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Published online: 2024-05-31

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Role of epithelial-to-mesenchymal transition and cancer stem cells in colorectal cancer

Marta Fudalej12, Agata Mormul3, Andrzej Deptała12, Anna M. Badowska-Kozakiewicz1
DOI: 10.5603/ocp.99669

Abstract

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths. To properly investigate the biology of the tumor and the molecular mechanisms leading to cancer progression or treatment resistance, it seems imperative to explore the key pathways like epithelial-to-mesenchymal transition (EMT) and cancer stem cells (CSCs). This review aimed to collect up-to-date knowledge on the subject of EMT and CSC in colorectal malignancies. In CRC, both EMT and CSC are associated with aggressive tumor behavior, metastases, cancer recurrence, and chemotherapy resistance. Due to their close relationship, the potential for targeting these pathways as therapeutic interventions is promising. However, direct usage of EMT and CSCs as therapeutic targets requires further investigation. Future studies should focus on unraveling the complex mechanisms underlying EMT and CSC involvement in CRC progression and developing tailored therapeutic strategies with acceptable toxicity profiles and minimal adverse events.

Keywords: colorectal cancerepithelial-to-mesenchymal transitioncancer stem cells

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References

  1. Baidoun F, Elshiwy K, Elkeraie Y, et al. Colorectal Cancer Epidemiology: Recent Trends and Impact on Outcomes. Curr Drug Targets. 2021; 22(9): 998–1009.
    CrossRefPubMed
  2. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3): 209–249.
    CrossRefPubMed
  3. Dekker E, Tanis P, Vleugels J, et al. Colorectal cancer. The Lancet. 2019; 394(10207): 1467–1480.
    CrossRef
  4. Li J, Ma X, Chakravarti D, et al. Genetic and biological hallmarks of colorectal cancer. Genes Dev. 2021; 35(11-12): 787–820.
    CrossRefPubMed
  5. Sninsky JA, Shore BM, Lupu GV, et al. Risk Factors for Colorectal Polyps and Cancer. Gastrointest Endosc Clin N Am. 2022; 32(2): 195–213.
    CrossRefPubMed
  6. O'Sullivan DE, Sutherland RL, Town S, et al. Risk Factors for Early-Onset Colorectal Cancer: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2022; 20(6): 1229–1240.e5.
    CrossRefPubMed
  7. Sawicki T, Ruszkowska M, Danielewicz A, et al. A Review of Colorectal Cancer in Terms of Epidemiology, Risk Factors, Development, Symptoms and Diagnosis. Cancers (Basel). 2021; 13(9).
    CrossRefPubMed
  8. Simon K. Colorectal cancer development and advances in screening. Clin Interv Aging. 2016; 11: 967–976.
    CrossRefPubMed
  9. Grady WM, Markowitz SD. The molecular pathogenesis of colorectal cancer and its potential application to colorectal cancer screening. Dig Dis Sci. 2015; 60(3): 762–772.
    CrossRefPubMed
  10. Medema JP. Cancer stem cells: the challenges ahead. Nat Cell Biol. 2013; 15(4): 338–344.
    CrossRefPubMed
  11. Vermani L, Kumar R, Kannan RR, et al. Expression pattern of ALDH1, E-cadherin, Vimentin and Twist in early and late onset sporadic colorectal cancer. Biomark Med. 2020; 14(14): 1371–1382.
    CrossRefPubMed
  12. Zhang Y, Weinberg RA. Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. Front Med. 2018; 12(4): 361–373.
    CrossRefPubMed
  13. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019; 20(2): 69–84.
    CrossRefPubMed
  14. Nieto MA, Huang RYJ, Jackson RA, et al. EMT: 2016. Cell. 2016; 166(1): 21–45.
    CrossRefPubMed
  15. Mittal V. Epithelial Mesenchymal Transition in Tumor Metastasis. Annu Rev Pathol. 2018; 13: 395–412.
    CrossRefPubMed
  16. Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014; 15(3): 178–196.
    CrossRefPubMed
  17. Cho ES, Kang HE, Kim NH, et al. Therapeutic implications of cancer epithelial-mesenchymal transition (EMT). Arch Pharm Res. 2019; 42(1): 14–24.
    CrossRefPubMed
  18. Zhang JX, Mai SJ, Huang XX, et al. MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of β-catenin signaling. Ann Oncol. 2014; 25(11): 2196–2204.
    CrossRefPubMed
  19. Qi L, Sun B, Liu Z, et al. Wnt3a expression is associated with epithelial-mesenchymal transition and promotes colon cancer progression. J Exp Clin Cancer Res. 2014; 33(1): 107.
    CrossRefPubMed
  20. Ahmadiankia N, Khosravi A. Significance of epithelial-to-mesenchymal transition inducing transcription factors in predicting distance metastasis and survival in patients with colorectal cancer: A systematic review and meta-analysis. J Res Med Sci. 2020; 25: 60.
    CrossRefPubMed
  21. Toiyama Y, Yasuda H, Saigusa S, et al. Increased expression of Slug and Vimentin as novel predictive biomarkers for lymph node metastasis and poor prognosis in colorectal cancer. Carcinogenesis. 2013; 34(11): 2548–2557.
    CrossRefPubMed
  22. Shioiri M, Shida T, Koda K, et al. Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Br J Cancer. 2006; 94(12): 1816–1822.
    CrossRefPubMed
  23. Prall F. Tumour budding in colorectal carcinoma. Histopathology. 2006; 50(1): 151–162.
    CrossRef
  24. De Smedt L, Palmans S, Sagaert X. Tumour budding in colorectal cancer: what do we know and what can we do? Virchows Arch. 2016; 468(4): 397–408.
    CrossRefPubMed
  25. Cao H, Xu E, Liu H, et al. Epithelial-mesenchymal transition in colorectal cancer metastasis: A system review. Pathol Res Pract. 2015; 211(8): 557–569.
    CrossRefPubMed
  26. Dallas NA, Xia L, Fan F, et al. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res. 2009; 69(5): 1951–1957.
    CrossRefPubMed
  27. Yang AD, Fan F, Camp ER, et al. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006; 12(14 Pt 1): 4147–4153.
    CrossRefPubMed
  28. Guo C, Ma J, Deng G, et al. ZEB1 Promotes Oxaliplatin Resistance through the Induction of Epithelial - Mesenchymal Transition in Colon Cancer Cells. J Cancer. 2017; 8(17): 3555–3566.
    CrossRefPubMed
  29. Escalante PI, Quiñones LA, Contreras HR, et al. Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX. Pharmaceutics. 2021; 13(1): 1376638.
    CrossRefPubMed
  30. Jiao L, Li DD, Yang CL, et al. Reactive oxygen species mediate oxaliplatin-induced epithelial-mesenchymal transition and invasive potential in colon cancer. Tumour Biol. 2016; 37(6): 8413–8423.
    CrossRefPubMed
  31. Trumpp A, Wiestler OD. Mechanisms of Disease: cancer stem cells--targeting the evil twin. Nat Clin Pract Oncol. 2008; 5(6): 337–347.
    CrossRefPubMed
  32. Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693): 544–548.
    CrossRefPubMed
  33. Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018; 554(7693): 538–543.
    CrossRefPubMed
  34. Strosberg JR, Yeatman T, Weber J, et al. A phase II study of RO4929097 in metastatic colorectal cancer. Eur J Cancer. 2012; 48(7): 997–1003.
    CrossRefPubMed
  35. Krop I, Demuth T, Guthrie T, et al. Phase I pharmacologic and pharmacodynamic study of the gamma secretase (Notch) inhibitor MK-0752 in adult patients with advanced solid tumors. J Clin Oncol. 2012; 30(19): 2307–2313.
    CrossRefPubMed
  36. van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008; 65(23): 3756–3788.
    CrossRefPubMed
  37. Daulagala AC, Bridges MC, Kourtidis A. E-cadherin Beyond Structure: A Signaling Hub in Colon Homeostasis and Disease. Int J Mol Sci. 2019; 20(11).
    CrossRefPubMed
  38. Jiang WG, Mansel RE. E-cadherin complex and its abnormalities in human breast cancer. Surg Oncol. 2000; 9(4): 151–171.
    CrossRefPubMed
  39. Coopman P, Djiane A. Adherens Junction and E-Cadherin complex regulation by epithelial polarity. Cell Mol Life Sci. 2016; 73(18): 3535–3553.
    CrossRefPubMed
  40. Bure IV, Nemtsova MV, Zaletaev DV. Roles of E-cadherin and Noncoding RNAs in the Epithelial-mesenchymal Transition and Progression in Gastric Cancer. Int J Mol Sci. 2019; 20(12).
    CrossRefPubMed
  41. Canel M, Serrels A, Frame MC, et al. E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci. 2013; 126(Pt 2): 393–401.
    CrossRefPubMed
  42. He X, Chen Z, Jia M, et al. Downregulated E-cadherin expression indicates worse prognosis in Asian patients with colorectal cancer: evidence from meta-analysis. PLoS One. 2013; 8(7): e70858.
    CrossRefPubMed
  43. Palaghia M, Mihai C, Lozneanu L, et al. E-cadherin expression in primary colorectal cancer and metastatic lymph nodes. Rom J Morphol Embryol. 2016; 57(1): 205–209.
    PubMed
  44. Chang K, Jiang L, Sun Y, et al. Effect of E-cadherin on Prognosis of Colorectal Cancer: A Meta-Analysis Update. Mol Diagn Ther. 2022; 26(4): 397–409.
    CrossRefPubMed
  45. Hu Y, Dai M, Zheng Y, et al. Epigenetic suppression of E-cadherin expression by Snail2 during the metastasis of colorectal cancer. Clin Epigenetics. 2018; 10(1): 154.
    CrossRefPubMed
  46. Rubinstein MR, Wang X, Liu W, et al. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe. 2013; 14(2): 195–206.
    CrossRefPubMed
  47. Tamura S, Isobe T, Ariyama H, et al. E‑cadherin regulates proliferation of colorectal cancer stem cells through NANOG. Oncol Rep. 2018; 40(2): 693–703.
    CrossRefPubMed
  48. Huntly BJP, Gilliland DG. Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer. 2005; 5(4): 311–321.
    CrossRefPubMed
  49. Munro MJ, Wickremesekera SK, Peng L, et al. Cancer stem cells in colorectal cancer: a review. J Clin Pathol. 2018; 71(2): 110–116.
    CrossRefPubMed
  50. Reya T, Morrison SJ, Clarke MF, et al. Stem cells, cancer, and cancer stem cells. Nature. 2001; 414(6859): 105–111.
    CrossRefPubMed
  51. Chen Ke, Huang Yh, Chen Jl. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin. 2013; 34(6): 732–740.
    CrossRefPubMed
  52. Abdullah LN, Chow EKH. Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med. 2013; 2(1): 3.
    CrossRefPubMed
  53. Rich J. Cancer stem cells. Medicine. 2016; 95(1S): S1.
    CrossRef
  54. Brabletz T, Jung A, Spaderna S, et al. Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005; 5(9): 744–749.
    CrossRefPubMed
  55. Walcher L, Kistenmacher AK, Suo H, et al. Cancer Stem Cells-Origins and Biomarkers: Perspectives for Targeted Personalized Therapies. Front Immunol. 2020; 11: 1280.
    CrossRefPubMed
  56. Phi LT, Sari IN, Yang YG, et al. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int. 2018; 2018: 5416923.
    CrossRefPubMed
  57. Garcia-Mayea Y, Mir C, Masson F, et al. Insights into new mechanisms and models of cancer stem cell multidrug resistance. Semin Cancer Biol. 2020; 60: 166–180.
    CrossRefPubMed
  58. Cherciu I, Bărbălan A, Pirici D, et al. Stem cells, colorectal cancer and cancer stem cell markers correlations. Curr Health Sci J. 2014; 40(3): 153–161.
  59. Conciatori F, Bazzichetto C, Falcone I, et al. Colorectal cancer stem cells properties and features: evidence of interleukin-8 involvement. Cancer Drug Resist. 2019; 2(4): 968–979.
    CrossRefPubMed
  60. Ohta Y, Fujii M, Takahashi S, et al. Visualization and targeting of LGR5 human colon cancer stem cells. Nature. 2017; 545(7653): 187–192.
    CrossRefPubMed
  61. Angius A, Scanu AM, Arru C, et al. Portrait of Cancer Stem Cells on Colorectal Cancer: Molecular Biomarkers, Signaling Pathways and miRNAome. Int J Mol Sci. 2021; 22(4).
    CrossRefPubMed
  62. Lei X, He Q, Li Z, et al. Cancer stem cells in colorectal cancer and the association with chemotherapy resistance. Med Oncol. 2021; 38(4): 43.
    CrossRefPubMed
  63. Jeong S, Yun HK, Jeong YA, et al. Cannabidiol-induced apoptosis is mediated by activation of Noxa in human colorectal cancer cells. Cancer Lett. 2019; 447: 12–23.
    CrossRefPubMed
  64. Ma YS, Li W, Liu Yu, et al. Targeting Colorectal Cancer Stem Cells as an Effective Treatment for Colorectal Cancer. Technol Cancer Res Treat. 2020; 19: 1533033819892261.
    CrossRefPubMed
  65. Gupta R, Bhatt LK, Johnston TP, et al. Colon cancer stem cells: Potential target for the treatment of colorectal cancer. Cancer Biol Ther. 2019; 20(8): 1068–1082.
    CrossRefPubMed
  66. Sophos NA, Vasiliou V. Aldehyde dehydrogenase gene superfamily: the 2002 update. Chem Biol Interact. 2003; 143-144: 5–22.
    CrossRefPubMed
  67. Tomita H, Tanaka K, Tanaka T, et al. Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget. 2016; 7(10): 11018–11032.
    CrossRefPubMed
  68. Li B, Yang K, Liang D, et al. Discovery and development of selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors. Eur J Med Chem. 2021; 209: 112940.
    CrossRefPubMed
  69. Morgan CA, Hurley TD. Characterization of two distinct structural classes of selective aldehyde dehydrogenase 1A1 inhibitors. J Med Chem. 2015; 58(4): 1964–1975.
    CrossRefPubMed
  70. Zhou JH, Hanna EY, Roberts D, et al. ALDH1 immunohistochemical expression and its significance in salivary adenoid cystic carcinoma. Head Neck. 2013; 35(4): 575–578.
    CrossRefPubMed
  71. Wei D, Peng JJ, Gao H, et al. ALDH1 Expression and the Prognosis of Lung Cancer: A Systematic Review and Meta-Analysis. Heart Lung Circ. 2015; 24(8): 780–788.
    CrossRefPubMed
  72. Panigoro SS, Kurnia D, Kurnia A, et al. ALDH1 Cancer Stem Cell Marker as a Prognostic Factor in Triple-Negative Breast Cancer. Int J Surg Oncol. 2020; 2020: 7863243.
    CrossRefPubMed
  73. Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev Rep. 2011; 7(2): 292–306.
    CrossRefPubMed
  74. Chen J, Xia Q, Jiang B, et al. Prognostic Value of Cancer Stem Cell Marker ALDH1 Expression in Colorectal Cancer: A Systematic Review and Meta-Analysis. PLoS One. 2015; 10(12): e0145164.
    CrossRefPubMed
  75. Mohamed SY, Kaf RM, Ahmed MM, et al. The Prognostic Value of Cancer Stem Cell Markers (Notch1, ALDH1, and CD44) in Primary Colorectal Carcinoma. J Gastrointest Cancer. 2019; 50(4): 824–837.
    CrossRefPubMed
  76. Holah NS, Aiad HAE, Asaad NY, et al. Evaluation of the Role of ALDH1 as Cancer Stem Cell Marker in Colorectal Carcinoma: An Immunohistochemical Study. J Clin Diagn Res. 2017; 11(1): EC17–EC23.
    CrossRefPubMed
  77. Deng Y, Zhou J, Fang L, et al. ALDH1 is an independent prognostic factor for patients with stages II-III rectal cancer after receiving radiochemotherapy. Br J Cancer. 2014; 110(2): 430–434.
    CrossRefPubMed
  78. Deng S, Yang X, Lassus H, et al. Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers. PLoS One. 2010; 5(4): e10277.
    CrossRefPubMed
  79. Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat Rev Clin Oncol. 2017; 14(10): 611–629.
    CrossRefPubMed
  80. Tanabe S, Quader S, Cabral H, et al. Interplay of EMT and CSC in Cancer and the Potential Therapeutic Strategies. Front Pharmacol. 2020; 11: 904.
    CrossRefPubMed
  81. Shibue T, Brooks MW, Inan MF, et al. The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discov. 2012; 2(8): 706–721.
    CrossRefPubMed
  82. Shibue T, Brooks MW, Weinberg RA. An integrin-linked machinery of cytoskeletal regulation that enables experimental tumor initiation and metastatic colonization. Cancer Cell. 2013; 24(4): 481–498.
    CrossRefPubMed
  83. Song Y, Chen Y, Li Y, et al. Resveratrol Suppresses Epithelial-Mesenchymal Transition in GBM by Regulating Smad-Dependent Signaling. Biomed Res Int. 2019; 2019: 1321973.
    CrossRefPubMed
  84. Babaei G, Aziz SGG, Jaghi NZ. EMT, cancer stem cells and autophagy; The three main axes of metastasis. Biomed Pharmacother. 2021; 133: 110909.
    CrossRefPubMed
  85. Choi JiE, Bae JS, Kang MJ, et al. Expression of epithelial-mesenchymal transition and cancer stem cell markers in colorectal adenocarcinoma: Clinicopathological significance. Oncol Rep. 2017; 38(3): 1695–1705.
    CrossRefPubMed
  86. Yan X, Liu L, Li H, et al. Clinical significance of , epithelial-mesenchymal transition, and cancer stem cell markers in stage III/IV colorectal cancer patients. Onco Targets Ther. 2017; 10: 5031–5046.
    CrossRefPubMed
  87. Li Y, Wang W, Wu M, et al. LncRNA LINC01315 silencing modulates cancer stem cell properties and epithelial-to-mesenchymal transition in colorectal cancer via miR-484/DLK1 axis. Cell Cycle. 2022; 21(8): 851–873.
    CrossRefPubMed
  88. Wang JJ, Chong QY, Sun XB, et al. Autocrine hGH stimulates oncogenicity, epithelial-mesenchymal transition and cancer stem cell-like behavior in human colorectal carcinoma. Oncotarget. 2017; 8(61): 103900–103918.
    CrossRefPubMed

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