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Scientists are trying to develop antibodies to the receptor that causes cancer

Studies: high levels of the hormone IGF double the chance of getting cancer

By Uri Nitzan
Photo: Ariel Shalit
Prof. Haim Werner. "Uncovering the mechanism that suppresses increased expression of IGF receptors in the normal cell will make it possible to define the involvement of the receptor in the malignant process"

Cancerous tumors are often detected at a stage where they have already developed into clumps of malignant cells. These cells originate from a single progenitor cell whose division control systems have been damaged. Many proteins schedule and carry out cell division at the appropriate time, and some ensure that divisions do not take place before their time. Random mutations in the hereditary material can damage the genes that code for the
these control proteins, and as a result the cell begins to produce defective proteins that do not fulfill their duties. As a result, the cell divides rapidly until the cancerous mass is formed.

Many of the hormonal proteins are also involved in the development of malignant processes. These proteins are secreted by various glands into the blood circulation, and act in the body on distant target cells. The hormone IGF (insulin-like growth factor) is known to the scientific community mainly thanks to its involvement in the growth process. Growth hormone is secreted into the blood from the pituitary gland, binds to specific receptors on the surface of cells
the liver and causes them to produce IGF. The liver cells secrete the hormone IGF into the blood, and it binds to the IGF receptors on the surface of the bone cells and causes growth and hardening of the bones in the adolescent boy.

In addition to their involvement in normal growth processes, high levels of IGF in the blood are linked to an increased chance of getting certain types of cancer. Two large-scale studies conducted in the late 90s in the USA proved that high levels of IGF in the blood increased 2.4 times the chance of a man getting prostate cancer, and 4.6 times the chance of a woman getting breast cancer.

In the last decade it became clear that in almost all tissues of the body there are cells on the surface of whose membrane there is a low concentration of IGF receptors. The binding of the hormone to the receptor causes the cell to divide. In malignant cells, the expression of the receptors is much higher than in cells
the normal ones. They respond vigorously to the hormone in the bloodstream, and divide at an accelerated rate. In laboratory experiments, it has been shown that cells lacking IGF receptors are unable to become malignant, even after exposure to various carcinogens. Only after the introduction of the gene for the IGF receptors into the cells did these cells become malignant, and from this it was concluded that the receptors play a central role in the cancerous transformation process.

Prof. Haim Werner, from the Department of Clinical Biochemistry at the Faculty of Medicine at Tel Aviv University, studies the IGF receptor and its involvement in the development of malignant tumors. "Revealing the mechanism that suppresses increased expression of IGF receptors in the normal cell," says Werner, "will make it possible to define the involvement of the receptor in the malignant process."

What, then, prevents all normal cells from expressing high levels of the receptor and undergoing cancerous transformation?

Werner focused on a known control protein called p53. p53 maintains the integrity of the hereditary material and prevents cells from becoming malignant. It senses the damage (mutations) caused to the hereditary material and delays cell division until the damage is repaired. A cell that is irreversibly damaged "suicides" in a mechanism that is also mediated by p53, provided that it does not turn into a malignant cell.

Prof. Werner revealed another anti-cancer role of p53 - suppressing the expression of the gene that codes for IGF receptors. Mutations in the p53 gene (which characterize many types of cancer) cause, among other things, an increased production of the receptor in the transduced cells, which is accompanied by the binding of high levels of IGF, division uncontrolled cells, and the development of a cancerous tumor.

Since then, Prof. Werner's research group has managed to reveal the central role of the receptor in several types of cancer. In children there are tumors characterized by a mutation known as "chromosomal translocation". This event, caused in some cases as a result of an environmental hazard such as radiation or chemicals, causes the breakage of two chromosomes and the incorrect fusion of the fragments. The fusion cancels the action of the two original genes that are located at the break point, and creates a new gene (fusion gene) that usually has pro-cancer activity. Werner and his research students found that the new gene functions as a disease control protein, causing increased expression of IGF receptors and the development of malignant disease.

Additional studies have shown that the common breast cancer (it develops in one in ten women) is also associated with increased expression of the receptor. A mutation in the BRCA1 gene is common in Ashkenazi families with a high incidence of breast cancer. And Prof. Werner found that the protein BRCA1, which is normally found in the cell nucleus and functions as a tumor suppressor (similar to p53), is able to suppress the expression of the gene that codes for IGF receptors. "Different types of cancer, in seemingly unrelated tissues, are based on similar molecular mechanisms Rabbi," says Werner.

The IGF receptor has already been defined by the pharmaceutical companies as a central research target, and today they are trying to develop antibodies and other substances that will neutralize its activity in the diseased cells. The researchers expect that these innovative methods, in combination with conventional treatment methods, will increase the chances of curing various types of cancer in which IGF proteins are involved.

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