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New Insights on Metastasis Formation in Colon Cancer

Potential New Approach for Diagnosis and Treatment

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 β

normal'>-catenin / T-cell

factor (TCF) signaling in colon cancer

 

Short title: β-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 CancerCenter,

GeorgetownUniversity

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, MaxDelbrückCenter

for Molecular Medicine, Berlin, Germany

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC)
Berlin-Buch
Robert-Rössle-Straße 10
13125 Berlin
Germany
Phone.: +49 (0) 30 94 06 - 38 96
Fax:  +49 (0) 30 94
06 - 38 33
e-mail: presse@mdc-berlin.de
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