Jan. 6, 2004 Weizmann Institute scientists have succeeded in reversing the metastatic properties of colon cancer cells, in vitro. The findings, published in the Nov. 24 issue of The Journal of Cell Biology, uncover a key process involved in the metastasis of colon cancer cells and raise hopes that target-specific drugs might be devised to prevent, or reverse, the invasive behavior of metastatic colon cancer cells. Colon cancer is the second most prevalent type of cancer in men and third in women in the Western world.
The researchers, headed by Prof. Avri Ben-Ze'ev of the Molecular Cell Biology Department, have confirmed that the invasive behavior of colon cancer cells results from the malfunction of adhesion-related ("cell-gluing") mechanisms.
Cells are held together by "adhesive molecules," including two key molecules called beta-catenin and E-cadherin, which are found near the surfaces of cells. Beta-catenin also has another function: when inside the nuclei of cells, it regulates the expression of genes. Beta-catenin is known to be involved in various cancers, including colon cancer, by aberrantly activating genes whose identity is mostly unclear. In previous research, Ben-Ze'ev's team identified several such genes that are involved in the progression of human melanoma and colon cancer.
Now, the scientists have found that when a colon cancer cell becomes metastatic, abnormally large amounts of beta-catenin are found in its nucleus and, unexpectedly, they bring about a reduction in adhesion. The cell can thus break loose from the tissue and migrate to form another tumor at a distant site.
Beta-catenin in the nucleus does this by activating a gene called Slug. Slug inhibits the production of beta-catenin's partner in cell adhesion, E-cadherin. The shortage of E-cadherin prevents the cell from adhering to adjacent cells. The cell takes on a boat-like shape and, leaving the pack, invades neighboring tissues until it enters the bloodstream. This migrating cancer cell can, in time, form a new tumor by entering distant tissue via the bloodstream and multiplying there.
Ben-Ze'ev's team discovered that when such a colon cancer cell becomes surrounded by other such cells in a crowded environment (whether in the body or in the lab), minute quantities of E-cadherin in the cell recruit beta-catenin from the nucleus and can thus begin the process of binding together.
Lower levels of beta-catenin in the nucleus result in decreased Slug production (and increased E-cadherin production). As a result, the cells stick together and form a tissue-like organization – losing their metastatic properties. This is precisely the process that the scientists hope to be able to induce in patients to block metastasis.
"The fact that the invasive process in colon cancer can be reversed is surprising," says Ben-Ze'ev. "It offers hope of reversing the metastatic process or even preventing it in the future by designing a drug that targets Slug."
Prof. Avri Ben-Ze'ev's research is supported by the M.D. Moross Institute for Cancer Research, the Yad Abraham Center for Cancer Diagnostics and Therapy, and the late Maria Zondek. Prof. Ben-Ze'ev is the incumbent of the Samuel Lunenfeld-Reuben Kunin Chair of Genetics.
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