Home LiteratureArticle Details
PMID: 23201165 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis.

Cancer cell ·Vol. 22 ·No. 6 ·2012-12-11 ·Pages 725-36

Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J

Abstract

Epithelial-mesenchymal transition (EMT) is implicated in converting stationary epithelial tumor cells into motile mesenchymal cells during metastasis. However, the involvement of EMT in metastasis is still controversial, due to the lack of a mesenchymal phenotype in human carcinoma metastases. Using a spontaneous squamous cell carcinoma mouse model, we show that activation of the EMT-inducing transcription factor Twist1 is sufficient to promote carcinoma cells to undergo EMT and disseminate into blood circulation. Importantly, in distant sites, turning off Twist1 to allow reversion of EMT is essential for disseminated tumor cells to proliferate and form metastases. Our study demonstrates in vivo the requirement of "reversible EMT" in tumor metastasis and may resolve the controversy on the importance of EMT in carcinoma metastasis.

MeSH Terms
Animals Breast Neoplasms/genetics,metabolism,pathology Carcinoma, Squamous Cell/genetics,metabolism,pathology,secondary Cell Proliferation Epithelial Cells/metabolism,pathology Epithelial-Mesenchymal Transition/genetics,physiology Female Humans Lung Neoplasms/genetics,metabolism,pathology,secondary Mice Neoplasm Invasiveness Neoplasm Metastasis Nuclear Proteins/genetics,metabolism Transcription Factors/genetics,metabolism Twist-Related Protein 1/genetics,metabolism
Chemicals
Nuclear Proteins TWIST1 protein, human Transcription Factors Twist-Related Protein 1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Tsai Jeff H
Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
Donaher Joana Liu
Murphy Danielle A
Chau Sandra
Yang Jing
References (59)
59 references, click to expand
  1. Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients.
    Breast Cancer Res. 2011 Jun 10;13(3):R59 PMID: 21663619
  2. Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis.
    J Clin Invest. 2005 Jul;115(7):1714-23 PMID: 15937546
  3. High expression of Snail mRNA in blood from hepatocellular carcinoma patients with extra-hepatic metastasis.
    Clin Exp Metastasis. 2009;26(7):759-67 PMID: 19533388
  4. Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth.
    Cancer Res. 2008 Dec 15;68(24):10377-86 PMID: 19074907
  5. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression.
    Nat Cell Biol. 2000 Feb;2(2):76-83 PMID: 10655586
  6. Epithelial-mesenchymal transitions in development and disease.
    Cell. 2009 Nov 25;139(5):871-90 PMID: 19945376
  7. Multistage carcinogenesis in mouse skin.
    Pharmacol Ther. 1992;54(1):63-128 PMID: 1528955
  8. Role of Twist in head and neck carcinoma with lymph node metastasis.
    Anticancer Res. 2008 Mar-Apr;28(2B):1355-9 PMID: 18505078
  9. Twist1-induced invadopodia formation promotes tumor metastasis.
    Cancer Cell. 2011 Mar 8;19(3):372-86 PMID: 21397860
  10. Metastatic inefficiency: the scientific basis for resection of liver metastases from colorectal cancer.
    J Surg Oncol Suppl. 1993;3:158-60 PMID: 8503973
  11. Modeling metastasis biology and therapy in real time in the mouse lung.
    J Clin Invest. 2010 Aug;120(8):2979-88 PMID: 20644255
  12. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells.
    Oncogene. 2005 Mar 31;24(14):2375-85 PMID: 15674322
  13. Long term survival following the detection of circulating tumour cells in head and neck squamous cell carcinoma.
    BMC Cancer. 2009 Dec 06;9:424 PMID: 19961621
  14. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers.
    Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10069-74 PMID: 17537911
  15. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells.
    Nat Cell Biol. 2000 Feb;2(2):84-9 PMID: 10655587
  16. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?
    Nat Rev Cancer. 2007 Jun;7(6):415-28 PMID: 17508028
  17. Efficient method to generate single-copy transgenic mice by site-specific integration in embryonic stem cells.
    Genesis. 2006 Jan;44(1):23-8 PMID: 16400644
  18. Does tumour dormancy offer a therapeutic target?
    Nat Rev Cancer. 2010 Dec;10(12):871-7 PMID: 21048784
  19. Snail blocks the cell cycle and confers resistance to cell death.
    Genes Dev. 2004 May 15;18(10):1131-43 PMID: 15155580
  20. An overview of epithelio-mesenchymal transformation.
    Acta Anat (Basel). 1995;154(1):8-20 PMID: 8714286
  21. Circulating tumor cells as a window on metastasis biology in lung cancer.
    Am J Pathol. 2011 Mar;178(3):989-96 PMID: 21356352
  22. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion.
    Mol Cell. 2001 Jun;7(6):1267-78 PMID: 11430829
  23. The basics of epithelial-mesenchymal transition.
    J Clin Invest. 2009 Jun;119(6):1420-8 PMID: 19487818
  24. Temporal progression of metastasis in lung: cell survival, dormancy, and location dependence of metastatic inefficiency.
    Cancer Res. 2000 May 1;60(9):2541-6 PMID: 10811137
  25. Epithelial mesenchymal transition traits in human breast cancer cell lines.
    Clin Exp Metastasis. 2008;25(6):629-42 PMID: 18461285
  26. Twist, an independent prognostic marker for predicting distant metastasis and survival rates of esophageal squamous cell carcinoma patients.
    Clin Exp Metastasis. 2009;26(8):1025-32 PMID: 19816777
  27. Breast cancer cells isolated by chemotaxis from primary tumors show increased survival and resistance to chemotherapy.
    Cancer Res. 2004 Nov 1;64(21):7664-7 PMID: 15520165
  28. Multistep skin cancer in mice as a model to study the evolution of cancer cells.
    Semin Cancer Biol. 2005 Dec;15(6):460-73 PMID: 16039870
  29. Significance of Twist expression and its association with E-cadherin in esophageal squamous cell carcinoma.
    J Exp Clin Cancer Res. 2009 Dec 21;28:158 PMID: 20025748
  30. Circulating tumor cells in patients with breast cancer dormancy.
    Clin Cancer Res. 2004 Dec 15;10(24):8152-62 PMID: 15623589
  31. Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells.
    J Clin Invest. 2012 May;122(5):1849-68 PMID: 22505459
  32. Epithelial cells in the peripheral blood of patients with cancer of the head and neck: incidence, detection and possible clinical significance.
    Radiother Oncol. 2001 May;59(2):213-7 PMID: 11325451
  33. Isolation and molecular profiling of bone marrow micrometastases identifies TWIST1 as a marker of early tumor relapse in breast cancer patients.
    Clin Cancer Res. 2007 Sep 1;13(17):5001-9 PMID: 17785550
  34. Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer.
    Nat Rev Cancer. 2006 Jul;6(7):506-20 PMID: 16794634
  35. Systemic spread is an early step in breast cancer.
    Cancer Cell. 2008 Jan;13(1):58-68 PMID: 18167340
  36. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition.
    Mol Cancer. 2010 Jul 07;9:179 PMID: 20609236
  37. Correlation of increased twist with lymph node metastasis in patients with oral squamous cell carcinoma.
    J Oral Maxillofac Surg. 2012 Jun;70(6):1473-9 PMID: 21864967
  38. Identification and testing of a gene expression signature of invasive carcinoma cells within primary mammary tumors.
    Cancer Res. 2004 Dec 1;64(23):8585-94 PMID: 15574765
  39. Epithelial--mesenchymal and mesenchymal--epithelial transitions in carcinoma progression.
    J Cell Physiol. 2007 Nov;213(2):374-83 PMID: 17680632
  40. Metastatic inefficiency.
    Adv Cancer Res. 1990;54:159-211 PMID: 1688681
  41. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition?
    Cancer Res. 2005 Jul 15;65(14):5991-5; discussion 5995 PMID: 16024595
  42. PRAK is essential for ras-induced senescence and tumor suppression.
    Cell. 2007 Jan 26;128(2):295-308 PMID: 17254968
  43. Inducible expression of transforming growth factor beta1 in papillomas causes rapid metastasis.
    Cancer Res. 2001 Oct 15;61(20):7435-43 PMID: 11606377
  44. Significance of circulating tumor cells in patients with squamous cell carcinoma of the head and neck: initial results.
    Arch Otolaryngol Head Neck Surg. 2010 Dec;136(12):1274-9 PMID: 21173379
  45. Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial-mesenchymal transition.
    Cancer Cell. 2009 May 5;15(5):402-15 PMID: 19411069
  46. Cancer theory faces doubts.
    Nature. 2011 Apr 21;472(7343):273 PMID: 21512545
  47. Stem-cell hierarchy in skin cancer.
    Nat Rev Cancer. 2003 Jun;3(6):434-43 PMID: 12778133
  48. Upregulation of Twist in oesophageal squamous cell carcinoma is associated with neoplastic transformation and distant metastasis.
    J Clin Pathol. 2007 May;60(5):510-4 PMID: 16822877
  49. Epithelial-mesenchymal transitions in tumour progression.
    Nat Rev Cancer. 2002 Jun;2(6):442-54 PMID: 12189386
  50. The fallacy of epithelial mesenchymal transition in neoplasia.
    Cancer Res. 2005 Jul 15;65(14):5996-6000; discussion 6000-1 PMID: 16024596
  51. Multi-stage chemical carcinogenesis in mouse skin: fundamentals and applications.
    Nat Protoc. 2009;4(9):1350-62 PMID: 19713956
  52. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases.
    Am J Pathol. 1998 Sep;153(3):865-73 PMID: 9736035
  53. EMT and dissemination precede pancreatic tumor formation.
    Cell. 2012 Jan 20;148(1-2):349-61 PMID: 22265420
  54. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis.
    Cell. 2004 Jun 25;117(7):927-39 PMID: 15210113
  55. Epithelial-to-mesenchymal transition is important to metastasis, but questions remain.
    J Natl Cancer Inst. 2008 Feb 20;100(4):232-3, 239 PMID: 18270330
  56. Dissemination and growth of cancer cells in metastatic sites.
    Nat Rev Cancer. 2002 Aug;2(8):563-72 PMID: 12154349
  57. The SLUG zinc-finger protein represses E-cadherin in breast cancer.
    Cancer Res. 2002 Mar 15;62(6):1613-8 PMID: 11912130
  58. Conditional gene expression in the epidermis of transgenic mice using the tetracycline-regulated transactivators tTA and rTA linked to the keratin 5 promoter.
    J Invest Dermatol. 2000 Nov;115(5):788-94 PMID: 11069615
  59. Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression.
    Clin Exp Metastasis. 2008;25(6):643-55 PMID: 18398687
Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2012.09.022
Published
2012-12-11
Epub
2012-00-29
Pages
725-36
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3522773
Subset
IM
Grants
NCI NIH HHS · T32 CA121938 · United States
NCI NIH HHS · P30 CA23100 · United States
NCI NIH HHS · P30 CA023100 · United States
NIH HHS · DP2 OD002420-01 · United States
NIH HHS · DP2 OD002420 · United States
Corrections
CommentIn
PMID: 23258155
External Links
PubMed source DOI: 10.1016/j.ccr.2012.09.022 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2