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

Main Category: Cancer/Oncology News
Article Date: 05 Mar 2006 - 0:00am (UK)

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.”

University of Texas Medical Branch at Galveston
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Galveston, TX 77555-0144
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http://www.medicalnewstoday.com/medicalnews.php?newsid=38863

Public release date: 29-Mar-2006
Contact: Becky Oskin
becky.oskin@duke.edu
919-684-4966
Duke University Medical Center
Liver cancer linked to cellular repair pathway
DURHAM, N.C. – The unchecked activity of a cell signaling pathway crucial in embryonic development and the liver's response to injury leads to liver cancer, researchers from Duke University Medical Center and John Hopkins University School of Medicine have found.

Because the pathway, called Hedgehog, is present only in immature, stem-like liver cells, the discovery offers hope for targeted treatment of liver cancer, one of the leading causes of cancer-related death in the world. Laboratory experiments show that blocking the Hedgehog pathway kills cancer cells but leaves mature healthy liver cells intact, the researchers report. Treating patients with medications to interrupt the pathway would likely eliminate the cancer cells while sparing healthy liver tissue, said Jason Sicklick, M.D., a postdoctoral fellow at Duke and lead author of the study.

"Currently, there are no good chemotherapies for liver cancer, and many people with advanced liver disease are too ill for surgery to remove tumors," Sicklick said. "There is a desperate need for effective anticancer treatments that are safe for patients with liver disease."

The results will be published in the April 4, 2006, issue of Carcinogenesis. The research was funded by the National Institutes of Health.

Finding the overactivated Hedgehog pathway in liver cancer, but not in mature liver cells, also opens the door for development of new diagnostic tests for the disease, Sicklick said. "Signs of excessive Hedgehog activity in cirrhotic patients could alert us to early stages of liver cancer, as well as provide valuable prognostic information for patients," he said.

Sicklick and colleagues also discovered a new Hedgehog pathway mutation in a patient with liver cancer that may lead to overactivation of Hedgehog and trigger abnormal cell growth, promoting cancer development. In test tube and cell culture experiments, blocking the Hedgehog pathway reduced growth of cancer cells by over 90 percent.

Liver cancer, or hepatocellular carcinoma, often develops in people with cirrhotic livers damaged by chronic infections, such as hepatitis, by alcohol abuse or other causes. It is rare in people with healthy livers. The cancer's incidence is rising in the United States, with an estimated 17,550 new cases diagnosed in 2005 and 15,420 deaths. One reason for the rising rates is the increasing prevalence of obesity, which raises the risk of liver cancer five- to six-fold, said Anna Mae Diehl, M.D., chief of Duke's gastroenterology division and senior author on the study.

The liver's attempts to repair itself and regenerate new tissue after injury can trigger the Hedgehog pathway. During embryonic development, Hedgehog tells cells where and when to grow. In adult tissue, it signals the body to grow new tissue. "If the liver is injured badly, it uses some of the same mechanisms to repair itself as a fetus uses in growing a liver," Diehl said.

The Hedgehog pathway is also linked to certain brain, skin and muscle cancers and has recently been implicated in cancers of the pancreas, esophagus, lungs and prostate. The work by the Duke and Johns Hopkins team now adds liver cancer to the growing body of evidence suggesting these cancerous tumors are generated by stem-like cells.

Stem-like cells in the liver require the Hedgehog pathway for survival, the researchers discovered. These primitive cells are similar to stem cells, but differ in basic ways involving cell reproduction. Hedgehog may lead to liver and other cancers because of over-activation of Hedgehog pathway's components or genetic mutations that accumulate in these components during tissue repair.

"Ordinarily, the process is very tightly regulated, but apparently something goes wrong in these cells and the pathway is not turned off. That's what conveys malignancy," Sicklick said.

Study co-authors include Yin-Xiong Li, Yi Qi, Kouros Owzar and Wei Chen of Duke University Medical Center; Aruna Jayaraman, Rajesh Kannangai, Perumal Vivekanandan and Michael Torbenson of the Johns Hopkins University School of Medicine; and John Ludlow of Vesta Therapeutics.

Carcinogenesis. 2006 Feb 25; [Epub ahead of print]
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Activation of the hedgehog pathway in human hepatocellular carcinomas.

Huang S, He J, Zhang X, Bian Y, Yang L, Xie G, Zhang K, Tang W, Stelter AA, Wang Q, Zhang H, Xie J.

Institute of Developmental Biology, School of Life Sciences, Shandong University, Jinan, P.R. China.

Liver cancers, the majority of which are hepatocellular carcinomas (HCCs), rank as the fourth in cancer mortality worldwide and are the most rapidly increasing type of cancer in the United States. However, the molecular mechanisms underlying HCC development are not well understood. Activation of the hedgehog pathway is shown to be involved in several types of gastrointestinal cancers. Here we provide evidence to indicate that hedgehog signaling activation occurs frequently in HCC. We detect expression of Shh, PTCH1 and Gli1 in 115 cases of HCC and in 44 liver tissues adjacent to the tumor. Expression of Shh is detectable in about 60% HCCs examined. Consistent with this, hedgehog target genes PTCH1 and Gli1 are expressed in over 50% of the tumors, suggesting that the hedgehog pathway is frequently activated in HCCs. Of five cell lines screened, we found Hep3B, Huh7 and PLC/PRF/5 cells with detectable hedgehog target genes. [b]Specific inhibition of hedgehog signaling in these three cell lines by smoothened (SMO) antagonist, KAAD-cyclopamine, or with Shh neutralizing antibodies decreases expression of hedgehog target genes, inhibits cell growth and results in apoptosis. In contrast, no effects are observed after these treatments in HCC36 and HepG2 cells, which do not have detectable hedgehog signaling. Thus, our data indicate that hedgehog signaling activation is an important event for development of human HCCs.[/b