Epithelial-zu-mesenchymale Transition (EMT) – Neue molekulare Einsichten in die Tumorprogression

Zusammenfassung

Die maligne Progression gynäkologischer Tumoren wird wesentlich durch ihr Invasions- und Metastasierungsverhalten bestimmt. Es bedarf verschiedener Veränderungen auf molekularer und zellulärer Ebene, damit sich Krebszellen aus dem epithelialen Zellverband lösen und in die Umgebung invadieren bzw. metastasieren können. Für beide Prozesse müssen Tumorzellen die Fähigkeit erwerben, von einem epithelialen in einen mesenchymalen Zustand überzugehen, einen Vorgang, den man als epithelial-zu-mesenchymale Transition (EMT) bezeichnet. In dieser Arbeit beschreiben wir die Bedeutung der EMT für gynäkologische Karzinome anhand aktueller Forschungsergebnisse. In den hier betrachteten Malignomen – Mamma-, Ovarial- und Zervixkarzinom – wurde eine Vielzahl von EMT-typischen Veränderungen beschrieben. Dabei waren der Verlust epithelialer Marker (E-Cadherin, Zytokeratine) und die Zunahme mesenchymaler Marker (z. B. N-Cadherin, Vimentin) charakteristisch. Auch Transkriptionsfaktoren der EMT wie Snail und Twist wurden in verschiedenen Tumorentitäten nachgewiesen. Als wesentliche Stimuli der EMT gelten Wachstumsfaktoren (z. B. TGF-β), WNT- und Notch-Signaling sowie Tumorhypoxie. Typische EMT-Veränderungen lassen sich in gynäkologischen Malignomen nachweisen und man muss davon ausgehen, dass auch in diesen Karzinomen Invasions- und Metastasierungsvorgänge – und damit die maligne Progression – durch EMT getriggert werden. Aus der genauen Analyse der EMT lassen sich neue molekulare Targets für eine gezielte Tumortherapie identifizieren.

Abstract

The malignant progression of gynecologic tumors is determined by their potential for invasion and metastasis. Specifically, epithelial tumor cells need to leave the primary tumor mass to invade the environment and/or metastasize to distant regions. To do so, these tumor cells undergo distinct changes from an epithelial to a mesenchymal phenotype, a process called epithelial-to-mesenchymal transition (EMT). In this article, we review the significance of EMT-related mechanisms in gynecologic malignancies. For the cancers considered here – breast, ovarian and cervical carcinomas – a multitude of EMT events have been described, including the loss of epithelial markers (E-cadherin, cytokeratines) and an increase in mesenchymal markers (e.g. N-cadherin, vimentin). In addition, the expression of the EMT transcription factors Snail and Twist has been observed in different malignancies. EMT can be induced by several stimuli, e.g. growth factors, WNT and notch signaling as well as tumor hypoxia, a common feature of solid tumors. Characteristic EMT-related changes can be detected in gynecologic cancers, suggesting a role for EMT in triggering invasion, metastasis and, therefore, malignant progression in these tumor entities. Further investigation of EMT pathways will result in the identification of new targets for tailored cancer therapies.

Schlüsselwörter

epithelial‐zu‐mesenchymale Transition - Hypoxie - Mammakarzinom - Zervixkarzinom - Ovarialkarzinom

Key words

epithelial‐to‐mesenchymal transition - hypoxia - breast cancer - cervical cancer - ovarian cancer

Literatur

• 1 Thiery J P. Epithelial-mesenchymal transitions in tumour progression.  Nat Rev Cancer. 2002;  2 442-454
• 2 Yang J, Weinberg R A. Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis.  Dev Cell. 2008;  14 818-829
• 3 Iwano M. Emt and tgf-beta in renal fibrosis.  Front Biosci (Schol Ed). 2010;  2 229-238
• 4 Yap A S, Brieher W M, Gumbiner B M. Molecular and functional analysis of cadherin-based adherens junctions.  Annu Rev Cell Dev Biol. 1997;  13 119-146
• 5 Boyer B, Thiery J P. Epithelium-mesenchyme interconversion as example of epithelial plasticity.  APMIS. 1993;  101 257-268
• 6 Hay E D. An overview of epithelio-mesenchymal transformation.  Acta Anat (Basel). 1995;  154 8-20
• 7 Brizel D M, Scully S P, Harrelson J M et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma.  Cancer Res. 1996;  56 941-943
• 8 Hockel M, Schlenger K, Aral B et al. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix.  Cancer Res. 1996;  56 4509-4515
• 9 Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck.  Radiother Oncol. 1996;  41 31-39
• 10 Chan D A, Giaccia A J. Hypoxia, gene expression, and metastasis.  Cancer Metastasis Rev. 2007;  26 333-339
• 11 Leo C, Giaccia A J, Denko N C. The hypoxic tumor microenvironment and gene expression.  Semin Radiat Oncol. 2004;  14 207-214
• 12 Erler J T, Bennewith K L, Nicolau M et al. Lysyl oxidase is essential for hypoxia-induced metastasis.  Nature. 2006;  440 1222-1226
• 13 Peinado H, Olmeda D, Cano A. Snail, zeb and bhlh factors in tumour progression: An alliance against the epithelial phenotype?.  Nat Rev Cancer. 2007;  7 415-428
• 14 Erler J T, Giaccia A J. Lysyl oxidase mediates hypoxic control of metastasis.  Cancer Res. 2006;  66 10238-10241
• 15 Yang M H, Wu M Z, Chiou S H et al. Direct regulation of twist by hif-1alpha promotes metastasis.  Nat Cell Biol. 2008;  10 295-305
• 16 Mani S A, Guo W, Liao M J et al. The epithelial-mesenchymal transition generates cells with properties of stem cells.  Cell. 2008;  133 704-715
• 17 Battula V L, Evans K W, Hollier B G et al. Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells.  Stem Cells. 2010;  28 1435-1445
• 18 Sarrio D, Rodriguez-Pinilla S M, Hardisson D et al. Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype.  Cancer Res. 2008;  68 989-997
• 19 Park D, Karesen R, Axcrona U et al. Expression pattern of adhesion molecules (e-cadherin, alpha-, beta-, gamma-catenin and claudin-7), their influence on survival in primary breast carcinoma, and their corresponding axillary lymph node metastasis.  APMIS. 2007;  115 52-65
• 20 Yoder B J, Wilkinson E J, Massoll N A. Molecular and morphologic distinctions between infiltrating ductal and lobular carcinoma of the breast.  Breast J. 2007;  13 172-179
• 21 Mohammadizadeh F, Ghasemibasir H, Rajabi P et al. Correlation of e-cadherin expression and routine immunohistochemistry panel in breast invasive ductal carcinoma.  Cancer Biomark. 2009;  5 1-8
• 22 Baranwal S, Alahari S K. Molecular mechanisms controlling e-cadherin expression in breast cancer.  Biochem Biophys Res Commun. 2009;  384 6-11
• 23 Hazan R B, Qiao R, Keren R et al. Cadherin switch in tumor progression.  Ann N Y Acad Sci. 2004;  1014 155-163
• 24 Knudsen K A, Wheelock M J. Cadherins and the mammary gland.  J Cell Biochem. 2005;  95 488-496
• 25 Mariotti A, Perotti A, Sessa C et al. N-cadherin as a therapeutic target in cancer.  Expert Opin Investig Drugs. 2007;  16 451-465
• 26 Aktas B, Tewes M, Fehm T et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients.  Breast Cancer Res. 2009;  11 R46
• 27 Salamanca C M, Maines-Bandiera S L, Leung P C et al. Effects of epidermal growth factor/hydrocortisone on the growth and differentiation of human ovarian surface epithelium.  J Soc Gynecol Investig. 2004;  11 241-251
• 28 Sundfeldt K. Cell-cell adhesion in the normal ovary and ovarian tumors of epithelial origin; an exception to the rule.  Mol Cell Endocrinol. 2003;  202 89-96
• 29 Davidson B, Nielsen S, Christensen J et al. The role of desmin and n-cadherin in effusion cytology: A comparative study using established markers of mesothelial and epithelial cells.  Am J Surg Pathol. 2001;  25 1405-1412
• 30 Kurrey N K, K A, Bapat S A. Snail and slug are major determinants of ovarian cancer invasiveness at the transcription level.  Gynecol Oncol. 2005;  97 155-165
• 31 Bagnato A, Salani D, Di Castro V et al. Expression of endothelin 1 and endothelin a receptor in ovarian carcinoma: Evidence for an autocrine role in tumor growth.  Cancer Res. 1999;  59 720-727
• 32 Rosano L, Spinella F, Di Castro V et al. Endothelin-1 promotes epithelial-to-mesenchymal transition in human ovarian cancer cells.  Cancer Res. 2005;  65 11649-11657
• 33 Del Bufalo D, Di Castro V, Biroccio A et al. Endothelin-1 protects ovarian carcinoma cells against paclitaxel-induced apoptosis: Requirement for akt activation.  Mol Pharmacol. 2002;  61 524-532
• 34 Lee M Y, Chou C Y, Tang M J et al. Epithelial-mesenchymal transition in cervical cancer: Correlation with tumor progression, epidermal growth factor receptor overexpression, and snail up-regulation.  Clin Cancer Res. 2008;  14 4743-4750
• 35 Hagemann T, Bozanovic T, Hooper S et al. Molecular profiling of cervical cancer progression.  Br J Cancer. 2007;  96 321-328
• 36 Leo C, Horn L C, Einenkel J et al. Tumor hypoxia and expression of c-met in cervical cancer.  Gynecol Oncol. 2007;  104 181-185
• 37 Horn L C, Fischer U, Raptis G et al. Pattern of invasion is of prognostic value in surgically treated cervical cancer patients.  Gynecol Oncol. 2006;  103 906-911