Making cancer cells die a 'good death'
Dana-Farber researchers are harnessing programmed cell death, or
apoptosis, to attack tumors
By Richard Saltus
The final stage of apoptosis (natural cell death) involves a
white blood cell called a macrophage (at right) consuming cell
debris from the suicidal cell.
(Image courtesy of U.S. National Library of Medicine)
There comes a time in every cell's life to die for body's greater good. When the orders do come—from outside the cell or within it—the cell obediently destroys itself, and the body disposes of the corpse without a trace.
Though some have called it "suicide without grief," the process of apoptosis, or "programmed cell death," is neither quick nor gentle. Over 24 to 48 hours, a poison cocktail released from within the cell chops up its DNA; the cell shrinks, is dismembered into neatly wrapped pieces, and—after posting a chemical "Eat Me" sign on its surface—is devoured by hungry immune system cells.
Apoptosis rids the body of 50 to 70 billion unwanted cells a day, including worn-out or obsolete cells and those with DNA damage that are prone to running amok and causing cancer.
When a cell senses that its genetic blueprint has been damaged—by random events, radiation, or chemicals, for example — it turns on a "death program" of apoptotic events to cull itself from the body.
Findings by Stanley Korsmeyer, MD, who joined Dana-Farber in 1998, changed scientific thinking about cell death and survival.
But this defensive purging can hit a snag, as Dana-Farber's Stanley Korsmeyer, MD, famously discovered about 15 years ago. If a surge of "survival" signals within a damaged cell outweighs its death signals, the cell may escape apoptosis and become the seed of a tumor. Genetic mutations in a cell's DNA, among other events, can turn on an excess of survival signals—just one more way in which cancer exploits natural processes to do its dirty work.
Before Korsmeyer made his discovery while based at Washington University in St. Louis, researchers likened the development of cancer to water flowing into a lake faster than it drained out. Triggered by abnormal genes called oncogenes, cells went into overdrive, proliferating abnormally and uncontrollably, forming tumors.
But this picture acquired a new dimension when Korsmeyer, who was studying a form of blood cancer called follicular lymphoma, showed that a broken chromosome caused overproduction of a cell survival factor known as Bcl-2. This protein protected cancerous cells from being shunted off for execution—and made the lymphoma harder to treat. "Bcl-2 was quite a shock and a surprise," he recalled last winter. "We noticed that cells containing mutated Bcl-2 never died." Now the metaphorical lake was not only filling rapidly; its outlet was also blocked, speeding tumor growth.
"Stan's contribution was the realization that this was because Bcl-2 blocks apoptosis, a major insight that profoundly affected how we thought about cell death and survival," says Douglas Green, of the University of California, San Diego, a leading scientist in the field. This conceptual advance was the start of Korsmeyer's considerable scientific legacy; he died in late March of lung cancer unrelated to smoking.
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