Researchers have isolated and characterized the progenitor cells that give rise to malignant hepatocellular carcinoma tumors long before the actual tumors can be detected. These results may have profound implications for the diagnosis and treatment of hepatocellular carcinoma, the most common form of liver cancer.

Hepatocellular carcinoma develops slowly and often does not produce symptoms until it is at an advanced stage, making it difficult to diagnose. Although treatments are available for the early stages, no effective treatment exists for the advanced stages of hepatocellular carcinoma, which is usually fatal within 3 to 6 months of diagnosis.

An estimated 30,000 new cases of liver cancer are diagnosed annually in the United States, mostly in men. More than 21,600 Americans die from liver cancer each year and that rate has doubled over the past 20 years. Hepatocellular carcinoma is the third leading cause of cancer-related deaths worldwide.

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Michael Karin, PhD, of the University of California, San Diego School of Medicine and his colleagues found that hepatocellular carcinoma progenitor cells occur in dysplastic liver lesions in mouse models of hepatocellular carcinoma. Liver damage in humans can be caused by viral infections such as hepatitis or chronic alcohol abuse.

“It was never established whether dysplastic lesions are just a regenerative (healing) response of the liver triggered by tissue damage or are actually premalignant lesions that harbor tumor progenitor cells,” said study coauthor Debanjan Dhar, PhD, a postdoctoral researcher in Karin’s laboratory. “Here we show that hepatocellular carcinoma progenitor cells are likely derived from dysplastic lesions, can progress to malignant tumors, and further demonstrate that the malignant progression of hepatocellular carcinoma progenitor cells to full-blown liver cancer depends upon the microenvironment that surrounds them.”

The researchers characterized the progenitor cells based on several biomarkers that distinguish them from normal cells, and identified cellular signaling pathways critical for development of the cells’ malignant potential. Elevated expression of LIN28, a regulatory protein, is required for production of autocrine IL-6, a cytokine involved in cell signaling; together, they control the development of progenitor cells into hepatocellular carcinoma cells. Cells with elevated LIN28 and IL-6 expression exist in both mouse and human premalignant liver lesions.

Researchers were able to detect potential malignant lesions in needle biopsies of a subset of patients infected with the hepatitis C virus who had not developed hepatocellular carcinoma. Hepatitis C is a major risk factor for hepatocellular carcinoma development.

Dhar said that identifying premalignant lesions in high-risk patients based on markers associated with the progenitor cells would allow for earlier detection as well as therapeutic interventions. “Better understanding of … the cellular networks will provide us with new and effective therapeutic targets … therapies can be developed to specifically eliminate the hepatocellular carcinoma progenitor cells even before a tumor has developed.”

This study was published in Cell (2013;