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Hypoxia effects on cancer stem cell phenotype in colorectal cancer: a mini-review

Abstract

Colorectal cancer (CRC) is ranked third most incident and second most deadly around the world, and even though treatments significantly developed over the years, overall survival remains low. This scenario has the contribution of cancer stem cells (CSC), a subpopulation of the heterogeneous tumor bulk, considered to be responsible for the tumor maintenance, conventional therapies resistance, metastasis, and recurrence. In this regard, hypoxia appears as an important component of tumor microenvironment and CSC niche, being associated with a worse prognosis. Therefore, it is vital the study of hypoxia influence on CSC phenotype in CRC. The aim of this mini-review article is to present a brief overview on this field. Recent articles discoursed about CSC molecular regulation, signalling pathways, methods for the study of the topic, as well as molecules and drugs capacity of inhibiting the interplay of hypoxia-CSC. Finally, the studies demonstrated important results, extensively accessing the topics of cellular and molecular regulation and therapeutic intervention, being morphology an area to be more explored.

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References

  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Van Der Jeught K, Xu HC, Li YJ, Lu X, Bin, Ji G (2018) Drug resistance and new therapies in colorectal cancer. World J Gastroenterol 24:3834–3848. https://doi.org/10.3748/wjg.v24.i34.3834

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Batlle E, Clevers H (2017) Cancer stem cells revisited. Nat Med 23:1124–1134. https://doi.org/10.1038/nm.4409

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Eun K, Ham SW, Kim H (2017) Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting. BMB Rep 50:117–125. https://doi.org/10.5483/BMBRep.2017.50.3.222

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Lytle NK, Barber AG, Reya T (2018) Stem cell fate in cancer growth, progression and therapy resistance. Nat Rev Cancer 18:669–680. https://doi.org/10.1038/s41568-018-0056-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Nassar D, Blanpain C (2016) Cancer stem cells: basic concepts and therapeutic implications. Annu Rev Pathol Mech Dis 11:47–76. https://doi.org/10.1146/annurev-pathol-012615-044438

    CAS  Article  Google Scholar 

  7. 7.

    Dongre A, Weinberg RA (2019) New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 20:69–84. https://doi.org/10.1038/s41580-018-0080-4

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110. https://doi.org/10.1038/nature05372

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Zeuner A, Todaro M, Stassi G, De Maria R (2014) Colorectal cancer stem cells: from the crypt to the clinic. Cell Stem Cell 15:692–705. https://doi.org/10.1016/j.stem.2014.11.012

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Zhou Y, Xia L, Wang H, Oyang L, Su M, Liu Q et al (2018) Cancer stem cells in progression of colorectal cancer. Oncotarget 9:33403–33415. https://doi.org/10.18632/oncotarget.23607

    Article  Google Scholar 

  11. 11.

    Gupta R, Bhatt LK, Johnston TP, Prabhavalkar KS (2019) Colon cancer stem cells: potential target for the treatment of colorectal cancer. Cancer Biol Ther 20:1068–1082. https://doi.org/10.1080/15384047.2019.1599660

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Höckel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93:266–276. https://doi.org/10.1093/jnci/93.4.266

    Article  PubMed  Google Scholar 

  13. 13.

    Greenspan HP (1972) Models for the growth of a solid tumor by diffusion. Stud Appl Math 51:317–340. https://doi.org/10.1002/sapm1972514317

    Article  Google Scholar 

  14. 14.

    Bersten DC, Sullivan AE, Peet DJ, Whitelaw ML (2013) BHLH-PAS proteins in cancer. Nat Rev Cancer 13:827–841. https://doi.org/10.1038/nrc3621

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Keith B, Johnson RS, Simon MC (2012) HIF1 α and HIF2 α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9–22. https://doi.org/10.1038/nrc3183

    CAS  Article  Google Scholar 

  16. 16.

    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732. https://doi.org/10.1038/nrc1187

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Wigerup C, Påhlman S, Bexell D (2016) Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther 164:152–169. https://doi.org/10.1016/j.pharmthera.2016.04.009

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Simon MC, 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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Carnero A, Lleonart M (2016) The hypoxic microenvironment: a determinant of cancer stem cell evolution. Insid Cell 1:96–105. https://doi.org/10.1002/bies.201670911

    Article  Google Scholar 

  20. 20.

    Dong HJ, Jang GB, Lee HY, Park SR, Kim JY, Nam JS et al (2016) The Wnt/β-catenin signaling/Id2 cascade mediates the effects of hypoxia on the hierarchy of colorectal-cancer stem cells. Sci Rep 6:1–13. https://doi.org/10.1038/srep22966

    CAS  Article  Google Scholar 

  21. 21.

    Giles RH, Lolkema MP, Snijckers CM, Belderbos M, Van Der Groep P, Mans DA et al (2006) Interplay between VHL/HIF1α and Wnt/β-catenin pathways during colorectal tumorigenesis. Oncogene 25:3065–3070. https://doi.org/10.1038/sj.onc.1209330

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Yeung TM, Gandhi SC, Bodmer WF (2011) Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells. Proc Natl Acad Sci USA 108:4382–4387. https://doi.org/10.1073/pnas.1014519107

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Goodall GJ, Wickramasinghe VO (2021) RNA in cancer. Nat Rev Cancer 21:22–36. https://doi.org/10.1038/s41568-020-00306-0

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Fanale D, Barraco N, Listì A, Bazan V, Russo A (2016) Non-coding RNAs functioning in colorectal cancer stem cells. Adv Exp Med Biol 937:93–108. https://doi.org/10.1007/978-3-319-42059-2_5

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Khan A, Ahmed E, Elareer N, Junejo K, Steinhoff M, Uddin S (2019) Role of miRNA-regulated cancer stem cells in the pathogenesis of human malignancies. Cells 8:840. https://doi.org/10.3390/cells8080840

    CAS  Article  PubMed Central  Google Scholar 

  27. 27.

    Shirmohamadi M, Eghbali E, Najjary S, Mokhtarzadeh A, Kojabad AB, Hajiasgharzadeh K et al (2020) Regulatory mechanisms of microRNAs in colorectal cancer and colorectal cancer stem cells. J Cell Physiol 235:776–789. https://doi.org/10.1002/jcp.29042

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Yao J, Li J, Geng P, Li Y, Chen H, Zhu Y (2015) Knockdown of a HIF-2α promoter upstream long noncoding RNA impairs colorectal cancer stem cell properties in vitro through HIF-2α downregulation. Onco Targets Ther 8:3467–3474. https://doi.org/10.2147/OTT.S81393

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Ullmann P, Qureshi-Baig K, Rodriguez F, Ginolhac A, Nonnenmacher Y, Ternes D et al (2016) Hypoxia-responsive miR-210 promotes self-renewal capacity of colon tumor-initiating cells by repressing ISCU and by inducing lactate production. Oncotarget 7:65454–65470. https://doi.org/10.18632/oncotarget.11772

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Ullmann P, Nurmik M, Schmitz M, Rodriguez F, Weiler J, Qureshi-Baig K et al (2019) Tumor suppressor miR-215 counteracts hypoxia-induced colon cancer stem cell activity. Cancer Lett 450:32–41. https://doi.org/10.1016/j.canlet.2019.02.030

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Lai HT, Chiang CT, Tseng WK, Chao TC, Su Y (2020) GATA6 enhances the stemness of human colon cancer cells by creating a metabolic symbiosis through upregulating LRH-1 expression. Mol Oncol 14:1327–1347. https://doi.org/10.1002/1878-0261.12647

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Bian J, Dannappel M, Wan C, Firestein R (2020) Transcriptional regulation of Wnt/β-catenin pathway in colorectal cancer. Cells 9:1–29. https://doi.org/10.3390/cells9092125

    CAS  Article  Google Scholar 

  33. 33.

    Oncol WJH, Zhang Y, Wang X (2020) Targeting the Wnt/β- catenin signaling pathway in cancer. J Hematol Oncol. https://doi.org/10.1186/s13045-020-00990-3

    Article  Google Scholar 

  34. 34.

    Lee S, Rauch J, Kolch W (2020) Targeting MAPK signaling in cancer: mechanisms of drug resistance and sensitivity. Int J Mol Sci 21:1–29. https://doi.org/10.3390/ijms21031102

    CAS  Article  Google Scholar 

  35. 35.

    Hou PC, Li YH, Lin SC, Lin SC, Lee JC, Lin BW et al (2017) Hypoxia-induced downregulation of DUSP-2 phosphatase drives colon cancer stemness. Cancer Res 77:4305–4316. https://doi.org/10.1158/0008-5472.can-16-2990

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Folkerts H, Hilgendorf S, Vellenga E, Bremer E, Wiersma VR (2019) The multifaceted role of autophagy in cancer and the microenvironment. Med Res Rev 39:517–560. https://doi.org/10.1002/med.21531

    Article  PubMed  Google Scholar 

  37. 37.

    Li X, He S, Ma B (2020) Autophagy and autophagy-related proteins in cancer. Mol Cancer Mol Cancer 19:1–16. https://doi.org/10.1186/s12943-020-1138-4

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Wei R, Xiao Y, Song Y, Yuan H, Luo J, Xu W (2019) FAT4 regulates the EMT and autophagy in colorectal cancer cells in part via the PI3K-AKT signaling axis. J Exp Clin Cancer Res 38:1–14. https://doi.org/10.1186/s13046-019-1043-0

    CAS  Article  Google Scholar 

  39. 39.

    Ma Z, Lou S, Jiang Z (2020) PHLDA2 regulates EMT and autophagy in colorectal cancer via the PI3K/AKT signaling pathway. Aging (Albany NY) 12:7985–8000. https://doi.org/10.18632/aging.103117

    CAS  Article  Google Scholar 

  40. 40.

    Shi L, Yan H, An S, Shen M, Jia W, Zhang R et al (2019) SIRT5-mediated deacetylation of LDHB promotes autophagy and tumorigenesis in colorectal cancer. Mol Oncol 13:358–375. https://doi.org/10.1002/1878-0261.12408

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Qureshi-Baig K, Kuhn D, Viry E, Pozdeev VI, Schmitz M, Rodriguez F et al (2020) Hypoxia-induced autophagy drives colorectal cancer initiation and progression by activating the PRKC/PKC-EZR (ezrin) pathway. Autophagy 16:1436–1452. https://doi.org/10.1080/15548627.2019.1687213

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Vara-Perez M, Felipe-Abrio B, Agostinis P (2019) Mitophagy in cancer: a tale of adaptation. Cells 8:493. https://doi.org/10.3390/cells8050493

    CAS  Article  PubMed Central  Google Scholar 

  43. 43.

    Junttila MR, De Sauvage FJ (2013) Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501:346–354. https://doi.org/10.1038/nature12626

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Fatrai S, Van Schelven SJ, Ubink I, Govaert KM, Raats D, Koster J et al (2015) Maintenance of clonogenic KIT+ human colon tumor cells requires secretion of stem cell factor by differentiated tumor cells. Gastroenterology 149:692–704. https://doi.org/10.1053/j.gastro.2015.05.003

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Tang YA, Chen Y, Feng, Bao Y, Mahara S, Yatim SMJM, Oguz G et al (2018) Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer. Proc Natl Acad Sci USA 115:5990–5999. https://doi.org/10.1073/pnas.1801348115

    CAS  Article  Google Scholar 

  46. 46.

    Nyga A, Cheema U, Loizidou M (2011) 3D tumour models: novel in vitro approaches to cancer studies. J Cell Commun Signal 5:239–248. https://doi.org/10.1007/s12079-011-0132-4

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Paolillo M, Colombo R, Serra M, Belvisi L, Papetti A, Ciusani E et al (2019) Stem-like cancer cells in a dynamic 3D culture system: a model to study metastatic cell adhesion and anti-cancer drugs. Cells. https://doi.org/10.3390/cells8111434

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Zhang C, Yang Z, Dong DL, Jang TS, Knowles JC, Kim HW et al (2020) 3D culture technologies of cancer stem cells: promising ex vivo tumor models. J Tissue Eng 11:204173142093340

    Article  Google Scholar 

  49. 49.

    Stankevicius V, Kunigenas L, Stankunas E, Kuodyte K, Strainiene E, Cicenas J et al (2017) The expression of cancer stem cell markers in human colorectal carcinoma cells in a microenvironment dependent manner. Biochem Biophys Res Commun 484:726–733. https://doi.org/10.1016/j.bbrc.2017.01.111

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Wohlleben G, Hauff K, Gasser M, Waaga-Gasser AM, Grimmig T, Flentje M et al (2018) Hypoxia induces differential expression patterns of osteopontin and CD44 in colorectal carcinoma. Oncol Rep 39:442–448. https://doi.org/10.3892/or.2017.6068

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Okada M, Kawai K, Sonoda H, Shiratori H, Kishikawa J, Nagata H et al (2021) Epithelial–mesenchymal transition and metastatic ability of CD133+ colorectal cancer stem-like cells under hypoxia. Oncol Lett 21:1–9. https://doi.org/10.3892/ol.2020.12280

    CAS  Article  Google Scholar 

  52. 52.

    Min SJ, Lim JY, Kim HR, Kim SJ, Kim Y (2015) Sasa quelpaertensis leaf extract inhibits colon cancer by regulating cancer cell stemness in vitro and in vivo. Int J Mol Sci 16:9976–9997. https://doi.org/10.3390/ijms16059976

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Wu C, Zhuang Y, Zhou J, Liu S, Wang R, Shu P (2019) Cinnamaldehyde enhances apoptotic effect of oxaliplatin and reverses epithelial-mesenchymal transition and stemnness in hypoxic colorectal cancer cells. Exp Cell Res 383:111500. https://doi.org/10.1016/j.yexcr.2019.111500

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Haynes J, McKee TD, Haller A, Wang Y, Leung C, Gendoo DMA et al (2018) Administration of hypoxia-activated prodrug evofosfamide after conventional adjuvant therapy enhances therapeutic outcome and targets cancer-initiating cells in preclinical models of colorectal cancer. Clin Cancer Res 24:2116–2127. https://doi.org/10.1158/1078-0432.CCR-17-1715

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Kotlarz A, Przybyszewska M, Swoboda P, Neska J, Miłoszewska J, Grygorowicz MA et al (2019) Imatinib inhibits the regrowth of human colon cancer cells after treatment with 5-FU and cooperates with vitamin D analogue PRI-2191 in the downregulation of expression of stemness-related genes in 5-FU refractory cells. J Steroid Biochem Mol Biol 189:48–62. https://doi.org/10.1016/j.jsbmb.2019.02.003

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Przybyszewska M, Miłoszewska J, Kotlarz A, Swoboda P, Pyśniak K, Szczepek W et al (2017) Imatinib inhibits the renewal and tumorigenicity of CT-26 colon cancer cells after cytoreductive treatment with doxorubicin. Arch Immunol Ther Exp (Warsz) 65:51–67. https://doi.org/10.1007/s00005-016-0391-0

    CAS  Article  Google Scholar 

  57. 57.

    To KKW, Poon DC, Wei Y, Wang F, Lin G, Fu LW (2015) Vatalanib sensitizes ABCB1 and ABCG2-overexpressing multidrug resistant colon cancer cells to chemotherapy under hypoxia. Biochem Pharmacol 97:27–37. https://doi.org/10.1016/j.bcp.2015.06.034

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Yoshii Y, Furukawa T, Matsumoto H, Yoshimoto M, Kiyono Y, Zhang MR et al (2016) 64Cu-ATSM therapy targets regions with activated DNA repair and enrichment of CD133+ cells in an HT-29 tumor model: sensitization with a nucleic acid antimetabolite. Cancer Lett 376:74–82. https://doi.org/10.1016/j.canlet.2016.03.020

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Lee YT, Tan YJ, Oon CE (2018) Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol 834:188–196. https://doi.org/10.1016/j.ejphar.2018.07.034

    CAS  Article  Google Scholar 

  60. 60.

    Piawah S, Venook AP (2019) Targeted therapy for colorectal cancer metastases: a review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer 125:4139–4147. https://doi.org/10.1002/cncr.32163

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful for Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro.

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This study was funded by Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro.

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Conceptualization: [MDAR], [ALM], [AAT]; Literature search, data analysis and manuscript draft: [MDAR]; Critical revision: [ALM], [AAT].

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Correspondence to Mateus de Almeida Rainho.

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Rainho, M.d.A., Mencalha, A.L. & Thole, A.A. Hypoxia effects on cancer stem cell phenotype in colorectal cancer: a mini-review. Mol Biol Rep (2021). https://doi.org/10.1007/s11033-021-06809-9

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Keywords

  • Colorectal cancer
  • Cancer stem cells
  • Hypoxia
  • Stem cell phenotype