[tt] Cancer Cells Revert To Normal At Specific Signal Threshold, Researchers Find

[Brian Atkins]

http://www.sciencedaily.com/releases/2008/07/080701083529.htm

ScienceDaily (July 2, 2008) — Cancer starts when key cellular signals run amok, 
driving uncontrolled cell growth. But scientists at the Stanford University 
School of Medicine report that lowering levels of one cancer signal under a 
specific threshold reverses this process in mice, returning tumor cells to their 
normal, healthy state. The finding could help target cancer chemotherapy to 
tumors while minimizing side effects for the body's healthy cells.

The researchers identified a precise threshold level of the signaling molecule 
Myc that determined the fate of tumor cells in a cancer of the immune system in 
mice. Above the threshold, high levels of Myc drove immune cells to grow too 
large and multiply uncontrollably. When the researchers lowered Myc levels below 
the threshold, the same cells shrank to normal size, stopped multiplying and 
began dying normally.

"This is a new concept," said Catherine Shachaf, PhD, an instructor in 
microbiology and immunology who shared lead authorship of the study with 
colleague Andrew Gentles, PhD, a research associate in radiology. Previous 
research demonstrated that turning Myc and other cancer signals all the way off 
can kill a tumor, but this is the first time scientists have demonstrated a 
specific midway point at which a cancer signal reverted to a healthy level, 
Shachaf said. The findings will be published in the July 1 issue of Cancer Research.

Identifying the threshold was important because Myc functions in both healthy 
and cancerous cells as a transcription factor, a protein signal that binds DNA 
to turn genes on or off. Excess Myc contributes to about 50 percent of human 
cancers, including malignancies of the immune system and lung.

But Myc is essential, at lower levels, for normal cell function. So, switching 
Myc all the way off is not an option for treating cancer.

"I wanted to figure out, if we had a drug to turn off Myc, how could we give it 
to people without hurting them?" said Dean Felsher, MD, PhD, associate professor 
of oncology and of pathology. Felsher and Sylvia Plevritis, PhD, associate 
professor of radiology, are the study's senior authors and are both members of 
the Stanford Cancer Center.

In the past, scientists have shown that cancer signals such as Myc are "like 
light switches," Felsher said. "Now we know that, in some cases, you don't need 
to turn the light completely off."

"The real significance of this paper is that it demonstrates that there is a 
defined amount of Myc that switches the balance between normal cell growth and 
tumorigenesis," said Bill Tansey, PhD, a professor and expert on cancer-gene 
regulation at Cold Spring Harbor Laboratory in New York, who was not involved in 
the research. "The idea that this is a threshold is really not the way we were 
all thinking."

Using mice that were genetically engineered to develop Myc-driven tumors in 
response to a chemical in their drinking water, the researchers slowly lowered 
Myc from an elevated, cancer-causing level to the precise point at which tumor 
cells returned to normal. Near the threshold, they examined many aspects of cell 
metabolism to obtain a detailed picture of how the cancer cells changed as Myc 
dropped. They measured changes in gene activity, protein levels, protein 
activation inside the cells and the appearance of cell-labeling proteins on the 
exterior surface of the cells. The scientists wrote a new piece of computer 
software to help them see how these different types of data fit together into 
detailed metabolic pathways.

"At the Myc threshold, there is a big change: Programmed cell death becomes 
dominant over growth," said Gentles.

The threshold was characterized by both a return of normal controls on the 
cell's life cycle, which stopped inappropriate growth, and re-activation of the 
pathways that prompt normal cell death, Gentles said.

"We were able to experimentally prove that we can turn Myc off a little bit, or 
for a little time, and that's enough to have a profound effect on cancer," 
Felsher said.

The multidisciplinary research team that conducted the work included 14 
scientists from seven different Stanford departments.

The study's results will be used to design future cancer treatments, the team 
said. At present, no drugs target Myc. Understanding the Myc threshold will make 
it easier to design new drugs that focus on Myc itself or target other key 
signals required to switch from tumor to healthy cells. Armed with a detailed 
profile of cellular changes near the Myc threshold, researchers now have a much 
better idea of where to look for new cancer treatments. "It allowed us to narrow 
down the hunt," Felsher said.

The research was supported by grants from the National Cancer Institute, the 
National Cancer Institute Integrative Cancer Biology Program, the Leukemia and 
Lymphoma Society, the Damon Runyon Foundation, the Burroughs Wellcome Fund, a 
Weiland Family Fellowship and a Flight Attendant Medical Research Institute 
Young Clinical Scientist Award.

Felsher and colleagues published a companion paper June 6 in Public Library of 
Science-Genetics examining bone cancer.

-- 
Brian Atkins
Singularity Institute for Artificial Intelligence
http://www.singinst.org/