Tissue microenvironment implicated in susceptibility to liver cancer metastases
A new research study reports that, in addition to the metastatic potential of tumor cells, a permissive target environment plays a critical role in promoting progression and metastases of liver cancer. The findings, which appear in the August issue of Cancer Cell, published by Cell Press, may lead to strategies for identifying and possibly treating patients that are highly likely to develop metastases.
Hepatocellular carcinoma (HCC) is a liver cancer with an extremely poor prognosis because of its propensity to spread and invade surrounding tissues. Dr. Xin Wei Wang from the National Cancer Institute, Bethesda, Maryland, Dr. Zhao-You Tang from Fudan University, Shanghai, China, and colleagues recently identified a gene expression signature for primary HCC tumor cell specimens that could predict the metastatic potential of HCC in patients with 78% accuracy. To better understand the mechanisms underlying HCC metastases, the researchers went on to examine whether the metastatic propensity of HCC might also be influenced by the microenvironment of the local tissue.
A thorough examination of noncancerous hepatic tissues from two groups of HCC patients, those with and those without detectable metastases, revealed profound differences in gene expression profiles. Specifically, a unique 17 gene expression signature involving genes associated with inflammation and the immune system was identified in patients with the metastatic phenotype. These patients exhibited a global decrease in gene products associated with inflammation and an increase in anti-inflammatory gene products. Importantly, the genetic signature described in this study provided greater than 92% accuracy in predicting metastases, a result that far exceeds the accuracy of the previously described profile based on primary HCC cells.
The researchers also found that the colony-stimulating factor 1 (CSF1) is playing a prominent role in metastasis of liver cancer cells. "The CSF1 may be reprogramming the immune cells to switch from secreting cytokines that create a pro-inflammatory microenvironment to one that is anti-inflammatory--a condition that supports the growth and metastases of liver tumor cells," explains Dr. Wang.
The findings suggest that, in addition to the metastatic potential of the tumor cells themselves, the inflammatory status of the tissues surrounding the tumor cells may play a key role in tumor metastases and progression. "The genetic signature identified in this study is a superior predictive tool to determine HCC metastases and relapse and may have possible utility in clinical settings to identify HCC patients who might benefit from certain postsurgical treatment to prevent metastases and/or recurrence," said Dr. Wang.
The researchers include Anuradha Budhu and Marshonna Forgues of the Center for Cancer Research, National Cancer Institute, in Bethesda Maryland; Qing-Hai Ye of the Liver Cancer Institute and Zhongshan Hospital, Fudan University in Shanghai, China; Hu-Liang Jia of the Center for Cancer Research, National Cancer Institute, in Bethesda Maryland and the Liver Cancer Institute and Zhongshan Hospital, Fudan University in Shanghai, China; Ping He of the Center for Biologics Evaluation and Research, Food and Drug Administration in Bethesda, Maryland; Krista A. Zanetti of the Laboratory of Human Carcinogenesis and Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute in Bethesda, Maryland; Udai S. Kammula of the Surgery Branch, National Cancer Institute in Bethesda, Maryland; Yidong Chen of the Laboratory of Cancer Genetics, National Human Genome Research Institute in Bethesda, Maryland; Lun-Xiu Qin and Zhao-You Tang of the Liver Cancer Institute and Zhongshan Hospital, Fudan University in Shanghai, China; Xin Wei Wang of the Center for Cancer Research, National Cancer Institute, in Bethesda Maryland.
This study was supported by the Intramural Research Program of the Center for Cancer Research, the US National Cancer Institute, the China National Natural Science Foundation for Distinguished Young Scholars, the China National ''863'' R&D High-Tech Key Project, the State Key Basic Research Program of China, and the Key Program Project of National Natural Science Foundation of China.
Budhu et al.: "Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment." Publishing in Cancer Cell 10, 99–111, August 2006. DOI 10.1016/j.ccr.2006.06.016
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