A team of Vanderbilt-Ingram Cancer Center investigators have identified a new secreted protein and its receptors that appear to give a cancer cell the ability to fuel its own growth. This finding could reveal a new potential target for anti-cancer drugs.

Secreted proteins are released from one cell to transmit a signal to another cell, instructing a particular behavior such as cell growth, migration or survival. These proteins cannot act alone; they must act through a receptor or receptors on the receiving cell, so the discovery of the receptor is also important.

This new protein, called Interleukin 24 (IL-24), is typically secreted by immune system cells in response to a triggering event, such as injury or infection. However, the Vanderbilt-Ingram team found that IL-24 and two receptors are also expressed in certain cancer cells, making it the first interleukin to be found along with its receptors in tumor cells.

Writing in the Journal of Biological Chemistry, Peng Liang, Ph.D. and colleagues reported on their use of a process called differential display to compare gene expression between cancerous and normal cells. The team found IL-24 to be expressed only in tumor cells and particularly those in which the oncogene (cancer-causing gene) RAS is activated. RAS is mutated frequently in colon and pancreas cancers, among others, and it appears from this group's work that RAS activation leads to unregulated expression of IL-24 and its receptors.

The scientists also demonstrated that IL-24 can promote cell growth or prevent cell death. This was done using hemopoietic mouse cells that must have interleukin-3 (IL-3) to grow and survive. When the cells were made to express IL-24 receptors, in the absence of both Il-3 and IL-24, the cells died. In the absence of IL-3 but the presence of IL-24, the cells continued to live and grow.

Finding that IL-24 can support cell survival, and finding both IL-24 and its receptors in tumor cells, has an important implication, Liang said. This creates what is called an "autocinre loop," through which a cell secretes a protein that then binds to a receptor on itself, sending its own signal to its nucleus. "The cell could then fuel its own growth and survival without the checks and balances by the neighboring cells," Liang said.

The next step for Liang's team will be to try to develop molecules to interrupt this autocrine loop, either by intercepting the IL-24 protein outside the cell after it is secreted, or by blocking the receptors so that the protein cannot bind and therefore transmit its signal back into the cell.

SOURCES:
Journal of Biological Chemistry, March 1, 2002; 277(9): 7341-7347
Vanderbilt-Ingram Cancer Center (http://www.mc.vanderbilt.edu)