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Low-fat diet helps genetically predisposed animals avoid liver cancer
June 12, 2009Penn study could lead to screening methods to detect precancerous conditions and cancer prevention strategies related to obesity
PHILADELPHIA - In a study comparing two strains of mice, one susceptible to developing cancer and the other not, researchers found that a high-fat diet predisposed the cancer-susceptible strain to liver cancer, and that by switching to a low-fat diet early in the experiment, the same high-risk mice avoided the malignancy. The switched mice were lean rather than obese and had healthy livers at the end of the study.
The findings, from a joint University of Pennsylvania School of Medicine and Case Western Reserve University study, appear online this month in Human Molecular Genetics.
The investigators studied hepatocellular carcinoma (HCC), a type of liver cancer that is one of the leading causes of cancer death worldwide. Thirty percent of cases of this type of liver cancer are associated with obesity, type 2 diabetes, and related metabolic diseases, although a direct link between these and liver cell cancer has not been completely established. "The connection between obesity and cancer is not well understood at this point," says senior co-author John Lambris, PhD, the Dr. Ralph and Sallie Weaver Professor of Research Medicine at Penn. The researchers hope the results will lead to the development of blood tests that can detect precancerous conditions related to diet.
The remaining seventy percent of HCC cases result from hepatitis B and C viral infections, exposure to the fungal toxin aflatoxin, chronic alcohol use, or genetic liver diseases.
The usual outcome of hepatocellular carcinoma is poor, because only 10 to 20 percent of these tumors can be surgically removed. If the cancer cannot be completely removed, the disease is usually deadly within 3 to 6 months. Hepatocellular carcinoma causes close to 700,000 deaths worldwide per year, mostly outside the US.
The researchers tested the long-term effects of high-fat and low-fat diets on males of two inbred strains of mice and discovered that one strain, named C57BL/6J, was susceptible to non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma on a high-fat, but not a low-fat diet. The other strain, called A/J, was not susceptible to disease on a high-fat diet. The mice were fed their respective diets for close to 500 days, weighed periodically, and then analyzed for the presence of disease.
RNA profiles of hepatocellular carcinoma versus tumor-free liver tissue at the end of the experiment showed that two signaling networks - one centered on Myc and the other on NF-kappa B - were involved. This result is similar to findings obtained from studies on the two major classes of hepatocellular carcinoma in humans.
At the end of the experiment, mice susceptible to cancer showed characteristics of NASH such as inflammation and fibrosis, and, in some cases, cirrhosis as well as hepatocellular carcinoma, in their livers. A switch from a high-fat to a low-fat diet reversed these outcomes in groups of C57BL/6J mice that were fed a high-fat diet early in the experiment. The switched C57BL/6J mice were lean rather than obese and had healthy livers at the end of the study. All mice kept on a high-fat diet for the duration of the experiment had liver tumors at the end of 500 days.
A similar change in diet may have important implications for preventing liver cancers in humans, suggest the researchers. "The reason these findings are so provocative is that it relates to diet and we now have a unique model we know will develop cancer," says Lambris.
"By waiting for evidence of disease before terminating the study, instead of using an arbitrary endpoint as is done in most experimental studies, we were able to discover an important new experimental model for a common cancer in humans," says senior co-author Joseph Nadeau, Professor and Chair of the Department of Genetics at Case Western Reserve University School of Medicine.
University of Pennsylvania School of Medicine
The investigators studied hepatocellular carcinoma (HCC), a type of liver cancer that is one of the leading causes of cancer death worldwide. Thirty percent of cases of this type of liver cancer are associated with obesity, type 2 diabetes, and related metabolic diseases, although a direct link between these and liver cell cancer has not been completely established. "The connection between obesity and cancer is not well understood at this point," says senior co-author John Lambris, PhD, the Dr. Ralph and Sallie Weaver Professor of Research Medicine at Penn. The researchers hope the results will lead to the development of blood tests that can detect precancerous conditions related to diet.
The remaining seventy percent of HCC cases result from hepatitis B and C viral infections, exposure to the fungal toxin aflatoxin, chronic alcohol use, or genetic liver diseases.
The usual outcome of hepatocellular carcinoma is poor, because only 10 to 20 percent of these tumors can be surgically removed. If the cancer cannot be completely removed, the disease is usually deadly within 3 to 6 months. Hepatocellular carcinoma causes close to 700,000 deaths worldwide per year, mostly outside the US.
The researchers tested the long-term effects of high-fat and low-fat diets on males of two inbred strains of mice and discovered that one strain, named C57BL/6J, was susceptible to non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma on a high-fat, but not a low-fat diet. The other strain, called A/J, was not susceptible to disease on a high-fat diet. The mice were fed their respective diets for close to 500 days, weighed periodically, and then analyzed for the presence of disease.
RNA profiles of hepatocellular carcinoma versus tumor-free liver tissue at the end of the experiment showed that two signaling networks - one centered on Myc and the other on NF-kappa B - were involved. This result is similar to findings obtained from studies on the two major classes of hepatocellular carcinoma in humans.
At the end of the experiment, mice susceptible to cancer showed characteristics of NASH such as inflammation and fibrosis, and, in some cases, cirrhosis as well as hepatocellular carcinoma, in their livers. A switch from a high-fat to a low-fat diet reversed these outcomes in groups of C57BL/6J mice that were fed a high-fat diet early in the experiment. The switched C57BL/6J mice were lean rather than obese and had healthy livers at the end of the study. All mice kept on a high-fat diet for the duration of the experiment had liver tumors at the end of 500 days.
A similar change in diet may have important implications for preventing liver cancers in humans, suggest the researchers. "The reason these findings are so provocative is that it relates to diet and we now have a unique model we know will develop cancer," says Lambris.
"By waiting for evidence of disease before terminating the study, instead of using an arbitrary endpoint as is done in most experimental studies, we were able to discover an important new experimental model for a common cancer in humans," says senior co-author Joseph Nadeau, Professor and Chair of the Department of Genetics at Case Western Reserve University School of Medicine.
University of Pennsylvania School of Medicine
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Huachansu, a Chinese medicine that comes from the dried venom secreted by the skin glands of toads, has tolerable toxicity levels, even at doses eight times those normally administered, and may slow disease progression in some cancer patients, say researchers from The University of Texas M. D. Anderson Cancer Center.
HBV genotype B/B3 and C/C1 are the major genotypes in Indonesia?
Previous studies revealed that HBV genotypes as well as mutations in the core promoter, precore or HBx gene have been shown to have an association with the clinical outcome of liver disease, however, this is still controversial.
Sequential TACE and cryosurgery can improve survival times for patients with HCC?
Hepatocellular carcinoma (HCC)--a liver cancer--is recognized as one of the most common cancers in the world that disproportionately affects Southeast Asians and Africans.
Is RTA a new potential option for the treatment of hydatid cysts?
Current treatment of cystic echinococcosis is surgery or percutaneous aspiration, injection and reaspiration (PAIR) using hypertonic saline or ethanol.
Targeting Tumor Behavior May Lead To New Liver Cancer Drugs
Ohio State University cancer researchers have used computational and genomic methods to identify possible anti-cancer agents that may block a particular kind of tumor behavior.
What is the relationship between hepatocellular carcinoma and type 2 diabetes mellitus?
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related deaths.
Study indicates cancer preventive effect for statins
The commonly used prescription statin drugs may have a protective effect in the prevention of liver cancer and lead to a reduction in the need for gallbladder removals, according to two studies published in Gastroenterologyiption statin drugs may have a protective effect in the prevention of liver cancer and lead to a reduction in the need for gallbladder removals, according to two studies published in Gastroenterology.
Is telmisartan effective in treating non-alcoholic steatohepatitis?
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are well-recognized causes of progressive liver disease leading to cirrhosis and hepatocellular carcinoma.
Targeting the protein AEG1 impairs human liver cancer growth in mice
Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer and one of the 5 most common cancers worldwide. Devanand Sarkar and colleagues, at Virginia Commonwealth University School of Medicine, Richmond, have now identified a gene that is expressed at high levels in human HCC tumor samples and generates a protein important for HCC progression.
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