25 January 2007

Gene manipulation may fight cancer

Manipulation of a gene that normally protects against malignancy but is switched off in cancer cells could open up a promising new frontier in research, according to new studies.

Manipulation of a gene that normally protects against malignancy but is switched off in cancer cells could open up a promising new frontier in research, according to two new US studies.

Whenever p53 was turned off, cancer cells in mice quickly went to work forming tumours, the studies found. But when researchers used high-tech tricks to switch the gene back on, "the tumour went away," said the leader of one of the studies, Scott Lowe, deputy director of the Cold Spring Harbor Cancer Center, in Cold Spring Harbor, New York.

"We would like to imagine that this would translate to human tumours," he said. "In such a system, you could have a very aggressive cancer that really depends on the continued inactivation of this gene to survive."

The study also uncovered surprising new insights into the power of the human immune system to "mop up" cancers weakened by reactivated p53.

Lowe's work and a related study were published online in the Jan. 25 issue of Nature.

"These studies indicate that this might be a fruitful path to explore from a cancer drug-development standpoint," said Dr Ronald DePinho, a pioneer in this type of work and a professor of medicine at Harvard Medical School.

Drugs still a long way off
Although an actual drug for use in a clinical setting is still a long way off, "there are compounds that are now being directed toward the p53 kinase pathway that may enable re-establishment of p53 activity," said DePinho, who also authored a related commentary on the studies.

Almost all forms of cancer involve an inactivation of the p53 tumour-suppressor gene and its related biochemical pathway. So, the pathway has long been a favourite target of cancer research.

"What p53 does is help cells solve problems when they are stressed," Lowe explained. "So, if a cell is damaged in some way, it can make them stop growing, so they aren't dangerous and form a cancer. In fact, it can even kill cancer cells through a process called apoptosis," or programmed cell death.

Unfortunately, this cancer "safety net" is almost always switched off in tumour cells. Scientists have long known that shutting down p53 is key to triggering a cancer - but what about maintaining its growth? Work by DePinho and others in the 1990s established that the genes that help start a cancer aren't always crucial to its continued survival.

How the research was done
Would that be the case with p53? To find out, Lowe's group used a highly advanced gene manipulation technique called RNA interference (RNAi) to first switch off p53 in cancer-prone mice and then switch it back on, watching to see what happened.

The results were heartening. Just like clockwork, the mouse tumours expanded in the absence of active p53, then shrank when the gene went back to work.

Lowe called the results "a nice proof-of-principle" that p53 inactivity is, indeed, crucial to tumour maintenance.

But there was a real surprise, too. Lowe said he had assumed that reactivated p53 would simply kill tumour cells directly by driving them into apoptosis.

"But when we looked carefully, that didn't seem to be the primary mechanism," he said. "In fact, we noticed something that was quite different - p53 was inducing a process called 'cellular senescence.'"

In essence, reactivation of the p53 pathway caused the cell to become arrested in a particular stage in its life cycle, effectively putting it to sleep.

But that didn't explain why tumours continued to shrink under the influence of p53. "Where did the cells go?" Lowe said.

Up-regulating the genes
Further research yielded the answer. According to Lowe, restarting p53 "appears to up-regulate genes that are involved in recruiting the [mouse] immune system. It was the immune system that was gobbling up these tumour cells."

What's more, it wasn't the immune system's highly targeted killer cells (such a B- or T-cells) that were eating away at senescent tumour cells, but garden-variety macrophages and other immune cells that drive everyday inflammatory processes.

"That's really exciting and surprising," Lowe said. "We didn't anticipate it. It seems there's this interplay between events that happen within the tumour cell and then this recruitment of the immune system. We'd like to understand that in a better way to perhaps exploit it for treatment."

More interesting clues to p53
Another study in the journal, this time led by Tyler Jacks, of the Massachusetts Institute of Technology, also turned up interesting clues to p53. In its study, also conducted with mice, Jacks' team found that switching the gene back on led to speedy tumour regression.

But the researchers also found that the reasons behind that regression varied depending on the type of cancer targeted. For example, lymphoma cells died off due to p53-induced apoptosis, but in the case of sarcomas, p53 triggered tumour cell senescence and a concurrent suppression of cellular proliferation.

The experts stressed that p53 is one of a number of important genes affecting tumour survival.

Work on the tumour-suppressor side
DePinho's group, and others, have already done groundbreaking work in manipulating various "oncogenes" - genes that, when they are turned on, actively promote cancer's spread.

"What these newer studies have done is look at the flip-side of that, to do work on the tumour-suppressor side," DePinho said.

Lowe said he also believes that "there are other members of the p53 pathway that can either turn the pathway on or execute the [relevant] biological response. All of them could have a similar biology, and we could imagine tinkering with them to do similar things."

But researchers have their work cut out for them, he said.

"It will still be a long time before we are finding small-molecule drugs that do exactly these things - before they make their way to the clinic," Lowe said. "This isn't cancer being cured tomorrow. But it remains very exciting." - (HealthDayNews, January 2007)

Read more:
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