Articles|Cell Apoptosis

On the TRAIL of Suicidal Cells

By Brona McVittie

Death is part of life. Trillions of molecular errors take place within our bodies daily, mistakes that could cause disease. Yet illness is kept at bay by a barrage of ingenious biological defence mechanisms, which act to isolate and eradicate the natural hazards posed by our biology and metabolism. Apoptosis or programmed cell death is something of a life saver, a daily disposal service for short-circuiting cells. Understanding this highly-evolved process of cell suicide has great implications for cancer, because tumour cells escape the body's natural apoptotic pathway.

New therapeutic possibilities provide an incentive for scientists to figure out ways of triggering apoptosis in cancer cells. The ApoNET project is a 3-year EU funded programme that brings together the work of leading European researchers to explore cell suicide in health and disease. “We're trying to identify new ways of treating cancer by studying the physiology of balanced (healthy) and unbalanced (diseased) systems. We'd like to find out how normal and cancerous liver cells respond to molecules called TRAIL and TNF,” explains Henning Walczak (Imperial College London, UK).

TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily, a large family of immune molecules. Some of the members of this family that can trigger apoptosis. TRAIL is made by cells of the immune system, such as the so-called natural killer cells, in part defining their capacity to eliminate unwanted tissue from the body. Each free-floating TNF molecule family member (ligand) binds faithfully to its receptor, usually embedded within the cell membrane.

Binding of the apoptosis-inducing ligands to their specific receptors elicits a whole cascade of internal signalling events that mediate the gene expression pathways characteristic to cell suicide. Apoptosis flags up cell damage and effectively disposes of cells in which the molecular machinery has gone awry. While TNF molecules can also induce apoptosis under certain circumstances, the primary function is to alarm the immune system by inducing a pro-inflammatory state. In a tumour this can result in resistance of cancer cells to TRAIL-induced apoptosis.

An appreciation of the signalling networks involved in the control of cell suicide is of significant medical benefit. Nodes in the network, which correspond to genes that regulate the system, are potential drug targets. If research can reveal which nodes, when stimulated with a drug, promote cell suicide in tumour cells, but not in normal body tissue, new therapeutic avenues will open up. With the risk of metastases in liver cancer, treatments are applied throughout the body, so it is crucial that new drugs do not have adverse affects on our healthy cells.

As Henning reveals, “the ultimate measure is not whether we can kill a cancer cell, but whether normal cells will survive.” Together with partners, Michael Boutros (University of Heidelberg and German Cancer Research Center, Germany) and Rainer Spang (University of Regensburg, Germany), Henning is exploring the effects, not only of TRAIL in isolation, but in combination with other molecules. “If we find a protein we can neutralise in cancer cells that renders them more susceptible to TRAIL (promoting cell suicide), we need to be sure that blocking the same factors in normal cells won't kill them. We're aiming to specifically sensitise cancer cells without affecting the normal cells.”

“Several years ago, together with Michael's research team, we identified factors required for TRAIL-induced apoptosis,” explains Henning, “and factors that are required to maintain resistance against TRAIL-induced apoptosis.” Resistance often evolves in tumours that are exposed to drug treatment, because cancer cells keep dividing and are more likely to mutate than normal cells. Mutations can equip them with an escape route from the naturally protective apoptotic pathway. “If we can neutralise the factors that specifically affect cancer cell resistance to TRAIL using different drug combinations,” reasons Henning, “there is less chance that these cells will evolve resistance to new treatment combinations.”

Within three years, the ApoNET project aims to put together the pieces of the puzzle to reveal a comprehensive picture of the natural control network for cell suicide. This will provide a yardstick, against which to compare the situation in tumour cells. Michael Boutros summarises the overarching goal. “We'd be happy to build models of the TRAIL and TNF pathways. How are these signalling networks rewired in cancer cells compared to normal cells? With an increased understanding of these processes, we hope to be able to make predictions about how TNF (or its inhibition) and TRAIL could be used in clinical studies.”

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