New Insights on Metastasis Formation in Colon Cancer
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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