August 19, 2002

Weizmann researchers have discovered a key molecule that could be used to suppress the replication of cancer cells.A research team from Weizmann Institute of Science in Rehovot, Israel, has discovered a process by which the coded information of a gene “expressed” in cells helps to drive the progression of cancer.

The team, led by Weizmann researcher Avri Ben-Ze’ev, considers the discovery a key milestone in the analysis of how cancer cells replicate and an important insight into the genetics of the disease that may serve as a foundation for the development of new cancer drugs.

Cancer can result from what scientists call the “overexpression” of certain genes, called oncogenes, which are responsible for normal cell growth. When these genes are overexpressed, the body’s cells multiply incessantly, threatening eventually to consume their host.

Several years ago, Ben-Ze’ev discovered that when a certain protein, known as B-catenin, is overexpressed in either normal or cancerous cells, the proteins unexpectedly gather in the cell’s nucleus rather than on the cell surface. Ben-Ze’ev inferred from this that the overexpression of this protein activates genes that lead to uncontrolled cell proliferation.

Many scientists have tried to identify which of the genes activated by B-catenin gives the cell a tendency to develop tumors.

“We expected to find genes that directly regulate cell proliferation. But much to our surprise, using various methods, we found that (the gene) Nr-CAM, that was thought to be expressed only in brain cells, was at the top of the list. No one knew it was involved in (cancer),” Ben-Ze’ev said.

Ben-Ze’ev and Weizmann Ph.D. student Maralice Conacci-Sorrell found that it is possible to induce the Nr-CAM gene in experiments by expressing B-catenin in a variety of cell types.

The next step was to directly introduce Nr-CAM into cells that do not normally express the gene in order to observe its effects. The process resulted in the enhanced ability of the cell to move spontaneously, and an improved ability to close artificial wounds, but also demonstrated a dangerous tendency for the cells to multiply rather than to stop proliferating. In addition, cells expressing Nr-CAM gained a new capacity to form tumors when injected into lab animals, confirming the gene’s involvement in the growth of cancer.

To address the relationship between Nr-CAM and B-catenin and its applicability to human cancer, Ben-Ze’ev and Conacci-Sorrell moved on to human melanoma (skin cancer) and colon cancer cells. In melanoma, they found that these cells express a great deal of Nr-CAM. Using cell lines from patients displaying different stages of melanoma development, they found that the quantity of Nr-CAM present in the cells correlated neatly with the development of cancer in the cells.

Ben-Ze’ev and his team then injected human melanoma cells displaying different levels of Nr-CAM into mice and again found a clear correlation between the presence of the protein and the ability to form rapidly growing tumors. In addition, they were able to arrest the movement of melanoma cells in culture by adding an antibody that blocked the part of the Nr-CAM molecule that protrudes from the cell surface – a result that has implications for the treatment of melanoma.

The team then moved on to study colon cancer tissue samples, since B-catenin is hyperactive in the vast majority of colon cancers. After analyzing 12 tissue samples, they found a 100 percent correlation between Nr-CAM expression and tumor formation: Nr-CAM was present in all the tissue samples from the tumors and in none of the normal samples.

From this data, Ben-Ze’ev concluded that Nr-CAM, a molecule not previously known to play a role in the development of cancer, is a target gene induced by B-catenin to promote uncontrolled cell proliferation.

“Since B-catenin is hyperactive to different degrees in almost every type of cancer, the discovery of Nr-CAM as a target for suppressing these cancers is very promising,” Ben-Ze’ev said. “We were especially excited when we could demonstrate its potential relevance to some of the most prevalent types of cancer in the Western world – melanoma and colon carcinoma.”

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