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 study.
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 liver cancer.
"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 their suspicion.
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 to mutation.
"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."