- REHOVOT, Israel - Weizmann Institute researchers have discovered a molecular
mechanism that may be involved in causing colon cancer, according to a
study reported in the May 11 issue of the Proceedings of the National Academy
- This research may one day contribute
to the development of potential therapies for this type of malignancy and
possibly for other types of cancer as well.
- The discovery of the new mechanism has
solved two seemingly unrelated molecular mysteries.
- One concerned an important finding made
some two years ago: the fact that colon cancer cells often have abnormally
large quantities of a protein called beta- catenin, one of today's "hottest"
research molecules. Beta-catenin has been dubbed a"moonlighter"
because it holds down two distinct cellular jobs. In its better-known task,
beta-catenin binds to adhesion molecules - those molecules that sit in
the cellular membrane and allow cells to stick together. In its other role,
beta-catenin is known to regulate the performance of genes in the nucleus.
However, how exactly beta-catenin does this - and which genes it controls
- remained unclear.
- The second molecular mystery centered
around the gene cyclin D1 - a major regulator of cell growth which, when
mutated, can act as an oncogene, or gene that causes cancer. The levels
of the protein produced by this gene are abnormally high in about 30 percent
of colon cancers, indicating that cyclin D1 may be involved in malignant
transformation. However, the cyclin D1 gene found in colon cancer cells
is perfectly normal. This baffled researchers because usually oncogenes
cause cancer only when they appear in mutated form.
- A team of researchers led by Prof. Avri
Ben-Ze'ev of the Weizmann Institute's Molecular Cell Biology Department,
in collaboration with the group of Dr. Richard Pestell from the Albert
Einstein College of Medicine in New York, has now put these two mysterious
puzzle pieces together.
- In a test-tube study, the scientists
discovered how both beta-catenin and cyclin D1 are involved in causing
- First, the levels of beta-catenin increase
to excessively high levels in one of two different scenarios. In one case,
the beta-catenin gene itself is mutated. In the second case, a mutation
is found in adenomatous polyposis coli (APC), a well-known tumor-suppressor
gene that is mutated in about 90% of colon cancers. APC's major role in
the cell is to reduce the level of beta-catenin. When the APC gene is mutated,
beta-catenin accumulates to high levels and enters the nucleus.
- Upon entering the nucleus, beta-catenin
can directly activate the cyclin D1 gene, leading to an abnormal surge
in the production of the cyclin D1 protein. Since cyclin D1 is a major
regulator of cell growth, the result is uncontrolled cell proliferation.
This contributes to abnormal tissue growth and the creation of a tumor.
- "In most cases, tumor formation
is triggered by mutated genes. Therefore, it was unclear how completely
normal copies of the cyclin D1 gene could be involved in colon cancer,"
Ben-Ze'ev says. "Now we have shown that the 'guilty' mutation doesn't
have to appear in cyclin D1 itself, but may be found in other molecules
by which it is affected.
- "As for beta-catenin, we and other
researchers have long wanted to know what kind of signals it conveys to
the nuclei of cancer cells. Our study has made it possible to 'eavesdrop'
on one of these signals, and to show how certain colon cancers may develop."
- Ben-Ze'ev and his colleagues have also
demonstrated how this signaling mechanism can be blocked, a finding that
may some day be of use in the development of cancer therapy.
- In one approach, cyclin D1 activity was
diminished by introducing a nonmutated copy of the tumor-suppressor APC
gene into colon cancer cells. The "good" APC lowered beta-catenin
levels, stopping the abnormal stimulation of the cyclin D1 gene.
- In another experiment, the scientists
introduced an adhesion molecule called cadherin into colon cancer cells.
Cadherin is known to bind with beta-catenin at the outer periphery of the
cell. Through this binding action, the cadherin "trapped" beta-catenin,
preventing it from traveling to the nucleus and excessively stimulating
the production of the cyclin D1 protein. A patent application for this
method has been filed by Yeda Research and Development Co., the Weizmann
Institute's technology transfer arm.
- These types of intervention may provide
the basis for developing future therapies for colon cancer, as well as
for melanoma and other types of cancer in which the levels of beta-catenin
are abnormally elevated.
- Ben-Ze'ev's research team consisted of
Weizmann Institute postdoctoral fellow Michael Shtutman, graduate student
Jacob Zhurinsky and technical assistant Inbal Simcha. The group headed
by Dr. Richard Pestell at the Albert Einstein College of Medicine included
Dr. Chris Albanese and graduate student Mark D'Amico.
- At the time this study was conducted,
another research team, headed by Dr. Frank McCormick of the University
of California at San Francisco, independently achieved similar results,
pointing to the role of beta-catenin and cyclin D1 in colon cancer.
- Prof. Ben-Ze'ev holds the Lunenfeld-Kunin
Chair in Cell Biology and Genetics. This study was supported by the US-Israel
Binational Science Foundation, the German- Israeli Foundation for Scientific
Research and Development (GIF), the Cooperation Program in Cancer Research
sponsored by the German Cancer Research Center (DKFZ) and the Israel Ministry
of Science, and the Susan G. Komen Breast Cancer Foundation.
- Note: This story has been adapted from
a news release issued by Weizmann Institute for journalists and other members
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credit Weizmann Institute as the original source. You may also wish to
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