Hostname: page-component-7bb8b95d7b-dvmhs Total loading time: 0 Render date: 2024-09-12T09:42:19.000Z Has data issue: false hasContentIssue false

Epithelial, mesenchymal and hybrid epithelial/mesenchymal phenotypes and their clinical relevance in cancer metastasis

Published online by Cambridge University Press:  21 March 2017

Minal Garg*
Affiliation:
Department of Biochemistry, University of Lucknow, Lucknow – 226007, UP, India
*
*Corresponding author: Dr. Minal Garg, Department of Biochemistry, University of Lucknow, Lucknow – 226007, UP, India. E-mail: minal14@yahoo.com

Abstract

Cancer metastasis occurs through local invasion of circulating tumour cells (CTCs), intravasation, transportation to distant sites, and their extravasation followed by colonisation at secondary sites. Epithelial–mesenchymal transition (EMT) is a normal developmental phenomenon, but its aberrant activation confers tumour cells with enhanced cell motility, metastatic properties, resistant to therapies and cancer stem cell (CSC) phenotype in epithelium-derived carcinoma.

Experimental studies from various research papers have been reviewed to determine the factors, which interlink cancer stemness and cellular plasticity with EMT. Although existence of CSCs has been linked with EMT, nevertheless, there are controversies with the involvement of type of tumour cells, including cells with E (epithelial) and M (mesenchymal) phenotype alone or hybrid E/M phenotype in different types of cancers. Studies on CTCs with hybrid E/M phenotypes during different stages of cancer metastasis reveal strong association with tumour -initiation potential, cellular plasticity and types of cancer cells. Cells with the hybrid E/M state are strictly controlled by phenotypic stability factors coupled to core EMT decision-making circuits, miR200/ZEB and miR-34/Snail.

Understanding the regulatory functions of EMT program in cancer metastasis can help us to characterise the biomarkers of prognostic and therapeutic potential. These biomarkers when targeted may act as metastatic suppressors, inhibit cellular plasticity and stemness ability of tumour cells and can block metastatic growth.

Type
Review
Copyright
Copyright © Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1. Boyer, B. and Thiery, J.P. (1993) Epithelium-mesenchyme interconversion as example of epithelial plasticity. APMIS 101, 257-268 Google Scholar
2. Lim, J. and Thiery, J.P. (2012) Epithelial-mesenchymal transitions: insights from development. Development 139, 3471-3486 Google Scholar
3. Garg, M. (2013) Epithelial-mesenchymal transition – activating transcription factors – multifunctional regulators in cancer. World Journal of Stem Cells 5, 188-195 Google Scholar
4. Nieto, M.A. et al. (2016) EMT: 2016. Cell 166, 21-45 CrossRefGoogle ScholarPubMed
5. Kim, M.Y. et al. (2009) Tumor self-seeding by circulating cancer cells. Cell 139, 1315-1326 CrossRefGoogle ScholarPubMed
6. Eckert, M.A. et al. (2011) Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell 19, 372-386 Google Scholar
7. Attisano, L. and Wrana, J.L. (2002) Signal transduction by the TGF-beta superfamily. Science 296, 1646-1647 Google Scholar
8. Grünert, S., Jechlinger, M. and Beug, H. (2003) Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nature Reviews Molecular Cell Biology 4, 657-665 CrossRefGoogle ScholarPubMed
9. Gordon, M.D. and Nusse, R. (2006) Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. Journal of Biological Chemistry 281, 22429-22433 Google Scholar
10. Wang, Y. and Zhou, B.P. (2011) Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chinese Journal of Cancer 30, 603-611 Google Scholar
11. Feldmann, G. et al. (2007) Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Research 67, 2187-2196 Google Scholar
12. Varnat, F. et al. (2009) Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signaling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Molecular Medicine 1, 338-351 CrossRefGoogle ScholarPubMed
13. Wu, Y. et al. (2009) Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15, 416-428 Google Scholar
14. Li, C.W. et al. (2012) Epithelial-mesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1. Cancer Research 72, 1290-1300 Google Scholar
15. Mak, P. et al. (2010) ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell 17, 319-332 CrossRefGoogle ScholarPubMed
16. Kim, S. et al. (2016) PD-L1 expression is associated with epithelial- to-mesenchymal transition in adenocarcinoma of the lung. Human Pathology 58, 7-14 Google Scholar
17. Panková, K. et al. (2010) The molecular mechanisms of transition between mesenchymal and amoeboid invasiveness in tumor cells. Cellular and Molecular Life Science 67, 63-71 Google Scholar
18. Sánchez-Tilló, E. et al. (2012) EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cellular and Molecular Life Science 69, 3429-3456 CrossRefGoogle ScholarPubMed
19. Tian, X.J., Zhang, H. and Xing, J. (2013) Coupled reversible and irreversible bistable switches underlyingTGFβ-induced epithelial to mesenchymal transition. Biophysics Journal 105, 1079-1089 CrossRefGoogle ScholarPubMed
20. Jolly, MK. et al. (2016) Stability of the hybrid epithelial/mesenchymal phenotype. Oncotarget 7, 27067-27084.CrossRefGoogle ScholarPubMed
21. Grigore, A.D. et al. (2016) Tumor budding: the name is EMT. Partial EMT. Journal of Clinical Medicine 5, pii: E51Google Scholar
22. Ribeiro, A.S., Paredes, J. (2015) P-Cadherin linking breast cancer stem cells and invasion: a promising marker to identify an “Intermediate/Metastable” EMT State. Frontiers in Oncology 4, 371 Google Scholar
23. Boareto, M. et al. (2016) Notch-Jagged signaling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype. Journal of the Royal Society Interface 13, pii: 20151106CrossRefGoogle ScholarPubMed
24. Garg, M. (2015a) Targeting microRNAs in epithelial-to-mesenchymal transition-induced cancer stem cells: therapeutic approaches in cancer. Expert Opinion in Therapeutic Targets 19, 285-297 CrossRefGoogle ScholarPubMed
25. Diepenbruck, M., Christofori, G. (2016) Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Current Opinion in Cell Biology 43, 7-13 Google Scholar
26. Kurrey, N.K. et al. (2009) Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 27, 2059-2068 Google Scholar
27. Hwang, W.L. et al. (2011) SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology 141, 279-291, 291.e1-5CrossRefGoogle ScholarPubMed
28. Islam, S.S. et al. (2016) Sonic hedgehog (Shh) signaling promotes tumorigenicity and stemness via activation of epithelial- to-mesenchymal transition (EMT) in bladder cancer. Molecular Carcinogenesis 55, 537-551 CrossRefGoogle ScholarPubMed
29. Garg, M. (2015b) Urothelial cancer stem cells and epithelial plasticity: current concepts and therapeutic implications in bladder cancer. Cancer and Metastasis Reviews 34, 691-701 CrossRefGoogle ScholarPubMed
30. Wu, D. et al. (2016) Aldehyde dehydrogenase 3A1 is robustly upregulated in gastric cancer stem-like cells and associated with tumorigenesis. International Journal of Oncology 49, 611-622 CrossRefGoogle ScholarPubMed
31. Cao, X. et al. (2016) 7-Difluoromethoxyl-5,4’-di-n-octyl genistein inhibits the stem-like characteristics of gastric cancer stemlike cells and reverses the phenotype of epithelial- mesenchymal transition in gastric cancer cells. Oncology Reports 36, 1157-1165 CrossRefGoogle Scholar
32. Avtanski, D.B. et al. (2016) Indolo-pyrido-isoquinolin based alkaloid inhibits growth, invasion and migration of breast cancer cells via activation of p53-miR34a axis. Molecular Oncology 10, 1118-1132 Google Scholar
33. Grosse-Wilde, A. et al. (2015) Stemness of the hybrid epithelial/ mesenchymal state in breast cancer and its association with poor survival. PLoS ONE 10, e0126522 Google Scholar
34. Jiang, B. et al. (2016) The co-stimulatory molecule B7-H3 promotes the epithelial-mesenchymal transition in colorectal cancer. Oncotarget 7, 31755-31771 CrossRefGoogle ScholarPubMed
35. Moon, Y. et al. (2016) Effect of CD133 overexpression on the epithelial-to-mesenchymal transition in oral cancer cell lines. Clinical & Experimental Metastasis 33, 487-496 Google Scholar
36. Farhana, L. et al. (2016) Role of cancer stem cells in racial disparity in colorectal cancer. Cancer Medicine 5, 1268-1278.CrossRefGoogle ScholarPubMed
37. Zhang, Y. et al. (2016) Targeting IκB Kinase β/NF-κB signaling in human prostate cancer by a novel IκB Kinase β inhibitor Cmpd A. Mol Cancer Ther 15, 1504-1514 Google Scholar
38. Ombrato, L. and Malanchi, I. (2014) The EMT universe: space between cancer cell dissemination and metastasis initiation. Critical Reviews in Oncogenesis 19, 349-361 Google Scholar
39. Moyret-Lalle, C., Ruiz, E. and Puisieux, A. (2014) Epithelial mesenchymal transition transcription factors and miRNAs: “Plastic surgeons” of breast cancer. World Journal of Clinical Oncology 5, 311-322 Google Scholar
40. Strauss, R. et al. (2011) Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. PLoS ONE 6, e16186 Google Scholar
41. Ruscetti, M. et al. (2015) Tracking and functional characterization of epithelial-mesenchymal transition and mesenchymal tumor cells during prostate cancer metastasis. Cancer Research 75, 2749-2759 Google Scholar
42. Hendrix, M.J. et al. (1997) Experimental co-expression of vimentin and keratin intermediate filaments in human breast cancer cells results in phenotypic interconversion and increased invasive behavior. American Journal of Pathology 150, 483-495 Google Scholar
43. Jolly, M.K. et al. (2015) Coupling the modules of EMT and stemness: a tunable ‘stemness window’ model. Oncotarget. 6, 25161-25174 Google Scholar
44. Jolly, M.K. et al. (2014) Towards elucidating the connection between epithelial-mesenchymal transitions and stemness. Journal of the Royal Society Interface 11, 20140962CrossRefGoogle ScholarPubMed
45. Pasquier, J. et al. (2015) Epithelial to mesenchymal transition in a clinical perspective. Journal of Oncology 2015, 792182Google Scholar
46. Zou, X. et al. (2013) Up-regulation of type I collagen during tumorigenesis of colorectal cancer revealed by quantitative proteomic analysis. Journal of Proteomics 94, 473-485 Google Scholar
47. Jung, H.Y., Fattet, L., Yang, J. (2015) Molecular pathways: linking tumor microenvironment to epithelial-mesenchymal transition in metastasis. Clinical Cancer Research 21, 962-968 Google Scholar
48. Park, J., Schwarzbauer, J.E. (2014) Mammary epithelial cell interactions with fibronectin stimulate epithelial-mesenchymal transition. Oncogene 33, 1649-1657 Google Scholar
49. Huang, L., Wu, R.L. and Xu, A.M. (2015) Epithelial-mesenchymal transition in gastric cancer. American Journal of Translational Research 7, 2141-2158 Google Scholar
50. Lakis, S. et al. (2016) Interaction between beta-catenin and EGFR expression by mmunohistochemistry identifies prognostic subgroups in early high-risk triple-negative breast cancer. Anticancer Research 36, 2365-2378.Google Scholar
51. Zhou, J. et al. (2016) Notch and TGFβ form a positive regulatory loop and regulate EMT in epithelial ovarian cancer cells. Cell Signaling 28, 838-849 Google Scholar
52. Dang, T.T. et al. (2016) ΔNp63α induces the expression of FAT2 and Slug to promote tumor invasion. Oncotarget 7, 28592-611CrossRefGoogle ScholarPubMed
53. Ye, Z. et al. (2015) Expression of lncRNA-CCAT1, E-cadherin and N-cadherin in colorectal cancer and its clinical significance. International Journal of Clinical & Experimental Medicine 8, 3707-3715 Google Scholar
54. Kodama, T. et al. (2016) Transposon mutagenesis identifies genes and cellular processes driving epithelial-mesenchymal transition in hepatocellular carcinoma. PNAS USA 113, E3384-E3393CrossRefGoogle ScholarPubMed
55. Rojas-Puentes, L. et al. (2016) Epithelial-mesenchymal transition, proliferation, and angiogenesis in locally advanced cervical cancer treated with chemoradiotherapy. Cancer Medicine 5, 1989-99Google Scholar
56. Chiang, S.P., Cabrera, R.M. and Segall, J.E. (2016) Tumor cell intravasation. A review in the theme: cell and molecular processes in cancer metastasis. American Journal of Physiology Cell Physiology 309, C444-56Google Scholar
57. Ota, I. et al. (2009) Induction of a MT1-MMP and MT2-MMPdependent basement membrane transmigration program in cancer cells by Snail. PNAS USA 106, 20318-20323 Google Scholar
58. Matrone, M.A. et al. (2010) Microtentacles tip the balance of cytoskeletal forces in circulating tumor cells. Cancer Research 70, 7737-7741 Google Scholar
59. Whipple, R.A. et al. (2010) Epithelial-to-mesenchymal transition promotes tubulin detyrosination and microtentacles that enhance endothelial engagement. Cancer Research 70, 8127-8137 CrossRefGoogle ScholarPubMed
60. Wu, S. et al. (2015) Classification of circulating tumor cells by epithelial-mesenchymal transition markers. PLoS ONE 10, e0123976 Google ScholarPubMed
61. Lecharpentier, A. et al. (2011) Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. British Journal of Cancer 105, 1338-1341 Google Scholar
62. Lindsay, C.R. et al. (2016) Vimentin and Ki67 expression in circulating tumour cells derived from castrate-resistant prostate cancer. BMC Cancer 16, 168 Google Scholar
63. Cierna, Z. et al. (2014) Matrix metalloproteinase 1 and circulating tumor cells in early breast cancer. BMC Cancer 14, 472 Google Scholar
64. Bock, C. et al. (2014) Distinct expression of cytokeratin, N-cadherin and CD133 in circulating tumor cells of metastatic breast cancer patients. Future Oncology 10, 1751-1765 Google Scholar
65. Li, Y.M. et al. (2013) Epithelial-mesenchymal transition markers expressed in circulating tumor cells in hepatocellular carcinoma patients with different stages of disease. Cell Death & Disease 4, e831 Google Scholar
66. Armstrong, A.J. et al. (2011) Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Molecular Cancer Research 9, 997-1007 Google Scholar
67. Wang, L. et al. (2015) Down-regulation of prostate stem cell antigen (PSCA) by Slug promotes metastasis in nasopharyngeal carcinoma. Journal of Pathology 237, 411-422 Google Scholar
68. Mendoza, A. et al. (2010) Modeling metastasis biology and therapy in real time in the mouse lung. Journal of Clinical Investigation 120, 2979-2988 CrossRefGoogle ScholarPubMed
69. Stoletov, K. et al. (2010) Visualizing extravasation dynamics of metastatic tumor cells. Journal of Cell Science 123(Pt 13), 2332-2341 Google Scholar
70. Shibue, T. et al. (2012) The outgrowth of micrometastases is enabled by the formation of filopodium-like protrusions. Cancer Discovery 2, 706-721 Google Scholar
71. Cameron, M.D. et al. (2000) Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency. Cancer Research 60, 2541-2546 Google Scholar
72. Hamilton, G. et al. (2016) Small cell lung cancer: circulating tumor cells of extended stage patients express a mesenchymal-epithelial transition phenotype. Cell Adhesion & Migration 10, 360-7Google Scholar
73. Yuan, J.H. et al. (2014) A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell 25, 666-681 Google Scholar
74. Sun, C. et al. (2013) NANOG promotes liver cancer cell invasion by inducing epithelial-mesenchymal transition through NODAL/SMAD3 signaling pathway. International Journal of Biochemistry & Cell Biology 45, 1099-1108 Google Scholar
75. Ocaña, O.H. et al. (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709-724 Google Scholar
76. Dai, X. et al. (2013) OCT4 regulates epithelial-mesenchymal transition and its knockdown inhibits colorectal cancer cell migration and invasion. Oncology Reports 29, 155-160 Google Scholar
77. Vafaizadeh, V. et al. (2012) Transforming growth factor β signaling regulates the invasiveness of normal mammary epithelial cells and the metastasis formation of tumor cells. Hormone Molecular Biology and Clinical Investigation 10, 227-239 Google Scholar
78. Breiman, A. et al. (2016) Carcinoma-associated fucosylated antigens are markers of the epithelial state and can contribute to cell adhesion through CLEC17A (Prolectin). Oncotarget 7, 14064-14082 Google Scholar
79. Sabbah, M. et al. (2008) Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resistance Updates 11, 123-151 Google Scholar