Research at the Weizmann Institute reveals a genetic mechanism involved in the formation of colon cancer metastases, and contributes to the understanding of the processes responsible for its violent outbreak
Colorectal cancer is one of the most common types of cancer in the Western world and in Israel. The tumor, which begins its life as a small bump, or a wound in the intestine, later becomes an invasive and violent cancer, when the main damage is caused by metastases that reach the liver. A study by Prof. Avri Ben-Zev and a research student from his group, Dr. Nancy Gebert, from the Department of Molecular Cell Biology at the Weizmann Institute of Science, which was recently published in the scientific journal Cancer Research, reveals a genetic mechanism involved in the formation of colon cancer metastases, and contributes to the understanding of the processes responsible for his violent outburst.
The factor that starts the snowball of the disease, in very many cases (90-80%), is damage to a certain cellular pathway for transmitting signals, and especially to its key protein - beta-catenin. This protein plays an important role in cell adhesion, but in certain situations, such as, for example, in the stage of embryonic development, or in the proliferation of stem cells, it has an additional role: it enters the cell nucleus, and encourages the expression of genes. When the beta-catenin protein accumulates in excessive amounts inside the cell, its uncontrolled activity can cause the expression of cancer-causing genes.
Surprisingly, one of those genes activated by beta-catenin in colon cancer cells, called L1-CAM, is a protein receptor that appears mainly on the surface of nerve cells, where it is responsible for the recognition between cells, their adhesion and their movement. What is its role in cancer cells? Previous studies by Prof. Ben-Zev showed that this receptor is not expressed in all tumor cells, but only in those on its "invasive front", and only at the stage when it becomes violent and metastatic. These findings implied that this gene plays an important role in the aggressive stage of colon cancer, by causing the invasive movement of the cells.
The researchers tested this hypothesis in mice, in a research model simulating the development of metastatic colon cancer. It turned out that colon cancer cells in which the L1-CAM gene was inserted formed cancer metastases in the liver, while cancer cells that do not express the gene did not metastasize. In addition, the researchers discovered that the expression of a certain enzyme, which is responsible for cutting the extracellular part of the receptor, is also increased by beta-catenin in the same cells, strengthening the invasive effect of L1-CAM.
Together with Prof. Eitan Domani and his research student, Michal Shaffer, from the Department of Physics of Complex Systems, the scientists mapped the genes activated in cells into which the L1-CAM gene was inserted, and compared them to the characteristics of gene activation in cancerous tissues taken from patients suffering from an advanced stage of colon cancer. About 160 genes were found whose expression is increased by L1-CAM, 70 of which also showed high expression in the colon cancer tissues of 170 patients, but not in 40 samples of healthy colon tissue. In the future, Prof. Ben-Zev intends to investigate the role of these genes in the development of cancer, with the aim of understanding the mechanisms through which L1-CAM induces the formation of colon cancer metastases.
