Cellular 'Self-Eating' Might Be Turned Against Tumors (10/30/2007)

A breast cancer cell engages in a major bout of autophagy - 'self eating.' The bright spots - a fluorescent label - shows the cell's garbage collection and recycling plants - called autophagosomes.

We all know that recycling can reduce the strain on global resources. But if we could see into the cellular world inside us, we might also notice that our cells are running a successful recycling campaign of their own.

Cells recycle and reuse their own contents through a process called autophagy, which means "self-eating."

That's not just a fun fact - autophagy plays a role in disease too. With their growing understanding of autophagy, some medical researchers, including UCSF's Jayanta Debnath, MD, believe that cellular recycling might be manipulated to better treat cancer.

But first, he wants to find out whether autophagy helps or hurts cancer cells. A cell undergoing autophagy might eat itself to death - which would be a good thing if it's a cancer cell. On the other hand, a cancer cell might undergo autophagy as a desperate tactic to recycle molecules for the extra fuel it needs in a hurry to respond to acute stress - during chemotherapy, for instance. In that case, it would be better to shut down autophagy.

Desperate Times Call for Desperate Measures

On a small scale, autophagy is routine. When cellular components are old or damaged, the cell will destroy them. Without autophagy, these old or damaged parts could accumulate and cause problems for the cell.

Material within cells that needs to be recycled is packaged into microscopic trash containers and delivered to the cell's garbage disposals, called lysosomes, which break it down for reuse.

Cells also use autophagy to deal with starvation or other stresses. When nutrients in the environment are lacking, the cell turns to its own components for survival. Survival by self-consumption has to be kept under a tight rein, Debnath says.

"Too little autophagy is bad for a cell," Debnath says. "During a time of stress, if it no longer has this adaptive mechanism, it will die. But at the other extreme, if there is too much autophagy, the cell will literally eat itself to death."

Scientists originally thought that autophagy was a kind of cellular suicide. That's because it often appeared in dying cells. They compared it to a better understood and distinctly different type of programmed cell death - called apoptosis - that often is set in motion by cells in distress. But now researchers have learned that autophagy sometimes can be an alternative to suicide that permits some cells to stay alive in harsh conditions.

Autophagy and Cancer

Debnath first became interested in learning what happens when cells that line organs, glands and the ducts within them - the epithelial cells that give rise to most cancers - detach from their neighbors.

Normally when an epithelial cell comes loose from its cell layer, it immediately begins to undergo apoptosis and dies. But when epithelial cells are tumor-causing, they can break free without dying. Scientists believe that this capability contributes to cancer progression and its spread.

Debnath found that when he blocked apoptosis in normal epithelial cells that had detached from their neighbors, they lived longer, but still eventually died. When he looked carefully at these cells, he saw large amounts of autophagy.

Turning to cancer cells, Debnath and his UCSF lab team found that detached, tumor-generating epithelial cells have high levels of autophagy. They wondered whether tumor cells use autophagy as a stress response to survive in the harsh environment away from their home cell layers. "If so," Debnath says, "if you now manipulate autophagy, either dialing it up or down, can you use that as a therapeutic strategy to kill the cancer cells?"

Debnath is trying to answer this question in tumor-causing milk duct cells from the breast, using genetic strategies to change levels of autophagy.

Autophagy and Drug Resistance

Manipulation of autophagy might be used to bolster the power of chemotherapy drugs. Many cancer treatments, Debnath explains, result in huge increases in autophagy in the cancer cells.

Scientists are not sure why cancer cells dial up autophagy when hit with drugs. And few assume that all cancers will act in the same way when it comes to autophagy and chemotherapy.

But already, while studying deadly brain cancer cells rather than breast cancer cells, UCSF researcher Russ Pieper, PhD, and his collaborators recently found that DNA-damaging chemotherapy caused the cells to become resistant to treatment by switching on autophagy.

Turning on autophagy allowed these cells to produce more usable energy, in the form of a molecule called ATP. Increased production of ATP made possible by autophagy was associated with increased cell survival. More tumor cells died when the researchers countered by adding a drug that blocks autophagy.

"Our understanding of autophagy has exponentially increased in the last few years and has broached the exciting possibility of using 'self-eating' as a therapeutic strategy to curtail tumor cell survival and expansion," Debnath concludes.

Note: This story has been adapted from a news release issued by The University of California, San Francisco

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