Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis

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.