“The fact that the invasive process in colon cancer can be reversed is surprising,” said chief researcher Avri Ben-Ze’evScientists at the Weizmann Institute have succeeded in reversing the ability of colon cancer cells to enter the blood stream and spread to other parts of the body, in laboratory experiments on animals.

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 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, killing 30,000 people annually. It is lethal largely because tumor cells easily migrate to other parts of the body.

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 including beta-catenin. This can lead to cells breaking loose from tissue and migrating to form another tumor in another part of the colon, and can result in rival e-cadherin molecules being overwhelmed by beta-catenin, activating a cancerous gene known as Slug.

But the researchers found that by supplementing e-cadherin molecules in parts of the colon they can subsequently reverse the process and make the cells stick together again.

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.

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,” said 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.”