Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Clinical & Experimental Metastasis
Published in: Clinical & Experimental Metastasis 8/2007

01-11-2007 | Research Paper

Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer

Authors: Geert Berx, Eric Raspé, Gerhard Christofori, Jean Paul Thiery, Jonathan P. Sleeman

Published in: Clinical & Experimental Metastasis | Issue 8/2007

Login to get access

Abstract

EMT (epithelial–mesenchymal transition) is a morphogenetic process in which cells loose their epithelial characteristics and gain mesenchymal properties during embryogenesis. Similar processes regulated by similar pathways are recapitulated during tumour progression, endowing cells with invasive properties, thereby contributing to the formation of metastases. In this review, we outline key features of EMT and discuss the evidence for its involvement in the dissemination of tumours. Finally we review the recent literature concerning the mechanisms that regulate EMT in the tumour context, with a particular focus on breast cancer.
Literature
1.
Thiery JP (2002) Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454PubMedCrossRef
2.
Thiery JP, Sleeman JP (2006) Complex networks orchestrate epithelial–mesenchymal transitions. Nat Rev Mol Cell Biol 7:131–142PubMedCrossRef
3.
4.
Kalluri R, Neilson EG (2003) Epithelial–mesenchymal transition and its implications for fibrosis. J Clin Invest 112:1776–1784PubMed
5.
6.
Christ B, Ordahl CP (1995) Early stages of chick somite development. Anat Embryol (Berl) 191:381–396CrossRef
7.
Takahashi Y, Sato Y, Suetsugu R et al (2005) Mesenchymal-to-epithelial transition during somitic segmentation: a novel approach to studying the roles of Rho family GTPases in morphogenesis. Cells Tissues Organs 179:36–42PubMedCrossRef
8.
Horster MF, Braun GS, Huber SM (1999) Embryonic renal epithelia: induction, nephrogenesis, and cell differentiation. Physiol Rev 79:1157–1191PubMed
9.
Vainio S, Lin Y (2002) Coordinating early kidney development: lessons from gene targeting. Nat Rev Genet 3:533–543PubMedCrossRef
10.
Christiansen JJ, Rajasekaran AK (2006) Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Res 66:8319–8326PubMedCrossRef
11.
Nollet F, Kools P, van Roy F (2000) Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J Mol Biol 299:551–572PubMedCrossRef
12.
Shin K, Fogg VC, Margolis B (2006) Tight junctions and cell polarity. Annu Rev Cell Dev Biol 22:207–235PubMedCrossRef
13.
Yin T, Green KJ (2004) Regulation of desmosome assembly and adhesion. Semin Cell Dev Biol 15:665–677PubMed
14.
Aigner K, Dampier B, Descovich L et al (2007) The transcription factor ZEB1 (deltaEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity. Oncogene (Epub ahead of print)
15.
De Craene B, Gilbert B, Stove C et al (2005) The transcription factor snail induces tumor cell invasion through modulation of the epithelial cell differentiation program. Cancer Res 65:6237–6244PubMedCrossRef
16.
Ikenouchi J, Matsuda M, Furuse M et al (2003) Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci 116:1959–1967PubMedCrossRef
17.
Moreno-Bueno G, Cubillo E, Sarrio D et al (2006) Genetic profiling of epithelial cells expressing e-cadherin repressors reveals a distinct role for snail, slug, and e47 factors in epithelial–mesenchymal transition. Cancer Res 66:9543–9556PubMedCrossRef
18.
Vandewalle C, Comijn J, De Craene B et al (2005) SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell–cell junctions. Nucleic Acids Res 33:6566–6578PubMedCrossRef
19.
LaGamba D, Nawshad A, Hay ED (2005) Microarray analysis of gene expression during epithelial–mesenchymal transformation. Dev Dyn 234:132–142PubMedCrossRef
20.
Hay ED (2005) The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it. Dev Dyn 233:706–720PubMedCrossRef
21.
Andersen H, Mejlvang J, Mahmood S et al (2005) Immediate and delayed effects of E-cadherin inhibition on gene regulation and cell motility in human epidermoid carcinoma cells. Mol Cell Biol 25:9138–9150PubMedCrossRef
22.
Capaldo CT, Macara IG (2007) Depletion of E-cadherin disrupts establishment but not maintenance of cell junctions in Madin-Darby canine kidney epithelial cells. Mol Biol Cell 18:189–200PubMedCrossRef
23.
Neve RM, Chin K, Fridlyand J et al (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10:515–527PubMedCrossRef
24.
Perou CM, Sorlie T, Eisen MB et al (2000) Molecular portraits of human breast tumours. Nature 406:747–752PubMedCrossRef
25.
van de Wetering M, Barker N, Harkes IC et al (2001) Mutant E-cadherin breast cancer cells do not display constitutive Wnt signaling. Cancer Res 61:278–284PubMed
26.
Ferlicot S, Vincent-Salomon A, Medioni J et al (2004) Wide metastatic spreading in infiltrating lobular carcinoma of the breast. Eur J Cancer 40:336–341PubMedCrossRef
27.
Bierie B, Moses HL (2006) Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 6:506–520PubMedCrossRef
28.
29.
Bolos V, Grego-Bessa J, de la Pompa JL (2007) Notch signaling in development and cancer. Endocr Rev 28:339–363PubMedCrossRef
30.
31.
Evangelista M, Tian H, de Sauvage FJ (2006) The hedgehog signaling pathway in cancer. Clin Cancer Res 12:5924–5928PubMedCrossRef
32.
33.
Siegel PM, Massague J (2003) Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3:807–821PubMedCrossRef
34.
Huber MA, Kraut N, Beug H (2005) Molecular requirements for epithelial–mesenchymal transition during tumor progression. Curr Opin Cell Biol 17:548–558PubMedCrossRef
35.
Savagner P (2001) Leaving the neighborhood: molecular mechanisms involved during epithelial–mesenchymal transition. Bioessays 23:912–923PubMedCrossRef
36.
Berx G, Van Roy F (2001) The E-cadherin/catenin complex: an important gatekeeper in breast cancer tumorigenesis and malignant progression. Breast Cancer Res 3:289–293PubMedCrossRef
37.
Cano A, Perez-Moreno MA, Rodrigo I et al (2000) The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2:76–83PubMedCrossRef
38.
Venkov CD, Link AJ, Jennings JL et al (2007) A proximal activator of transcription in epithelial–mesenchymal transition. J Clin Invest 117:482–491PubMedCrossRef
39.
Perez-Moreno MA, Locascio A, Rodrigo I et al (2001) A new role for E12/E47 in the repression of E-cadherin expression and epithelial–mesenchymal transitions. J Biol Chem 276:27424–27431PubMedCrossRef
40.
Mani SA, Yang J, Brooks M et al (2007) Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA 104:10069–10074PubMedCrossRef
41.
Hartwell KA, Muir B, Reinhardt F et al (2006) The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proc Natl Acad Sci USA 103:18969–18974PubMedCrossRef
42.
Wu X, Chen H, Parker B et al (2006) HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial–mesenchymal transition. Cancer Res 66:9527–9534PubMedCrossRef
43.
Comijn J, Berx G, Vermassen P et al (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7:1267–1278PubMedCrossRef
44.
Battle MA, Konopka G, Parviz F et al (2006) Hepatocyte nuclear factor 4alpha orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc Natl Acad Sci USA 103:8419–8424PubMedCrossRef
45.
Hajra KM, Chen DY, Fearon ER (2002) The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 62:1613–1618PubMed
46.
Yang J, Mani SA, Donaher JL et al (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117:927–939PubMedCrossRef
47.
Eger A, Aigner K, Sonderegger S et al (2005) DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 24:2375–2385PubMedCrossRef
48.
Sleeman JP (2000) The lymph node as a bridgehead in the metastatic dissemination of tumors. Recent Results Cancer Res 157:55–81PubMed
49.
Peinado H, Marin F, Cubillo E et al (2004) Snail and E47 repressors of E-cadherin induce distinct invasive and angiogenic properties in vivo. J Cell Sci 117:2827–2839PubMedCrossRef
50.
Korsching E, Packeisen J, Liedtke C et al (2005) The origin of vimentin expression in invasive breast cancer: epithelial–mesenchymal transition, myoepithelial histogenesis or histogenesis from progenitor cells with bilinear differentiation potential? J Pathol 206:451–457PubMedCrossRef
51.
Petersen OW, Nielsen HL, Gudjonsson T et al (2003) Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. Am J Pathol 162:391–402PubMed
52.
Tarin D, Thompson EW, Newgreen DF (2005) The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res 65:5996–6000; discussion 6000–5991PubMedCrossRef
53.
De Craene B, van Roy F, Berx G (2005) Unraveling signalling cascades for the Snail family of transcription factors. Cell Signal 17:535–547PubMedCrossRef
54.
Valcourt U, Kowanetz M, Niimi H et al (2005) TGF-beta and the Smad signaling pathway support transcriptomic reprogramming during epithelial–mesenchymal cell transition. Mol Biol Cell 16:1987–2002PubMedCrossRef
55.
Zavadil J, Bitzer M, Liang D et al (2001) Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci USA 98:6686–6691PubMedCrossRef
56.
Jechlinger M, Sommer A, Moriggl R et al (2006) Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest 116:1561–1570PubMedCrossRef
57.
Huber MA, Azoitei N, Baumann B et al (2004) NF-kappaB is essential for epithelial–mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest 114:569–581PubMed
58.
Dong M, How T, Kirkbride KC et al (2007) The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest 117:206–217PubMedCrossRef
59.
Eccles SA, Welch DR (2007) Metastasis: recent discoveries and novel treatment strategies. Lancet 369:1742–1757PubMedCrossRef
60.
61.
Moody SE, Perez D, Pan TC et al (2005) The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8:197–209PubMedCrossRef
62.
Wilmut I, Schnieke AE, McWhir J et al (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385:810–813PubMedCrossRef
63.
Slack JM (2007) Metaplasia and transdifferentiation: from pure biology to the clinic. Nat Rev Mol Cell Biol 8:369–378PubMedCrossRef
64.
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRef
65.
Wernig M, Meissner A, Foreman R et al (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448:318–324PubMedCrossRef
66.
Hendrix MJ, Seftor EA, Seftor RE et al (2007) Reprogramming metastatic tumour cells with embryonic microenvironments. Nat Rev Cancer 7:246–255PubMedCrossRef
67.
Xue C, Plieth D, Venkov C et al (2003) The gatekeeper effect of epithelial–mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Res 63:3386–3394PubMed
68.
Derksen PW, Liu X, Saridin F et al (2006) Somatic inactivation of E-cadherin and p53 in mice leads to metastatic lobular mammary carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell 10:437–449PubMedCrossRef
69.
Wicki A, Lehembre F, Wick N et al (2006) Tumor invasion in the absence of epithelial–mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell 9:261–272PubMedCrossRef
70.
Friedl P, Hegerfeldt Y, Tusch M (2004) Collective cell migration in morphogenesis and cancer. Int J Dev Biol 48:441–449PubMedCrossRef
71.
Friedl P, Wolf K (2003) Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer 3:362–374PubMedCrossRef
72.
Friedl P, Wolf K (2003) Proteolytic and non-proteolytic migration of tumour cells and leucocytes. Biochem Soc Symp (70):277–285
73.
Wolf K, Friedl P (2006) Molecular mechanisms of cancer cell invasion and plasticity. Br J Dermatol 154(Suppl 1):11–15PubMedCrossRef
74.
Barrallo-Gimeno A, Nieto MA (2005) The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development 132:3151–3161PubMedCrossRef
75.
Thuault S, Valcourt U, Petersen M et al (2006) Transforming growth factor-beta employs HMGA2 to elicit epithelial–mesenchymal transition. J Cell Biol 174:175–183PubMedCrossRef
76.
Mironchik Y, Winnard PT Jr, Vesuna F et al (2005) Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res 65:10801–10809PubMedCrossRef
77.
78.
Radisky DC, Levy DD, Littlepage LE et al (2005) Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436:123–127PubMedCrossRef
79.
Sternlicht MD, Lochter A, Sympson CJ et al (1999) The stromal proteinase MMP3/stromelysin-1 promotes mammary carcinogenesis. Cell 98:137–146PubMedCrossRef
80.
Yang L, Lin C, Zhao S et al (2007) Phosphorylation of p68 RNA helicase plays a role in platelet-derived growth factor-induced cell proliferation by up-regulating cyclin D1 and c-Myc expression. J Biol Chem 282:16811–16819PubMedCrossRef
81.
Kim HJ, Litzenburger BC, Cui X et al (2007) Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and snail. Mol Cell Biol 27:3165–3175PubMedCrossRef
82.
Lopez T, Hanahan D (2002) Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 1:339–353PubMedCrossRef
83.
Yook JI, Li XY, Ota I et al (2006) A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol 8:1398–1406PubMedCrossRef
84.
Imanishi Y, Hu B, Jarzynka MJ et al (2007) Angiopoietin-2 stimulates breast cancer metastasis through the alpha(5)beta(1) integrin-mediated pathway. Cancer Res 67:4254–4263PubMedCrossRef
85.
Waerner T, Alacakaptan M, Tamir I et al (2006) ILEI: a cytokine essential for EMT, tumor formation, and late events in metastasis in epithelial cells. Cancer Cell 10:227–239PubMedCrossRef
86.
Grunert S, Jechlinger M, Beug H (2003) Diverse cellular and molecular mechanisms contribute to epithelial plasticity and metastasis. Nat Rev Mol Cell Biol 4:657–665PubMedCrossRef
87.
Janda E, Lehmann K, Killisch I et al (2002) Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. J Cell Biol 156:299–313PubMedCrossRef
88.
Zhu Y, Xu G, Patel A et al (2002) Cloning, expression, and initial characterization of a novel cytokine-like gene family. Genomics 80:144–150PubMedCrossRef
89.
Brabletz T, Jung A, Spaderna S et al (2005) Opinion: migrating cancer stem cells – an integrated concept of malignant tumour progression. Nat Rev Cancer 5:744–749PubMedCrossRef
90.
Breiteneder-Geleff S, Soleiman A, Kowalski H et al (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154:385–394PubMed
91.
Wicki A, Christofori G (2007) The potential role of podoplanin in tumour invasion. Br J Cancer 96:1–5PubMedCrossRef
92.
Scholl FG, Gamallo C, Vilaro S et al (1999) Identification of PA2.26 antigen as a novel cell-surface mucin-type glycoprotein that induces plasma membrane extensions and increased motility in keratinocytes. J Cell Sci 112(Pt 24):4601–4613
93.
Martin-Villar E, Scholl FG, Gamallo C et al (2005) Characterization of human PA2.26 antigen (T1alpha-2, podoplanin), a small membrane mucin induced in oral squamous cell carcinomas. Int J Cancer 113:899–910PubMedCrossRef
94.
Martin-Villar E, Megias D, Castel S et al (2006) Podoplanin binds ERM proteins to activate RhoA and promote epithelial–mesenchymal transition. J Cell Sci 119:4541–4553PubMedCrossRef
95.
Kunita A, Kashima TG, Morishita Y et al (2007) The platelet aggregation-inducing factor aggrus/podoplanin promotes pulmonary metastasis. Am J Pathol 170:1337–1347PubMedCrossRef
96.
Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284PubMedCrossRef
97.
Balic M, Lin H, Young L et al (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12:5615–5621PubMedCrossRef
98.
Dontu G, Al-Hajj M, Abdallah WM et al (2003) Stem cells in normal breast development and breast cancer. Cell Prolif 36(Suppl 1):59–72PubMedCrossRef
99.
Sheridan C, Kishimoto H, Fuchs RK et al (2006) CD44+/CD24− breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res 8:R59PubMedCrossRef
100.
Shipitsin M, Campbell LL, Argani P et al (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11:259–273PubMedCrossRef
101.
Sleeman KE, Kendrick H, Ashworth A et al (2006) CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Res 8:R7PubMedCrossRef
Metadata
Title
Pre-EMTing metastasis? Recapitulation of morphogenetic processes in cancer
Authors
Geert Berx
Eric Raspé
Gerhard Christofori
Jean Paul Thiery
Jonathan P. Sleeman
Publication date
01-11-2007
Publisher
Springer Netherlands
Published in
Clinical & Experimental Metastasis / Issue 8/2007
Print ISSN: 0262-0898
Electronic ISSN: 1573-7276
DOI
https://doi.org/10.1007/s10585-007-9114-6

Other articles of this Issue 8/2007

Clinical & Experimental Metastasis 8/2007 Go to the issue

Reseach Paper

Rho GTPases: functions and association with cancer

Research Paper

Gene arrays for diagnosis, prognosis and treatment of breast cancer metastasis

Review

New concepts in breast cancer metastasis: tumor initiating cells and the microenvironment

Research Paper

Understanding h-prune biology in the fight against cancer

Research Paper

Bone metastasis: pathogenesis and therapeutic implications

Research Paper

Advances in optical imaging and novel model systems for cancer metastasis research
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits