Buck Scientists Identify “Jekyll-Hyde” Cancer Gene

The finding of a Jekyll-and-Hyde cancer gene is putting a new face on cancer research.  For about 20 years, scientists have focused on the role of oncogenes, which promote cancer growth, and tumor suppressor genes, which block its growth. Now, researchers at the University of Lyon in France, and the Buck Institute in Northern California, have discovered a third type of cancer gene.  This new type—which they dubbed a “conditional tumor suppressor”—can actually switch back and forth between blocking cancer and promoting it, depending on the environment.  Results of their study, which focused on colorectal cancer in mice, are being published in the September 2 edition of Nature.

This Jekyll-and-Hyde cancer gene, called DCC (from “deleted in colorectal cancer”), works something like a lock with a key—in the absence of the key, cancer development is locked down, and the cells are unable to proliferate to produce a tumor. On the other hand, when the local environment changes such that a key is available, then the door to cancer development is opened wide.  In this case, the “lock”—DCC—is a receptor that sits on the surface of cells in the intestines and other sites. DCC was formerly thought to be a standard tumor suppressor; however, what the researchers found was that DCC can actually support tumor growth when its “key”—a growth factor protein called netrin-1 that binds to DCC—is present in high amounts.  When netrin-1 is scarce, the presence of DCC causes cells to commit suicide (a process known as apoptosis), blocking cancer growth.  However, when netrin-1 is abundant, it appears that the cancer brake normally provided by DCC is unlocked. In the study, mice genetically engineered to over-produce netrin-1 not only had a slightly higher frequency of pre-cancerous growths, but, when combined with another mutation that produces, by itself, only benign tumors, the mice were ravaged by aggressive, full-blown cancers.

“This observation should lead researchers to look at cancer development from a completely different angle,” said Patrick Mehlen, PhD, a researcher at France’s National Center for Scientific Research and Adjunct Professor at the Buck Institute. “We demonstrate here that tumor formation is not only initiated by abnormal cells that proliferate without control, but may actually result from the loss of this safety brake.” Mehlen said, “This interaction described between a particular receptor and growth factor in digestive tumors is probably true for other pairs of receptors and growth factors and for other types of tumors.    

“This new line of research holds promise for potential therapies or predictive tests for cancer,” said Dale Bredesen, MD, President of the Buck Institute and co-author of the study. “Detecting abnormalities in levels of netrin-1, or other similar molecules, might help us identify those patients at risk for developing malignancies; furthermore, by manipulating the abundance of netrin-1 we might be able to stop the cancer in its tracks."

While it’s important, researchers say, to remember that cell death is protective when it comes to cancer development, it can potentially be damaging to other tissues by killing healthy cells.  The original discovery of a “suicide receptor” that triggers cell death blocked by growth factors like netrin-1 was made a decade ago in Bredesen’s laboratory, then at UCLA.  However, in that case, the suicide receptor led to the death of brain cells, in the very area most affected in Alzheimer’s disease.  That discovery led Bredesen and Mehlen, who was a visiting scientist in Bredesen’s laboratory, to postulate that a similar mechanism may drive tumors either toward growth or regression.  Mehlen, who returned to France in 1998, therefore began focusing his attention in that direction, leading to the identification of DCC as the first of what is likely to turn out to be quite a number of conditional tumor suppressors.

The study was supported in France by the Ligue Contre Cancer, the Schlumberger Foundation and the National Institutes of Health. Work at the Buck Institute was supported by the National Institutes of Health.

The Buck Institute is the only freestanding institute in the United States that is devoted solely to basic research on aging and age-associated disease. The Institute is an independent non-profit organization dedicated to extending the healthspan, the healthy years of each individual’s life.  Buck Institute scientists work in an innovative, interdisciplinary setting to understand the mechanisms of aging and to discover new ways of detecting, preventing and treating conditions such as Alzheimer’s, Parkinson’s, cancer and stroke.  Collaborative research at the Institute is supported by new developments in genomics, proteomics and bioinformatics technology.