A malfunctioning "traffic cop" gene apparently plays
an important role in the formation of liver cancer, according
to researchers from the Duke University Comprehensive Cancer Center
and Zeneca Pharmaceuticals of Chesire, United Kingdom.
The discovery that the gene-mannose 6-phosphate/insulin-like growth
factor II receptor (M6P/IGF2r)-acts as a tumor-suppressor gene
in human liver tumors could help researchers develop an early
diagnostic test for liver cancer as well as new treatments, the
researchers said. The disease is often far advanced at detection,
and the 5-year survival rate in the United States is only 4%.
A report on this tumor-suppressor gene appears in the December
1995 issue of Nature Genetics.
"Liver cancer is one of the most common cancers worldwide,
particularly because of its association with viral hepatitis,"
said Dr. Randy Jirtle, professor of radiation oncology at Duke
University Medical Center and prinicipal investigator of the study.
The lack of effective treatments also makes it a particularly
deadly disease, he said.
"As a consequence, knowing something about liver tumor formation
or having a handle on how one could detect these tumors when they're
much smaller could have a significant impact on survival,"
he said. Drs. Gerald R. Hankins and Mary K. Washington of Duke
and Drs. Angus T. De Souza and Terry C. Orton of Zeneca coauthored
The protein receptor produced by M6P/IGF2r is an attractive target
because it is present on the cell surface and in the plasma, Jirtle
said, making it readily accessible for use in both liver tumor
therapy and diagnosis.
Researchers often work backwards from the biologic changes involved
in cancer to find the genes responsible for these alterations.
In this case, however, the functions of an already identified
gene led Jirtle and his team to hypothesize its involvement in
"This is an 'old' gene for which we have characterized an
important new role," Jirtle said.
Three Distinct Regulatory Roles Within Cells
When working properly, the M6P/IGF2r receptor protein has at least
three distinct regulatory roles within a cell, said Jirtle. It
is involved in activating a very potent growth inhibitor, transforming
growth factor beta, and it disables a positive growth factor,
insulin-like growth factor II. The receptor also works inside
the cell as a shuttle craft, moving proteolytic enzymes to the
lysosomes, a part of the cellular digestive system that breaks
down proteins into simpler compounds.
Because the receptor is involved both in switching on a growth
inhibitor and inactivating a growth factor, the researchers hypothesized
that losing it might well predispose a cell to cancerous growth.
Their past studies showing that the protein was abundantly present
in normal liver cells but nearly absent in cancer cells strengthened
In research published earlier last year in Oncogene, Jirtle's
team found that liver tumors from 64% of patients studied had
lost one copy of the gene. The deletion of one copy, or allele,
means that a mutation in the remaining copy can limit or destroy
a cell's ability to produce functional protein.
Next, the researchers began the arduous process of screening the
large gene for one or more mutations that might disable it. Using
a method to detect mismatches in genetic material, they compared
strands of DNA from tumor cells and surrounding normal tissue,
and discovered mutations in the tumor samples. The discovery of
identical mutations in more than one tumor indicated potential
"hot spots"-regions of the gene that may be more susceptible
"One mutation results in an altered protein that lacks the
ability to insert itself into the cell membrane," according
to Dr. De Souza, who has spent three years at Duke University
investigating this gene. "Instead of carrying out its normal
regulatory functions, this shortened protein leaves the cell.
Once outside, it can no longer regulate cell growth."
The gene is also interesting to researchers because it could help
explain why mice appear to be more prone to liver tumor formation
than humans. Mice normally have only one active copy of this tumor-suppressor
gene rather than the two working copies humans possess. This evolutionary
oddity could have important implications for species susceptibility
to liver tumors and human risk assessment.
Animals and humans have two functional copies of almost every
gene, one from each parent. In rare cases, a gene is imprinted,
meaning that only one of the parental copies is active. The M6P/IGF2r
gene is especially unusual, because it is imprinted in mice but
not in humans. Lacking the back-up that humans have in case one
copy malfunctions, mice are more likely to lose complete function
of this gene, the researchers said. If further studies show that
loss of M6P/IGF2r function is important to the way that chemicals
cause liver tumors in rats, the scientists explained, pharmaceutical
companies could take into account the decreased likelihood of
this genetic loss occurring in humans when determining whether
to pursue the testing of a promising new drug.
Jirtle and colleagues are continuing their studies of M6P/IGF2r
by investigating whether this gene also plays a role in the formation
of other types of tumors. After 4 years of study, Jirtle said,
"We are at the end of the beginning."