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The prognosis for colon cancer depends on whether the tumor develops metastases. New insights on metastasis formation in colon cancer gained by researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch, the Robert Rössle Cancer Clinic in Berlin-Buch (both in Germany), and the National Cancer Institute (NCI), in Frederick, Maryland (USA) will open up an important new approach for colon cancer diagnosis and treatment. The paper describing this research by Assistant Professor Ulrike Stein, Professor Peter M. Schlag, and Professor Walter Birchmeier of MDC and the Rössle Cancer Clinic and Dr. Robert H. Shoemaker of the NCI has just been published in the American Journal Gastroenterology (Vol. 131, Issue 5, pp. 1486 - 1500).
The researchers were able to demonstrate that the S100A4/metastasin gene, which controls the proliferation and invasion of tumor cells, is regulated by a specific signaling cascade that scientists have named the beta catenin/TCF signaling cascade. This regulation is directly related to colon cancer metastasis formation.
In microarray studies, S100A4/metastasin was identified as the gene most strongly expressed by the mutated beta-catenin protein. One of the functions of beta-catenin is to regulate cellular adhesion. If it becomes mutated, cells dissociate from their neighboring cells and are thus able to migrate and settle in other organs and form metastases.
Ulrike Stein and her colleagues were able to identify the binding site on the S100A4/metastasin gene for the mutated beta-catenin protein from where it regulates the gene. The expression of the S100A4/metastasin gene triggered by beta-catenin leads to increased migration and to invasion of tumor cells. If this signaling chain is interrupted, the tumor cells can no longer migrate.
In animal experiments, it was shown that switching on the S100A4 gene greatly increases the rate of metastasis. This finding was substantiated over the course of the disease in colon cancer patients. Patients with elevated S100A4/metastasin levels in tumor biopsy samples were more likely to get metastases in the liver or lung.
The findings of the scientists in Berlin and Frederick demonstrate the interconnection of two previously unrelated cellular programs which have been shown to be important for tumor progression and metastasis formation: the beta catenin/TCF signaling pathway and the S100A4/metastasin gene, which controls migration and invasion.
To reduce or inhibit the development of metastases in colon cancer, the research group in Berlin-Buch is currently carrying out further testing of new therapeutic intervention strategies targeting beta catenin/TCF regulation.
*The metastasis-associated gene S100A4 is a novel target of beta-catenin / T-cell factor (TCF) signaling in colon cancer
Short title: beta-catenin/TCF regulates S100A4
Authors:
Ulrike Stein, PhD1, Franziska Arlt1, Wolfgang Walther, PhD1, Janice Smith1, Todd Waldman, MD, PhD2, Erik D. Harris3, Susan D. Mertins, PhD4, Claus W. Heizmann, PhD5, David Allard, PhD6, Walter Birchmeier, PhD7, Peter M. Schlag, MD, PhD1, and Robert H. Shoemaker, PhD4
1Department of Surgery and Surgical Oncology, Robert Rössle Cancer Clinic, Charité Campus Buch, and Max Delbrück Center for Molecular Medicine, Berlin, Germany;
2Lombardi Cancer Center, Georgetown University School of Medicine, Washington, DC;
3SAIC-Frederick, National Cancer Institute-Frederick, Frederick, MD;
4Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute-Frederick, Frederick, MD;
5Department of Pediatrics, Division of Clinical Chemistry and Biochemistry, University of Zurich, Zurich, Switzerland;
6Cancer and Polio Fund Laboratories, Biosciences Building, University of Liverpool, Liverpool, UK;
7Department of Cancer Research, Max Delbrück Center for Molecular Medicine, Berlin, Germany
Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
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Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de
http://www.mdc-berlin.de/englisch/about_the_mdc/public_relations/e_index.htm
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