September 03, 1998
Loss of Tumor Suppressor Gene Triggers Colon Cancer
Researchers have found the first connection between the loss of a tumor suppressor gene and activation of a cancer-promoting oncogene, a scenario thought to be prevalent in the initiation of many cancers but which has never been proven.
The newfound link also helps to explain the genesis of most cases of
colon cancer, the second leading cause of cancer deaths in the United
“Master genes such as p53, another tumor suppressor, or APC usually don't work on just one pathway. So c-MYC is probably not the only gene whose expression is controlled by APC. We are working to find the others.”
The scientists found that mutated
genes, regarded as one of the
body's master brakes on cell growth, switch on c-
a gene long
associated with cancers of various sorts in both animals and humans.
"This connection is fascinating and we hope it leads to further
understanding of this pathway," says
, an HHMI
investigator at The Johns Hopkins Oncology Center. The report by
Vogelstein and Johns Hopkins colleagues, Kenneth Kinzler and HHMI
associate Tong-Chuan He, appears in the September 4, 1998, issue of the
For Vogelstein, who has studied the genetic basis of colon cancer for
nearly 20 years, "this ends one chapter of the
story," but begins
many more. "Master genes such as
another tumor suppressor, or
usually don't work on just one pathway. So c-
is probably not the
only gene whose expression is controlled by APC. We are working to find
the others," he said.
The discovery also offers hope of finding new ways to treat colon
cancer. Knowing that the c-
oncogene is one final link in the colon
cancer chain "brings up an obvious and potentially powerful way to
disrupt that interaction," Vogelstein says. Vogelstein's team plans to
begin screening compounds that can block expression of the c-
oncogene through interference with the transcription factors regulated
In 1991, investigators including the Vogelstein-Kinzler team first
(adenomatous polyposis coli), and linked mutations in
that gene to colon cancer. Mutations in the
gene were found in the
hundreds of polyps that populate the colons of patients with an
inherited disease, familial adenomatous polyposis (FAP). Similar
mutations were found in about 85 percent of all colon cancers, including
patients who had no family history of colon cancer.
By 1993, the researchers showed that APC interacts with the protein
ß-catenin, a cell adhesion molecule commonly found in stomach tissue.
That finding later helped to explain why nearly 10 percent of colon
cancer cases develop with normal
genes; the mutations are in
Next it was shown that ß-catenin associates with the TCF family of
proteins that activates gene transcription, and that APC regulates this
association. This led to the hypothesis that APC, ß-catenin and Tcf-4
collaborate to regulate gene activity in colon cells, although the
precise targets of that complex remained unknown. Finding those targets
might tell the researchers how the protein complex promotes errant cell
The break came when the team used a powerful screening procedure to sort
out the genes that are turned on or off by APC. They found that the
gene quickly shut down after APC was applied, giving them direct
, a known oncogene.
Summarizing the results, Vogelstein explains that normal APC prevents
ß-catenin from binding to Tcf-4, which, in turn, foils c-
If APC or ß-catenin is mutated, however, the c-
oncogene is unchecked
and promotes cell growth.
While Vogelstein says it is too early to speculate whether this pathway
may be shared by a number of other cancers, he notes that "c-
powerful growth promoter, and this study should stimulate a lot of new
work in this area."