Discovery Of Mechanism Causing Colon Cancer

May 11, 1999

REHOVOT, Israel - May 11, 1999 -WeizmannInstitute 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 of Sciences.

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 colon cancer.

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.

American Committee for the Weizmann Institute of Science

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