Researchers have found that a unique pattern of activity in cells surrounding a liver tumor can accurately predict whether the cancer will spread to other parts of the liver or to other parts of the body. The preliminary research was led by a team of researchers*, including several from the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and other institutes, who reported these findings in the August 2006 issue of Cancer Cell**. A new follow-up study appearing online in the Feb 20, 2007 issue of Clinical Cancer Research*** has identified new biomarkers that may be useful in diagnosing early disease.

"Persistent and extensive inflammation of the liver is a common problem in hepatocellular carcinoma, or HCC, patients," said Xin Wei Wang, Ph.D., head, Liver Carcinogenesis Unit at NCI's Center for Cancer Research and study leader. "We wanted to examine the role that the large number of immune cells in the liver may play in supporting spread of the tumor."

"The tendency of hepatocellular carcinoma tumors to metastasize or recur following surgery contributes to the poor outcome associated with this disease," said NCI Director John E. Niederhuber, M.D. "Accurately predicting this cancer's risk of spread will help doctors decide on the best options to use in treating patients."

Researchers analyzed gene expression signatures -- patterns of gene activity --largely in immune cells within the liver microenvironment, which is the area immediately surrounding the tumor. The set of 17 genes included those that encode the messages for cytokines, which are small proteins produced by immune cells that are used to communicate messages between cells in the immune system to either turn up or down the immune response.

From the 17-gene set, researchers identified a unique pattern in the immune cells found in normal tissue of the liver microenvironment that could predict the potential for liver tumor metastasis. This metastasis-specific profile included gene activities responsible for increased production of certain cytokines that are associated with an anti-inflammatory response, as well as suppression of immune response. Increased levels of these cytokines are associated with a poor prognosis of cancer.

"When we used the gene signature of immune cells in the liver, we could predict tumors that would metastasize in 92 percent of the samples we studied," said Wang. "This is the first example where we can stratify HCC patients to identify those who would benefit from certain post-surgical treatments to prevent metastases and recurrence."

The 115 HCC patients included in the study were being treated at the Zhongsham Hospital, Shanghai, China. Fifty-two patients had tumors that had metastasized within the liver or to other organs, and 63 had tumors that had not metastasized. Samples from 22 patients with chronic liver disease and from eight normal livers were also studied as controls.

"We previously identified gene signatures in the liver tumor that could accurately predict the tumors that were capable of metastasis in 78 percent of the cases we studied," explained Wang. "This study is different because the immune cells associated with this signature are in the patient's normal liver tissue -- the microenvironment of the tumor. With this microenvironment gene signature, we could predict metastatic disease in 92 percent of the samples."

In the study that followed-up his microenvironment study, Wang and other colleagues looked for a set of biomarkers that could be used to diagnose early stage HCC. Currently, an elevated level of the protein alpha-fetoprotein (AFP) in the blood is the only known diagnostic biomarker for HCC. Unfortunately, an elevated level of AFP is detectable in only about two-thirds of patients with early-stage HCC, and high mortality from HCC is due to the inability to detect these cancers in their earliest stages. The results of the latest Wang study were reported online February 20, 2007 in Clinical Cancer Research***.

Using microarray techniques to examine a vast range of gene expression profiles from 218 HCC specimens, the Wang team and their collaborators at the Liver Cancer Institute of Fudan University identified five candidate genes that were overexpressed in HCC. Some of the specimens were taken from patients with early disease and low levels of AFP. In addition, since some of these markers are found in the blood of HCC patients, they may be useful biomarkers for early diagnosis of HCC. This latest finding in HCC, in combination with the earlier research into the tumor microenvironment, suggests a potential means for increased accuracy in diagnosis and monitoring recurrence during treatment.

HCC is the most common liver cancer diagnosed in adults and has a high prevalence in Asian and African populations. The rate of new HCC cases has been rising over the past 10 years in the United States. HCC is a very aggressive disease; patients usually survive less than one year after diagnosis. HCC occurs twice as often in men as in women. In 2006, an estimated 18,500 Americans will be newly diagnosed with liver cancer and an estimated 16,200 will die of the disease.

For more information about cancer, please visit the NCI Web site at http://www.cancer.gov, or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

For more information on Dr. Wang's research, go to http://ccr.cancer.gov/staff/staff.asp?profileid=5764.

*Researchers are from the Liver Cancer Institute and Zhongsham Hospital, Fudan University, Shanghai, China; Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Md.; Laboratory of Cancer Genetics, National Human Genome Research Institute, NIH, Bethesda, Md.; and NCI's Center for Cancer Research, Division of Cancer Prevention and Surgery Branch, Bethesda, Md.

**Budhu A, Forgues M, Ye Q, Jia H, He P, Zanetti KA, Kammula US, Chen Y, Qin L, Tang Z, and Wang XW. Prediction of venous metastases, recurrence and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. August 2006, Vol. 9, Issue 8.

***Jia H, Ye Q, Qin L, Budhu A, Forgues M, Chen Y, Liu Y, Sun H, Wang L, Lu H, Shen F, Tang Z, Wang, XW. Gene Expression Profiling Reveals Potential Biomarkers of Human Hepatocellular Carcinoma. Clinical Cancer Research. Online February 20, 2007. Vol 13, No. 4.

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