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Understanding autophagy role in cancer stem cell development

Molecular Biology Reports volume 49, pages 6741–6751 (2022)Cite this article

Abstract

Cancer stem cells (CSCs) are a small subpopulation of immature cells located in the tumor mass. These cells are responsible for tumor development, proliferation, resistance and spreading. CSCs are characterized by three unique features: the ability to self-renew, differentiation and tumor formation. CSCs are similar to stem cells, but they differ in the malignant phenotype. CSCs become immortal and survive harsh environmental conditions such as hypoxia, starvation and oxidative stress. However, this harsh tumor microenvironment induces the activation of autophagy, which further increases the CSCs stemness profile, and all these features further increase tumorigenicity and metastasis capacity. Autophagy is induced by the extracellular and cellular microenvironment. Hypoxia is one of the most common factors that highly increases the activity of autophagy in CSCs. Therefore, hypoxia-induced autophagy and CSCs proliferation should be elucidated in order to find a novel cure to defeat cancer cells (CSCs and non-CSCs). The remaining challenges to close the gap between the laboratory bench and the development of therapies, to use autophagy against CSCs in patients, could be addressed by adopting a 3D platform to better-mimic the natural environment in which these cells reside. Ultimately allowing to obtain the blueprints for bioprocess scaling up and to develop the production pipeline for safe and cost-effective autophagy-based novel biologics.

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References

  1. Jamieson CHM, Ailles LE, Dylla SJ et al (2004) Granulocyte–Macrophage Progenitors as Candidate Leukemic Stem Cells in Blast-Crisis CML. N Engl J Med 351(7):657–667. doi:https://doi.org/10.1056/nejmoa040258

    Article  CAS  PubMed  Google Scholar 

  2. Aguilar-Gallardo C, Rutledge EC, Martínez-Arroyo AM, Hidalgo JJ, Domingo S, Simón C (2012) Overcoming Challenges of Ovarian Cancer Stem Cells: Novel Therapeutic Approaches. Stem Cell Rev Reports 8(3):994–1010. doi:https://doi.org/10.1007/s12015-011-9344-5

    Article  CAS  Google Scholar 

  3. Huntly BJP, Shigematsu H, Deguchi K et al (2004) MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6(6):587–596. doi:https://doi.org/10.1016/j.ccr.2004.10.015

    Article  CAS  PubMed  Google Scholar 

  4. Krivtsov AV, Twomey D, Feng Z et al (2006) Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442(7104):818–822. doi:https://doi.org/10.1038/nature04980

    Article  CAS  PubMed  Google Scholar 

  5. Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3(12):895–902. doi:https://doi.org/10.1038/nrc1232

    Article  CAS  PubMed  Google Scholar 

  6. Al-Hajj M, Clarke MF (2004) Self-renewal and solid tumor stem cells. Oncogene. ;23(43 REV. ISS. 6):7274–7282. doi:https://doi.org/10.1038/sj.onc.1207947

  7. Kroemer G, Jäättelä M (2005) Lysosomes and autophagy in cell death control. Nat Rev Cancer 5(11):886–897. doi:https://doi.org/10.1038/nrc1738

    Article  CAS  PubMed  Google Scholar 

  8. Klionsky DJ, Autophagy (2007) From phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8(11):931–937. doi:https://doi.org/10.1038/nrm2245

    Article  CAS  PubMed  Google Scholar 

  9. Yorimitsu T, Klionsky DJ, Autophagy (2005) Molecular machinery for self-eating. Cell Death Differ 12:1542–1552. doi:https://doi.org/10.1038/sj.cdd.4401765

    Article  CAS  PubMed  Google Scholar 

  10. Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Sci (80-) 290(5497):1717–1721. doi:https://doi.org/10.1126/science.290.5497.1717

    Article  CAS  Google Scholar 

  11. Mizushima N, Autophagy (2007) Process and function. Genes Dev 21(22):2861–2873. doi:https://doi.org/10.1101/gad.1599207

    Article  CAS  PubMed  Google Scholar 

  12. Cao B, Camden AJ, Parnell LA, Mysorekar IU (2017) Autophagy regulation of physiological and pathological processes in the female reproductive tract. Am J Reprod Immunol 77(5). doi:https://doi.org/10.1111/aji.12650

  13. Ojha R, Bhattacharyya S, Singh SK (2015) Autophagy in Cancer Stem Cells: A Potential Link Between Chemoresistance, Recurrence, and Metastasis. Biores Open Access 4(1):97–108. doi:https://doi.org/10.1089/biores.2014.0035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Swartz MA, Iida N, Roberts EW et al (2012) Tumor microenvironment complexity: Emerging roles in cancer therapy. Cancer Res 72(10):2473–2480. doi:https://doi.org/10.1158/0008-5472.CAN-12-0122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gatenby RA, Gillies RJ (2008) A microenvironmental model of carcinogenesis. Nat Rev Cancer 8(1):56–61. doi:https://doi.org/10.1038/nrc2255

    Article  CAS  PubMed  Google Scholar 

  16. Clarke L, Van Der Kooy D (2009) Low oxygen enhances primitive and definitive neural stem cell colony formation by inhibiting distinct cell death pathways. Stem Cells 27(8):1879–1886. doi:https://doi.org/10.1002/stem.96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li Z, Bao S, Wu Q et al (2009) Hypoxia-Inducible Factors Regulate Tumorigenic Capacity of Glioma Stem Cells. Cancer Cell 15(6):501–513. doi:https://doi.org/10.1016/j.ccr.2009.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Plaks V, Kong N, Werb Z (2015) The cancer stem cell niche: How essential is the niche in regulating stemness of tumor cells? Cell Stem Cell 16(3):225–238. doi:https://doi.org/10.1016/j.stem.2015.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Conley SJ, Gheordunescu E, Kakarala P et al (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A 109(8):2784–2789. doi:https://doi.org/10.1073/pnas.1018866109

    Article  PubMed  PubMed Central  Google Scholar 

  20. Piao Y, Liang J, Holmes L et al (2012) Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro Oncol 14(11):1379–1392. doi:https://doi.org/10.1093/neuonc/nos158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Espina V, Liotta LA (2011) What is the malignant nature of human ductal carcinoma in situ? Nat Rev Cancer 11(1):68–75. doi:https://doi.org/10.1038/nrc2950

    Article  CAS  PubMed  Google Scholar 

  22. Espina V, Mariani BD, Gallagher RI et al (2010) Malignant Precursor Cells Pre-Exist in Human Breast DCIS and Require Autophagy for Survival. PLoS ONE 5(4). doi:https://doi.org/10.1371/journal.pone.0010240

  23. Ratcliffe PJ (2007) HIF-1 and HIF-2: Working alone or together in hypoxia? J Clin Invest 117(4):862–865. doi:https://doi.org/10.1172/JCI31750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. McDonald PC, Chafe SC, Dedhar S (2016) Overcoming hypoxia-mediated tumor progression: Combinatorial approaches targeting pH regulation, angiogenesis and immune dysfunction. Front Cell Dev Biol 4(MAR). doi:https://doi.org/10.3389/fcell.2016.00027

  25. Gao T, Li J, Lu Y et al (2016) The mechanism between epithelial mesenchymal transition in breast cancer and hypoxia microenvironment. Biomed Pharmacother 80:393–405. doi:https://doi.org/10.1016/j.biopha.2016.02.044

    Article  CAS  PubMed  Google Scholar 

  26. Babaei G, Aziz SG-G, Jaghi NZZ (2021) EMT, cancer stem cells and autophagy; The three main axes of metastasis. Biomed Pharmacother 133:110909. doi:https://doi.org/10.1016/j.biopha.2020.110909

    Article  CAS  PubMed  Google Scholar 

  27. Shibue T, Weinberg RA (2017) EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol 14(10):611–629. doi:https://doi.org/10.1038/nrclinonc.2017.44

    Article  PubMed  PubMed Central  Google Scholar 

  28. Marcucci F, Ghezzi P, Rumio C (2017) The role of autophagy in the cross-talk between epithelial-mesenchymal transitioned tumor cells and cancer stem-like cells. Mol Cancer 16(1):3. doi:https://doi.org/10.1186/s12943-016-0573-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu XW, Su Y, Zhu H et al (2010) HIF-1α-dependent autophagy protects HeLa cells from fenretinide (4-HPR)-induced apoptosis in hypoxia. Pharmacol Res 62(5):416–425. doi:https://doi.org/10.1016/j.phrs.2010.07.002

    Article  CAS  PubMed  Google Scholar 

  30. Zhang H, Bosch-Marce M, Shimoda LA et al (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283(16):10892–10903. doi:https://doi.org/10.1074/jbc.M800102200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sato A, Okada M, Shibuya K et al (2014) Pivotal role for ROS activation of p38 MAPK in the control of differentiation and tumor-initiating capacity of glioma-initiating cells. Stem Cell Res 12(1):119–131. doi:https://doi.org/10.1016/j.scr.2013.09.012

    Article  CAS  PubMed  Google Scholar 

  32. Diehn M, Cho RW, Lobo NA et al (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239):780–783. doi:https://doi.org/10.1038/nature07733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim YS, Kang MJ, Cho YM (2013) Low production of reactive oxygen species and high DNA repair: Mechanism of radioresistance of prostate cancer stem cells. Anticancer Res 33(10):4469–4474. https://www.ncbi.nlm.nih.gov/pubmed/24123017

    CAS  PubMed  Google Scholar 

  34. Menendez JA, Joven J, Cufí S et al (2013) The warburg effect version 2.0 : Metabolic reprogramming of cancer stem cells. Cell Cycle 12(8):1166–1179. doi:https://doi.org/10.4161/cc.24479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wei H, Wei S, Gan B, Peng X, Zou W, Guan JL (2011) Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev 25(14):1510–1527. doi:https://doi.org/10.1101/gad.2051011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wei H, Guan JL (2012) Pro-tumorigenic function of autophagy in mammary oncogenesis. Autophagy 8(1):129–131. doi:https://doi.org/10.4161/auto.8.1.18171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jiang S, Dupont N, Castillo EF, Deretic V (2013) Secretory versus degradative autophagy: Unconventional secretion of inflammatory mediators. J Innate Immun 5(5):471–479. doi:https://doi.org/10.1159/000346707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Martinez-Outschoorn UE, Whitaker-Menezes D, Lin Z et al (2011) Cytokine production and inflammation drive autophagy in the tumor microenvironment. Cell Cycle 10(11):1784–1793. doi:https://doi.org/10.4161/cc.10.11.15674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jonchère B, Bélanger A, Guette C, Barré B, Coqueret O (2013) STAT3 as a new autophagy regulator. Jak-Stat 2(3):e24353. doi:https://doi.org/10.4161/jkst.24353

    Article  PubMed  PubMed Central  Google Scholar 

  40. Trocoli A, Djavaheri-Mergny M (2011) The complex interplay between autophagy and NF-κB signaling pathways in cancer cells. Am J Cancer Res 1(5):629–649. http://www.ncbi.nlm.nih.gov/pubmed/21994903%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC3189824

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Bánréti Á, Sass M, Graba Y (2013) The emerging role of acetylation in the regulation of autophagy. Autophagy 9(6):819–829. doi:https://doi.org/10.4161/auto.23908

    Article  PubMed  PubMed Central  Google Scholar 

  42. Corominas-Faja B, Cuyàs E, Gumuzio J et al (2014) Chemical inhibition of acetyl-CoA carboxylase suppresses self-renewal growth of cancer stem cells. Oncotarget 5(18):8306–8316. doi:https://doi.org/10.18632/oncotarget.2059

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ma I, Allan AL (2011) The Role of Human Aldehyde Dehydrogenase in Normal and Cancer Stem Cells. Stem Cell Rev Reports 7(2):292–306. doi:https://doi.org/10.1007/s12015-010-9208-4

    Article  CAS  Google Scholar 

  44. Gong C, Bauvy C, Tonelli G et al (2013) Beclin 1 and autophagy are required for the tumorigenicity of breast cancer stem-like/progenitor cells. Oncogene 32(18):2261–2272. doi:https://doi.org/10.1038/onc.2012.252

    Article  CAS  PubMed  Google Scholar 

  45. Gong C, Song E, Codogno P, Mehrpour M (2012) The roles of BECN1 and autophagy in cancer are context dependent. Autophagy 8(12):1853–1855. doi:https://doi.org/10.4161/auto.21996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Milla LA, González-Ramírez CN, Palma V (2012) Sonic hedgehog in cancer stem cells: A novel link with autophagy. Biol Res 45(3):223–230. doi:https://doi.org/10.4067/S0716-97602012000300004

    Article  PubMed  Google Scholar 

  47. Jimenez-Sanchez M, Menzies FM, Chang YY, Simecek N, Neufeld TP, Rubinsztein DC (2012) The Hedgehog signalling pathway regulates autophagy. Nat Commun 3(1200). doi:https://doi.org/10.1038/ncomms2212

  48. Xu Y, An Y, Wang X, Zha W, Li X (2014) Inhibition of the Hedgehog pathway induces autophagy in pancreatic ductal adenocarcinoma cells. Oncol Rep 31(2):707–712. doi:https://doi.org/10.3892/or.2013.2881

    Article  CAS  PubMed  Google Scholar 

  49. Wang Y, Han C, Lu L, Magliato S, Wu T (2013) Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology 58(3):995–1010. doi:https://doi.org/10.1002/hep.26394

    Article  CAS  PubMed  Google Scholar 

  50. Holland JD, Klaus A, Garratt AN, Birchmeier W (2013) Wnt signaling in stem and cancer stem cells. Curr Opin Cell Biol 25(2):254–264. doi:https://doi.org/10.1016/j.ceb.2013.01.004

    Article  CAS  PubMed  Google Scholar 

  51. Takahashi-Yanaga F, Kahn M (2010) Targeting Wnt signaling: Can we safely eradicate cancer stem cells? Clin Cancer Res 16(12):3153–3162. doi:https://doi.org/10.1158/1078-0432.CCR-09-2943

    Article  CAS  PubMed  Google Scholar 

  52. Teng Y, Wang X, Wang Y, Ma D (2010) Wnt/β-catenin signaling regulates cancer stem cells in lung cancer A549 cells. Biochem Biophys Res Commun 392(3):373–379. doi:https://doi.org/10.1016/j.bbrc.2010.01.028

    Article  CAS  PubMed  Google Scholar 

  53. Hallett RM, Kondratyev MK, Giacomelli AO et al (2012) Small molecule antagonists of the Wnt/Beta-catenin signaling pathway target breast tumor-initiating cells in a Her2/Neu mouse model of breast cancer. PLoS ONE 7(3). doi:https://doi.org/10.1371/journal.pone.0033976

  54. Hsieh CH, Cheng LH, Hsu HH et al (2013) Apicidin-resistant HA22T hepatocellular carcinoma cells strongly activated the wnt/β-catenin signaling pathway and MMP-2 Expression via the IGF-IR/PI3K/Akt signaling pathway enhancing cell metastatic Effect. Biosci Biotechnol Biochem 77(12):2397–2404. doi:https://doi.org/10.1271/bbb.130503

    Article  CAS  PubMed  Google Scholar 

  55. Jing Y, Han Z, Zhang S, Liu Y, Wei L (2011) Epithelial-Mesenchymal Transition in tumor microenvironment. Cell Biosci 1(1). doi:https://doi.org/10.1186/2045-3701-1-29

  56. Jiang YG, Luo Y, He DL et al (2007) Role of Wnt/β-catenin signaling pathway in epithelial-mesenchymal transition of human prostate cancer induced by hypoxia-inducible factor-1α. Int J Urol 14(11):1034–1039. doi:https://doi.org/10.1111/j.1442-2042.2007.01866.x

    Article  CAS  PubMed  Google Scholar 

  57. Li X, Xu Y, Chen Y et al (2013) SOX2 promotes tumor metastasis by stimulating epithelial-to-mesenchymal transition via regulation of WNT/β-catenin signal network. Cancer Lett 336(2):379–389. doi:https://doi.org/10.1016/j.canlet.2013.03.027

    Article  CAS  PubMed  Google Scholar 

  58. Kaidi A, Williams AC, Paraskeva C (2007) Interaction between β-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 9(2):210–217. doi:https://doi.org/10.1038/ncb1534

    Article  CAS  PubMed  Google Scholar 

  59. Essers MAG, De Vries-Smits LMM, Barker N, Polderman PE, Burgering BMT, Korswagen HC (2005) Functional interaction between β-catenin and FOXO in oxidative stress signaling. Sci (80-) 308(5725):1181–1184. doi:https://doi.org/10.1126/science.1109083

    Article  CAS  Google Scholar 

  60. Petherick KJ, Williams AC, Lane JD et al (2013) Autolysosomal β-catenin degradation regulates Wnt-autophagy-p62 crosstalk. EMBO J 32(13):1903–1916. doi:https://doi.org/10.1038/emboj.2013.123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gao C, Cao W, Bao L et al (2010) Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation. Nat Cell Biol 12(8):781–790. doi:https://doi.org/10.1038/ncb2082

    Article  CAS  PubMed  Google Scholar 

  62. Ji Q, Hao X, Zhang M et al (2009) MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS ONE 4(8). doi:https://doi.org/10.1371/journal.pone.0006816

  63. Farnie G, Clarke RB, Spence K et al (2007) Novel cell culture technique for primary ductal carcinoma in situ: Role of notch and epidermal growth Factor Receptor Signaling Pathways. J Natl Cancer Inst 99(8):616–627. doi:https://doi.org/10.1093/jnci/djk133

    Article  CAS  PubMed  Google Scholar 

  64. Fan X, Khaki L, Zhu TS et al (2010) NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28(1):5–16. doi:https://doi.org/10.1002/stem.254

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Miele L (2006) Notch signaling. Clin Cancer Res 12(4):1074–1079. doi:https://doi.org/10.1158/1078-0432.CCR-05-2570

    Article  CAS  PubMed  Google Scholar 

  66. Wang Z, Li Y, Banerjee S, Sarkar FH (2008) Exploitation of the notch signaling pathway as a novel target for cancer therapy. Anticancer Res 28(6 A):3621–3630. https://www.ncbi.nlm.nih.gov/pubmed/19189643

    PubMed  Google Scholar 

  67. Shi J, Feng J, Xie J et al (2017) Targeted blockade of TGF-β and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted by bone marrow-derived myofibroblasts. Sci Rep 7(1). doi:https://doi.org/10.1038/s41598-017-09020-8

  68. Matsui WH (2016) Cancer stem cell signaling pathways. Med (Baltim) 95(1 Suppl 1):S8–S19. doi:https://doi.org/10.1097/MD.0000000000004765

    Article  CAS  Google Scholar 

  69. Zhou H, Yuan M, Yu Q, Zhou X, Min W, Gao D (2016) Autophagy regulation and its role in gastric cancer and colorectal cancer. Cancer Biomarkers 17(1):1–10. doi:https://doi.org/10.3233/CBM-160613

    Article  CAS  PubMed  Google Scholar 

  70. Zhou J, Wulfkuhle J, Zhang H et al (2007) Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc Natl Acad Sci U S A 104(41):16158–16163. doi:https://doi.org/10.1073/pnas.0702596104

    Article  PubMed  PubMed Central  Google Scholar 

  71. Ribatti D (2017) The concept of immune surveillance against tumors. The first theories. Oncotarget 8(4):7175–7180. doi:https://doi.org/10.18632/oncotarget.12739

    Article  PubMed  Google Scholar 

  72. Janji B, Viry E, Moussay E et al (2016) The multifaceted role of autophagy in tumor evasion from immune surveillance. Oncotarget 7(14):17591–17607. doi:https://doi.org/10.18632/oncotarget.7540

    Article  PubMed  PubMed Central  Google Scholar 

  73. Jiang G-M, Tan Y, Wang H et al (2019) The relationship between autophagy and the immune system and its applications for tumor immunotherapy. Mol Cancer 18(1):17. doi:https://doi.org/10.1186/s12943-019-0944-z

    Article  PubMed  PubMed Central  Google Scholar 

  74. Cadwell K (2016) Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 16(11):661–675. doi:https://doi.org/10.1038/nri.2016.100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schöning JP, Monteiro M, Gu W (2017) Drug resistance and cancer stem cells: the shared but distinct roles of hypoxia-inducible factors HIF1α and HIF2α. Clin Exp Pharmacol Physiol 44(2):153–161. doi:https://doi.org/10.1111/1440-1681.12693

    Article  CAS  PubMed  Google Scholar 

  76. Seo EJ, Kim DK, Jang IH et al (2016) Hypoxia-NOTCH1-SOX2 signaling is important for maintaining cancer stem cells in ovarian cancer. Oncotarget 7(34):55624–55638. doi:https://doi.org/10.18632/oncotarget.10954

    Article  PubMed  PubMed Central  Google Scholar 

  77. Sosa MS, Parikh F, Maia AG et al (2015) NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes. Nat Commun 6(1). doi:https://doi.org/10.1038/ncomms7170

  78. Taylor CT, Colgan SP (2017) Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol 17(12):774–785. doi:https://doi.org/10.1038/nri.2017.103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Salem A, Asselin MC, Reymen B et al (2018) Targeting hypoxia to improve non–small cell lung cancer outcome. J Natl Cancer Inst 110(1). doi:https://doi.org/10.1093/jnci/djx160

  80. Goulielmaki M, Assimomytis N, Rozanc J et al (2019) DPS-2: A Novel Dual MEK/ERK and PI3K/AKT Pathway Inhibitor with Powerful Ex Vivo and In Vivo Anticancer Properties. Transl Oncol 12(7):932–950. doi:https://doi.org/10.1016/j.tranon.2019.04.005

    Article  PubMed  PubMed Central  Google Scholar 

  81. Vera-Ramirez L, Vodnala SK, Nini R, Hunter KW, Green JE (2018) Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence. Nat Commun 9(1):1944. doi:https://doi.org/10.1038/s41467-018-04070-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Imamura Y, Mukohara T, Shimono Y et al (2015) Comparison of 2D- and 3D-culture models as drug-testing platforms in breast cancer. Oncol Rep 33(4):1837–1843. doi:https://doi.org/10.3892/or.2015.3767

    Article  CAS  PubMed  Google Scholar 

  83. Riedl A, Schlederer M, Pudelko K et al (2017) Comparison of cancer cells in 2D vs 3D culture reveals differences in AKT-mTOR-S6K signaling and drug responses. J Cell Sci 130(1):203–218. doi:https://doi.org/10.1242/jcs.188102

    Article  CAS  PubMed  Google Scholar 

  84. Emami A, Shojaei S, da Silva Rosa SC et al (2019) Mechanisms of simvastatin myotoxicity: The role of autophagy flux inhibition. Eur J Pharmacol 862:172616. doi:https://doi.org/10.1016/j.ejphar.2019.172616

    Article  CAS  PubMed  Google Scholar 

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    Authors and Affiliations

    1. Instituto de Investigación Sanitaria Hospital La Fe, Valencia, Spain

      Cristóbal Aguilar-Gallardo

    2. Department of Chemical Enginering, Facultad de Ingeniería y Ciencias, Universidad de La Frontera, Temuco, Chile

      Mauricio Zamorano & Jorge G. Farias

    3. Doctor in Medicine, Universitat de València, Valencia, Spain

      Karol De Aguiar Quevedo

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    Authorship Conception and design: CAG, MZ. Analysis and interpretation of data: JF, KDAQ. Drafting the article: CAG, KDAQ, MZ. Final approval of the version to be published: MZ, JF.

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    Aguilar-Gallardo, C., Zamorano, M., Farias, J.G. et al. Understanding autophagy role in cancer stem cell development. Mol Biol Rep 49, 6741–6751 (2022). https://doi.org/10.1007/s11033-022-07299-z

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    Keywords

    • CSCs, Cancer Stem cells
    • Autophagy
    • Hypoxia
    • Signaling pathway
    • Hypoxia-targeted therapies