  13. 13.
    Mariño G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 2014;15(2):81–94.CrossRefPubMedGoogle Scholar
  14. 14.
    Gozuacik D, Akkoc Y, Ozturk DG, Kocak M. Autophagy-regulating microRNAs and cancer. Front Oncol. 2017;7:65.CrossRefPubMedGoogle Scholar
  15. 15.
    Yang L, Wang H, Shen Q, Feng L, Jin H. Long non-coding RNAs involved in autophagy regulation. Cell Death Dis. 2017;8(10):e3073.CrossRefPubMedGoogle Scholar
  16. 16.
    Fuchs Y, Steller H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol. 2015;16(6):329–44.CrossRefPubMedGoogle Scholar
  17. 17.
    Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med. 2013;368(7):651–62.CrossRefPubMedGoogle Scholar
  18. 18.
    Goodell MA, Nguyen H, Shroyer N. Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments. Nat Rev Mol Cell Biol. 2015;16(5):299–309.CrossRefPubMedGoogle Scholar
  19. 19.
    Till JE, Mcculloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961;14:213–22.CrossRefGoogle Scholar
  20. 20.
    Weissman IL. Stem cells: units of development, units of regeneration, and units in evolution. Cell. 2000;100(1):157–68.CrossRefGoogle Scholar
  21. 21.
    Singh VK, Saini A, Kalsan M, Kumar N, Chandra R. Describing the stem cell potency: the various methods of functional assessment and in silico diagnostics. Front Cell Dev Biol. 2016;4:134.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Kelly SJ. Studies of the developmental potential of 4- and 8-cell stage mouse blastomeres. J Exp Zool. 1974;200(3):365–76.CrossRefGoogle Scholar
  23. 23.
    Yu J, Thomson JA. Pluripotent stem cell lines. Genes Dev. 2008;22(15):1987–97.CrossRefPubMedGoogle Scholar
  24. 24.
    Liao SY, Tse HF. Multipotent (adult) and pluripotent stem cells for heart regeneration: what are the pros and cons? Stem Cell Res Ther. 2013;4(6):151.CrossRefPubMedGoogle Scholar
  25. 25.
    Visvader JE, Clevers H. Tissue-specific designs of stem cell hierarchies. Nat Cell Biol. 2016;18(4):349–55.CrossRefGoogle Scholar
  26. 26.
    Takahashi K. Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.CrossRefPubMedGoogle Scholar
  27. 27.
    Cheung TH, Rando TA. Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol. 2013;14(6):329–40.CrossRefGoogle Scholar
  28. 28.
    Avgustinova A, Benitah SA. Epigenetic control of adult stem cell function. Nat Rev Mol Cell Biol. 2013;17(10):643–58.CrossRefGoogle Scholar
  29. 29.
    Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Schöler H, Smith A. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998;95(3):379–91.CrossRefGoogle Scholar
  30. 30.
    Nishimoto M, Fukushima A, Okuda A, Muramatsu M. The gene for the embryonic stem cell coactivator. UTF1 carries a regulatory element which selectively interacts with a complex composed of Oct-3/4 and Sox-2. Mol Cell Biol. 1999;19(8):5453–65.CrossRefPubMedGoogle Scholar
  31. 31.
    Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003;113(5):643–55.CrossRefGoogle Scholar
  32. 32.
    He S, Nakada D, Morrison SJ. Mechanisms of stem cell self-renewal. Annu Rev Cell Dev Biol. 2009;25:377–406.CrossRefGoogle Scholar
  33. 33.
    Zhang H, Wang ZZ. Mechanisms that mediate stem cell self-renewal and differentiation. J Cell Biochem. 2008;103(3):709–18.CrossRefGoogle Scholar
  34. 34.
    Holland JD, Klaus A, Garratt AN, Birchmeier W. Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol. 2013;25(2):254–64.CrossRefGoogle Scholar
  35. 35.
    Petrova R, Joyner AL. Roles for Hedgehog signaling in adult organ homeostasis and repair. Development. 2014;141(18):3445–57.CrossRefPubMedGoogle Scholar
  36. 36.
    Liu J, Sato C, Cerletti M, Wagers A. Notch signaling in the regulation of stem cell self-renewal and differentiation. Curr Top Dev Biol. 2010;92:367–409.CrossRefGoogle Scholar
  37. 37.
    Bjerkvig R, Tysnes BB, Aboody KS, Najbauer J, Terzis AJ. Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer. 2005;5(11):899–904.CrossRefPubMedGoogle Scholar
  38. 38.
    Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nat Rev Genet. 2006;7(1):21–33.CrossRefGoogle Scholar
  39. 39.
    Vermeulen L, Sprick MR, Kemper K, Stassi G, Medema JP. Cancer stem cells--old concepts, new insights. Cell Death Differ. 2008;15(6):947–58.CrossRefPubMedGoogle Scholar
  40. 40.
    Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17(3):313–9.CrossRefGoogle Scholar
  41. 41.
    Kleffel S, Schatton T. Tumor dormancy and cancer stem cells: two sides of the same coin? Adv Exp Med Biol. 2013;734:145–79.CrossRefGoogle Scholar
  42. 42.
    Wang J, Sullenger BA, Rich JN. Notch signaling in cancer stem cells. Adv Exp Med Biol. 2012;727:174–85.CrossRefGoogle Scholar
  43. 43.
    Cochrane CR, Szczepny A, Watkins DN, Cain JE. Hedgehog signaling in the maintenance of cancer stem cells. Cancers (Basel). 2015;7(3):1554–85.CrossRefGoogle Scholar
  44. 44.
    de Sousa E Melo F, Vermeulen L. Wnt signaling in cancer stem cell biology. Cancers (Basel). 2016;8(7):pii: E60.CrossRefGoogle Scholar
  45. 45.
    Matsui WH. Cancer stem cell signaling pathways. Medicine (Baltimore). 2016;95(1 Suppl 1):S8–S19.CrossRefGoogle Scholar
  46. 46.
    Kruyt FA, Schuringa JJ. Apoptosis and cancer stem cells: implications for apoptosis targeted therapy. Biochem Pharmacol. 2010;80(4):423–30.CrossRefGoogle Scholar
  47. 47.
    Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol. 2014;16(6):488–94.CrossRefGoogle Scholar
  48. 48.
    Yu LG. Cancer cell resistance to anoikis: MUC1 glycosylation comes to play. Cell Death Dis. 2017;8(7):e2962.CrossRefPubMedGoogle Scholar
  49. 49.
    Frisch SM, Schaller M, Cieply B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J Cell Sci. 2013;26(Pt 1):21–9.CrossRefGoogle Scholar
  50. 50.
    Singh SS, Vats S, Chia AY, Tan TZ, Deng S, Ong MS, Arfuso F, Yap CT, Goh BC, Sethi G, Huang RY, Shen HM, Manjithaya R, Kumar AP. Dual role of autophagy in hallmarks of cancer. Oncogene. 2018;37:1142.CrossRefGoogle Scholar
  51. 51.
    Kung CP, Budina A, Balaburski G, Bergenstock MK, Murphy M. Autophagy in tumor suppression and cancer therapy. Crit Rev Eukaryot Gene Expr. 2011;21(1):71–100.CrossRefPubMedGoogle Scholar
  52. 52.
    Pan H, Cai N, Li M, Liu GH, Izpisua Belmonte JC. Autophagic control of cell ‘stemness’. EMBO Mol Med. 2013;5(3):327–31.CrossRefPubMedGoogle Scholar
  53. 53.
    Naik PP, Panda PK, Bhutia SK. Oral cancer stem cells microenvironment. Adv Exp Med Biol. 2017;1041:207–33.CrossRefGoogle Scholar
  54. 54.
    Wolf J, Dewi DL, Fredebohm J, Müller-Decker K, Flechtenmacher C, Hoheisel JD, Boettcher M. A mammosphere formation RNAi screen reveals that ATG4A promotes a breast cancer stem-like phenotype. Breast Cancer Res. 2013;15(6):R109.CrossRefPubMedGoogle Scholar
  55. 55.
    Gong C, Bauvy C, Tonelli G, Yue W, Deloménie C, Nicolas V, Zhu Y, Domergue V, Marin-Esteban V, Tharinger H, Delbos L, Gary-Gouy H, Morel AP, Ghavami S, Song E, Codogno P, Mehrpour M. Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells. Oncogene. 2013;32(18):2261–72. 2272e.1-11.CrossRefGoogle Scholar
  56. 56.
    Rodríguez CE, Berardi DE, Abrigo M, Todaro LB, Bal de Kier Joffé ED, Fiszman GL. Breast cancer stem cells are involved in Trastuzumab resistance through the HER2 modulation in 3D culture. J Cell Biochem. 2018;119(2):1381–91.CrossRefGoogle Scholar
  57. 57.
    Maycotte P, Jones KL, Goodall ML, Thorburn J, Thorburn A. Autophagy supports breast cancer stem cell maintenance by regulating IL6 secretion. Mol Cancer Res. 2015;13(4):651–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Chaterjee M, van Golen KL. Breast cancer stem cells survive periods of farnesyl-transferase inhibitor-induced dormancy by undergoing autophagy. Bone Marrow Res. 2011;2011:362938.CrossRefPubMedGoogle Scholar
  59. 59.
    Bousquet G, El Bouchtaoui M, Sophie T, Leboeuf C, de Bazelaire C, Ratajczak P, Giacchetti S, de Roquancourt A, Bertheau P, Verneuil L, Feugeas JP, Espié M, Janin A. Targeting autophagic cancer stem-cells to reverse chemoresistance in human triple negative breast cancer. Oncotarget. 2017;8(21):35205–21.CrossRefPubMedGoogle Scholar
  60. 60.
    Zhang L, Xu L, Zhang F, Vlashi E. Doxycycline inhibits the cancer stem cell phenotype and epithelial-to-mesenchymal transition in breast cancer. Cell Cycle. 2017;16(8):737–45.CrossRefGoogle Scholar
  61. 61.
    Rodríguez CE, Reidel SI, Bal de Kier Joffé ED, Jasnis MA, Fiszman GL. Autophagy protects from trastuzumab-induced cytotoxicity in HER2 overexpressing breast tumor spheroids. PLoS One. 2015;10(9):e0137920.CrossRefPubMedGoogle Scholar
  62. 62.
    Berardi DE, Flumian C, Rodriguez CE, Bessone MI, Cirigliano SM, Joffé ED, Fiszman GL, Urtreger AJ, Todaro LB. PKCδ inhibition impairs mammary cancer proliferative capacity but selects cancer stem cells, involving autophagy. J Cell Biochem. 2016;117(3):730–40.CrossRefGoogle Scholar
  63. 63.
    Chang SJ, Ou-Yang F, Tu HP, Lin CH, Huang SH, Kostoro J, Hou MF, Chai CY, Kwan AL. Decreased expression of autophagy protein LC3 and stemness (CD44+/CD24-/low) indicate poor prognosis in triple-negative breast cancer. Hum Pathol. 2016;48:48–55.CrossRefGoogle Scholar
  64. 64.
    Ray A, Vasudevan S, Sengupta S. 6-Shogaol inhibits breast cancer cells and stem cell-like spheroids by modulation of notch signaling pathway and induction of autophagic cell death. PLoS One. 2015;10(9):e0137614.CrossRefPubMedGoogle Scholar
  65. 65.
    Galavotti S, Bartesaghi S, Faccenda D, Shaked-Rabi M, Sanzone S, McEvoy A, Dinsdale D, Condorelli F, Brandner S, Campanella M, Grose R, Jones C, Salomoni P. The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells. Oncogene. 2013;32(6):699–712.CrossRefGoogle Scholar
  66. 66.
    Angeletti F, Fossati G, Pattarozzi A, Würth R, Solari A, Daga A, Masiello I, Barbieri F, Florio T, Comincini S. Inhibition of the autophagy pathway synergistically potentiates the cytotoxic activity of givinostat (ITF2357) on human glioblastoma cancer stem cells. Front Mol Neurosci. 2016;9:107.CrossRefPubMedGoogle Scholar
  67. 67.
    Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, Bause A, Li Y, Stommel JM, Dell’antonio G, Mautner J, Tonon G, Haigis M, Shirihai OS, Doglioni C, Bardeesy N, Kimmelman AC. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25(7):717–29.CrossRefPubMedGoogle Scholar
  68. 68.
    Endo S, Nakata K, Sagara A, Koikawa K, Ando Y, Kibe S, Takesue S, Nakayama H, Abe T, Okumura T, Moriyama T, Miyasaka Y, Ohuchida K, Ohtsuka T, Mizumoto K, Nakamura M. Autophagy inhibition enhances antiproliferative effect of salinomycin in pancreatic cancer cells. Pancreatology. 2017;17(6):990–6.CrossRefGoogle Scholar
  69. 69.
    Yang MC, Wang HC, Hou YC, Tung HL, Chiu TJ, Shan YS. Blockade of autophagy reduces pancreatic cancer stem cell activity and potentiates the tumoricidal effect of gemcitabine. Mol Cancer. 2015;14:179.CrossRefPubMedGoogle Scholar
  70. 70.
    Peng Q, Qin J, Zhang Y, Cheng X, Wang X, Lu W, Xie X, Zhang S. Autophagy maintains the stemness of ovarian cancer stem cells by FOXA2. J Exp Clin Cancer Res. 2017;36(1):171.CrossRefPubMedGoogle Scholar
  71. 71.
    Yang Y, Yu L, Li J, Yuan YH, Wang XL, Yan SR, Li DS, Ding Y. Autophagy regulates the stemness of cervical cancer stem cells. Biologics. 2017;11:71–9.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Ran X, Zhou P, Zhang K. Autophagy plays an important role in stemness mediation and the novel dual function of EIG121 in both autophagy and stemness regulation of endometrial carcinoma JEC cells. Int J Oncol. 2017;51(2):644–56.CrossRefGoogle Scholar
  73. 73.
    Ojha R, Jha V, Singh SK, Bhattacharyya S. Autophagy inhibition suppresses the tumorigenic potential of cancer stem cell enriched side population in bladder cancer. Biochim Biophys Acta. 2014;1842(11):2073–86.CrossRefGoogle Scholar
  74. 74.
    Ojha R, Jha V, Singh SK. Gemcitabine and mitomycin induced autophagy regulates cancer stem cell pool in urothelial carcinoma cells. Biochim Biophys Acta. 2016;1863(2):347–59.CrossRefGoogle Scholar
  75. 75.
    Li J, Hu SB, Wang LY, Zhang X, Zhou X, Yang B, Li JH, Xiong J, Liu N, Li Y, Wu YZ, Zheng QC. Autophagy-dependent generation of Axin2+ cancer stem-like cells promotes hepatocarcinogenesis in liver cirrhosis. Oncogene. 2017;36(48):6725–37.CrossRefPubMedGoogle Scholar
  76. 76.
    Li J, Chen JN, Zeng TT, He F, Chen SP, Ma S, Bi J, Zhu XF, Guan XY. CD133+ liver cancer stem cells resist interferon-gamma-induced autophagy. BMC Cancer. 2016;16:15.CrossRefPubMedGoogle Scholar
  77. 77.
    Wiener Z, Högström J, Hyvönen V, Band AM, Kallio P, Holopainen T, Dufva O, Haglund C, Kruuna O, Oliver G, Ben-Neriah Y, Alitalo K. Prox1 promotes expansion of the colorectal cancer stem cell population to fuel tumor growth and ischemia resistance. Cell Rep. 2014;8(6):1943–56.CrossRefGoogle Scholar
  78. 78.
    Zhai H, Fesler A, Ba Y, Wu S, Ju J. Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy. Oncotarget. 2015;6(23):19735–46.CrossRefPubMedGoogle Scholar
  79. 79.
    Singla M, Bhattacharyya S. Autophagy as a potential therapeutic target during epithelial to mesenchymal transition in renal cell carcinoma: an in vitro study. Biomed Pharmacother. 2017;94:332–40.CrossRefGoogle Scholar
  80. 80.
    Fang D, Kitamura H. Cancer stem cells and epithelial-mesenchymal transition in urothelial carcinoma: possible pathways and potential therapeutic approaches. Int J Urol. 2018;25(1):7–17.CrossRefGoogle Scholar
  81. 81.
    Yang Y, Fan Y, Qi Y, Liu D, Wu K, Wen F, Zhao S. Side population cells separated from A549 lung cancer cell line possess cancer stem cell-like properties and inhibition of autophagy potentiates the cytotoxic effect of cisplatin. Oncol Rep. 2015;34(2):929–35.CrossRefGoogle Scholar
  82. 82.
    Li X, Wu XQ, Deng R, Li DD, Tang J, Chen WD, Chen JH, Ji J, Jiao L, Jiang S, Yang F, Feng GK, Senthilkumar R, Yue F, Zhang HL, Wu RY, Yu Y, Xu XL, Mai J, Li ZL, Peng XD, Huang Y, Huang X, Ma NF, Tao Q, Zeng YX, Zhu XF. CaMKII-mediated Beclin 1 phosphorylation regulates autophagy that promotes degradation of Id and neuroblastoma cell differentiation. Nat Commun. 2017;8(1):1159.CrossRefPubMedGoogle Scholar
  83. 83.
    Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017;16(7):487–511.CrossRefPubMedGoogle Scholar
  84. 84.
    Denton D, Xu T, Kumar S. Autophagy as a pro-death pathway. Immunol Cell Biol. 2015;93(1):35–42.CrossRefPubMedGoogle Scholar
  85. 85.
    Fulda S, Kögel D. Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy. Oncogene. 2015;34(40):5105–13.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Bakiye Goker Bagca
    • 1
  • Cigir Biray Avci
    • 1
  1. 1.Department of Medical Biology, Faculty of MedicineEge UniversityIzmirTurkey

Personalised recommendations