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Duke Researchers Show How Hepatitis Infection Leads To Liver Cancer

Date:
September 20, 1997
Source:
Duke University Medical Center
Summary:
Hepatitis B and C infections slowly eat away at a person's liver, severely damaging liver function and greatly increasing the risk of liver cancer. Now researchers at Duke University Medical Center have discovered the hepatitis virus makes the liver into a cancer time bomb by converting the organ into billions of cancer-prone cells.

DURHAM, N.C. -- Hepatitis B and C infections slowly eat away at a person's liver, severely damaging liver function and greatly increasing the risk of liver cancer. Now researchers at Duke University Medical Center have discovered the hepatitis virus makes the liver into a cancer time bomb by converting the organ into billions of cancer-prone cells.

The finding, published in the Sept. 16 issue of the Proceedings of the National Academy of Sciences, demonstrates that once a hepatitis infection takes hold in the liver, even apparently healthy cells have lost one of two copies of a protective tumor suppressor gene called M6P/IGF2R, making them highly vulnerable to further genetic damage. Without a working copy of this suppressor gene, cancerous cell growth can't be stopped.

"This finding demonstrates that hepatitis infection somehow favors survival of a subset of liver cells that are defective in a key cancer protective gene we know is an early marker for development of liver cancer," said Randy Jirtle, lead investigator of the study. "This is a first step in understanding how the hepatitis virus damages the liver and greatly increase the chance of developing liver cancer."

In addition, he said a test for the gene may help surgeons determine how much tissue surrounding cancerous liver lesions needs to be removed. Some of that "normal-looking" tissue may already be on the path to cancer, he said.

The discovery is particularly relevant because hepatitis, particularly hepatitis C, is responsible for about 85 percent of liver cancer cases in the United States. The Centers for Disease Control and Prevention (CDC) estimates that 3.9 million Americans are infected with hepatitis C. Complications from hepatitis C are blamed for 10,000 deaths per year, but the CDC estimates the fatality rate could triple or quadruple within 15 years.

There is no effective treatment for hepatitis C, which is transmitted through contaminated blood. Most people become infected through intravenous drug use, which accounts for half of all infection. But nearly half of the people who become infected have no identifiable risk factors. Eighty percent of those who become infected develop chronic hepatitis, in which symptoms may be vague or missing for a decade or more.

During this silent period, the viral infection is slowly killing off healthy liver cells. The cells that remain, the researchers discovered, are genetically damaged, but still capable of regenerating the liver. The result is that much of the liver becomes a clone of genetically identical pre-cancerous cells. Eventually, one of those cells may sustain additional genetic damage during its normal function of detoxifying chemicals. Since these cells are already cancer-prone, they may not be able to "fix" the genetic damage, said Jirtle, and they become cancerous tumors.

The research was supported by a grant from the National Institutes of Health, and in part by Sumitomo Chemical Co. and Zeneca Pharmaceuticals. The research team included Jirtle, professor of radiation oncology at Duke; Tomoya Yamada of Sumitomo Chemical Co., Osaka, Japan; Angus De Souza of Zeneca Pharmaceuticals, Cheshire, U.K.; and Sydney Finkelstein of the University of Pittsburgh Medical Center.

Previous studies by Duke researchers showed the tumor suppressor gene M6P/IGF2R, which stands for mannose 6-phosphate/insulin-like growth factor II receptor, is often mutated in early-stage liver tumors, demonstrating that it plays an important role in the initial progression to liver cancer. The new study now links loss of the gene to hepatitis infection.

Normally, people have two copies of this cancer-fighting gene. Even if one copy of the gene has a mutation, the other good copy can usually compensate. But when the remaining good copy becomes deleted through a second mutation, the protein's tumor-fighting ability is lost completely.

The M6P/IGF2R protein is present in all cells of the body, where it performs several important functions that control cell growth, Jirtle said. It deactivates the potent growth promoter, IGF2, and it helps to activate a potent growth inhibitor called transforming growth factor beta 1 (TGFB1).

Hepatitis infection may favor survival of defective cells that lack one copy of this growth inhibitor gene because these cells have a growth advantage, Jirtle said. Another possibility is that these cells are somehow protected from viral infection, he said.

"Our finding that M6P/IGF2R inactivation is an early event in the development of liver cancer may provide a powerful approaches for diagnosis and treatment of liver cancer," said Jirtle. "We now have a marker for one of the earliest events in the progression to liver cancer in hepatitis-infected patients."


Story Source:

The above story is based on materials provided by Duke University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Duke University Medical Center. "Duke Researchers Show How Hepatitis Infection Leads To Liver Cancer." ScienceDaily. ScienceDaily, 20 September 1997. <www.sciencedaily.com/releases/1997/09/970920100223.htm>.
Duke University Medical Center. (1997, September 20). Duke Researchers Show How Hepatitis Infection Leads To Liver Cancer. ScienceDaily. Retrieved October 20, 2014 from www.sciencedaily.com/releases/1997/09/970920100223.htm
Duke University Medical Center. "Duke Researchers Show How Hepatitis Infection Leads To Liver Cancer." ScienceDaily. www.sciencedaily.com/releases/1997/09/970920100223.htm (accessed October 20, 2014).

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