'Hedgehog' Find Could Lead To New Liver Cancer Tests And Treatments

Main Category: Cancer / Oncology
Article Date: 05 Mar 2006 - 0:00 PDT

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A discovery by researchers at the University of Texas Medical Branch at Galveston (UTMB) and their colleagues at China's Sun Yat-Sen and Shandong Universities could lead to new methods of diagnosing and treating the most common form of liver cancer, hepatocellular carcinoma (HCC).

HCC, one of the hardest kinds of cancer to diagnose and treat, kills 14,000 people every year in the United States alone, primarily striking those chronically infected by the hepatitis C virus. Its occurrence is increasing faster than that of any other kind of cancer.

In an article published online in the journal Carcinogenesis, the scientists report that HCC tissue samples taken from liver cancer patients and HCC experimental cell lines both tested positive for a particular series of biochemical reactions implicated in many other common cancers, including those of the skin, prostate, brain, lung and breast.

Activation of this so-called "hedgehog pathway" helps spark the runaway cell division that can lead to cancer, and substances that block it can cause cancer cells to die and tumors to shrink. (The pathway takes its name from one of its components, a signaling protein important to animal growth and development that was discovered by fruit-fly geneticists; mutations in the gene that produces this "hedgehog" protein cause the flies to develop a spiky, hedgehog-like skin.)

"We think that hedgehog signaling activation is one of the major events involved in the development of hepatocellular carcinomas, so identifying hedgehog signaling would be an important way to diagnose HCC in its early stages," said the study's lead author, Jingwu Xie, an associate professor of pharmacology and toxicology at UTMB and member of the university's Sealy Center for Cancer Cell Biology. "Currently, since most HCCs are diagnosed late, most patients are essentially not treatable. And if, as seems likely, the hedgehog pathway is responsible for maintaining liver cells that serve as the 'seeds' of hepatocellular carcinoma - what could be called cancer stem cells - we should be able to target those with an optimum dose of hedgehog inhibitors and, we hope, completely eliminate cancerous cells from the liver."

Xie's UTMB group and the Sun Yat-Sen and Shandong University researchers analyzed hepatocellular carcinoma tissue specimens taken from 115 Chinese liver-cancer patients. They detected molecular markers for hedgehog pathway activation in over half the specimens- a striking result, because the hedgehog pathway is normally completely dormant in adult liver cells.

The scientists also found signs of hedgehog pathway activity in three of the five lab-raised hepatocellular carcinoma cell lines they tested. When the cell lines were treated with substances known to interfere with hedgehog signaling - the plant-derived compound cyclopamine and antibodies to a specific hedgehog protein known as "sonic hedgehog"- cancer cell proliferation slowed, and in some cases cells actually underwent apoptosis, a process of "programmed suicide."

"Currently, there are no specific treatments for HCCs, and what treatments are available cause liver damage," Xie said. "The application of hedgehog signaling inhibitors to HCC gives hope for effective HCC treatment. In addition, now that we know hedgehog signaling activation is an early event prompting HCC development, we should be able to create a transgenic mouse with human genes, a model system that will help us identify other molecular events leading to HCC tumors, which could help us develop other new drug and diagnosis targets."

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