By Alexandra Goho
Finding Cancer's Self-Destruct Button
Cancer cells thrive by disabling a hardwired program that tells sick cells to die. Can researchers turn it back on?
By Alexandra Goho
It’s the ultimate self-sacrifice: When confronted with stress or an infection, cells in our bodies silently commit suicide to protect neighboring cells and tissues. It’s a sophisticated survival mechanism that has evolved over hundreds of millions of years. But as clever as this system is at keeping the body healthy, it sometimes fails. Such is the case with cancer.
Usually, when a cell begins to multiply in a dangerously abnormal way, a series of biochemical signals trigger it to commit suicide. Called apoptosis, this process involves a precisely orchestrated series of steps: The cell shrinks, packages itself into smaller pieces, and then is quickly engulfed by neighboring cells. But researchers believe cancer cells harbor a genetic mutation that lets them disable the molecular machinery of this built-in suicide program.
When a cell's self-destruct program is working, the process helps to protect the body from cells that are hurt by chemicals, ultraviolet rays or another stress (red dots). The sick cell (free red-brown cell) separates from healthy tissue and starts to alter itself (yellow-green cell). It packs up its internal structures and awaits engulfment by a clean-up cell known as a macrophage (purple cell). [Art: Nicolle Rager Fuller]
“It’s a very active process and it has to be working well in order to avoid disease,” explains biochemist Guy Salvesen, the director of the Apoptosis and Cell Death Research Program at the Burnham Institute in La Jolla, Calif.
That’s why, over the last decade, scientists have flocked to apoptosis research, hoping to learn how to develop drugs that effectively trigger suicide in cancer cells. The strategy looks promising, and a number of candidate drugs are already in clinical trials. According to structural biologist Stephen Fesik, the divisional vice president of preclinical cancer research at Abbott in Abbott Park, Ill., “We’ll soon know whether or not this approach will be a useful weapon against cancer.”
A HISTORY OF CELL VIOLENCE
The term “apoptosis” (a Greek phrase meaning “falling away”) was first coined in 1972 based on the characteristic appearance of a cell when it commits suicide. The dying cell follows a controlled sequence of events in which it breaks itself down and packs up its contents. In contrast, cell death caused by an acute injury appears chaotic—the cell busts open and releases its innards, causing the surrounding tissue to become inflamed.
Apoptosis does more than ward off disease. Millions of cells in our bodies kill themselves every day to make room for new healthy cells or to train the immune system. During an organism’s development in the womb, this type of cell death helps to sculpt tissues and organs and to separate fingers and toes. And when a tadpole becomes a frog, apoptosis steps in to eliminate the tadpole’s tail.
In the early 1980s, molecular biologist Robert Horvitz at the Massachusetts Institute of Technology and his colleagues identified the genetics underlying apoptosis in a species of worm called C. elegans. (Horvitz was awarded the 2002 Nobel Prize in Physiology or Medicine for his work on apoptosis.) And by the early 1990s, researchers had uncovered a definitive link between malfunctioning apoptosis and cancer. They found that in follicular cell lymphoma, parts of two chromosomes fuse together, causing a gene called Bcl-2 to become overactive and prevent cancer cells from committing suicide.