Institut für Pathologie
Trogerstrasse 18
D-81675 München
The lab page of Karl-Friedrich Becker
- Epithelial mesenchymal transition regulators
in tumorigenesis -
Group members mainly involved: Kareen Blechschmidt, Catarina Alves
Supported by:
Deutsche Krebshilfe
Marie Curie Training Site Munich
Background
Role of epithelial-mesenchymal-transition regulators in tumor cell invasion.
Expression of the transcription factors Snail and Slug, major regulators of epithelial-mesenchymal-transition (EMT), in E-cadherin positive epithelial cells results in downregulation of the cell adhesion molecule and the cells become invasive. Thus, Snail and Slug as well as additional EMT regulators (e.g. Sip1) could be markers of malignancy. For primary tumors only a few studies integrating expression of several EMT regulators have been reported so far.
Summary of project 1
Clinical significance of the epithelial-mesenchymal-transition regulators snail, sip1, and twist in gastrointestinal cancers
Recent reports have highlighted the role of epithelial mesenchymal transition (EMT) regulators snail and sip1 as strong direct transcriptional repressors of the cell adhesion molecule and tumor/invasion suppressor gene E-cadherin in tumor cell lines, thus inducing tumor cell invasion and metastasis Additionally, the transcription factor twist has been proposed to be involved in this process, as it is known as an activator of N-cadherin. N–cadherin enhances cell motility of various tumor cells and may even overcome strong E-cadherin dependent cell-cell contacts. E-cadherin alterations have been investigated extensively in many tumors by us and others, but to our knowledge no information is available for expression patterns and clinical significance of these EMT regulators in case-matched primary human gastrointestinal cancers (gastric, esophagous, and colon carcinomas). Consequently, the aim of our study is to better understand the role of EMT regulators in human carcinogenesis.
To evaluate the correlation between sip1, snail, twist, E- and N-cadherin expression and to elucidate their role in gastrointestinal cancers a total of 150 primary tumors (50 gastric, 50 esophageal, and 50 colon carcinomas) versus matched non-tumorous tissue from the same patients will be examined by quantitative real-time RT-PCR (QRT-PCR). In addition, monoclonal antibodies against these transcription factors will be generated and used to evalute the immunoreactivity of the proteins. The expression pattern (mRNA/Protein) of the EMT regulators and their intracellular localization will be compared to expression of E- and N-cadherin and correlated to histopathological parameters (grading, histological classification).
Summary of project 2
Functional analysis of the E-cadherin repressor Slug in gastric cancer
In collaboration with Prof. Dr. Fatima Carneiro, Institute of Molecular Pathology and Immunology of the University of Porto
Epithelial-mesenchymal transition (EMT) involving down-regulation of E-cadherin is known to play an important role in tumour progression. The aim of our study was to investigate the mRNA expression of two EMT regulators-Slug and E12/E47-in primary human gastric carcinomas and to compare this with the expression of E-cadherin and other EMT regulators (Snail, Twist, and SIP1). We studied a series of 59 gastric carcinomas by real-time quantitative RT-PCR in formalin-fixed and paraffin-embedded tissues. Thirty-four cases (58%) showed Slug up-regulation in the tumour; reduced or negative expression of E-cadherin was present in 24 of these (71%, p < 0.0001). Twenty-one cases (36%) showed E12/E47 up-regulation that was not significantly associated with E-cadherin down-regulation (p = 0.5734). Slug up-regulation accompanied by E-cadherin down-regulation correlated with the presence of distant metastases (p = 0.0029) and with advanced pTNM stages (p = 0.0424). A statistically significant association was found between Slug up-regulation and the expression of SIP1 in intestinal (p = 0.0014) and Snail in diffuse (p = 0.0067) carcinomas. We present the first study integrating the analysis of several EMT regulators in primary gastric carcinomas and conclude that Slug up-regulation is associated with E-cadherin down-regulation in diffuse and intestinal-type gastric carcinoma, and that this effect could be complemented by the presence of other EMT regulators.
© 2003-2006 Dr. Karl-Friedrich Becker, Institut für Pathologie, TU München
Monoclonal antibody against human Snail reacting with the active (nuclear) form
References
Rosivatz E, Becker KF, Kremmer E, Schott C, Blechschmidt K, Hofler H, Sarbia
M.
Expression and nuclear localization of Snail, an E-cadherin repressor, in
adenocarcinomas of the upper gastrointestinal tract.
Virchows Arch. 2006 Mar;448(3):277-87. Epub 2005 Nov 17
Rosivatz E, Becker I, Bamba M, Schott C, Diebold J, Mayr D, Hofler H, Becker KF. Neoexpression of N-cadherin in E-cadherin positive colon cancers. Int J Cancer. 2004 Sep 20;111(5):711-9
Rosivatz E, Becker I, Specht K, Fricke E, Luber B, Busch R, Hofler H, Becker KF. Differential expression of the epithelial mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am J Pathol. 2002 Nov;161(5):1881-91
Alves CC, Rosivatz E, Schott C, Hollweck R, Becker I, Sarbia M, Carneiro F,
Becker KF.
Slug is overexpressed in gastric carcinomas and may act synergistically with
SIP1 and Snail in the down-regulation of E-cadherin.
J Pathol. 2007 Feb 13;211(5):507-515 [Epub ahead of print]