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Researchers identify distinctive signature for metastatic prostate cancer

P> "This was a very striking observation, because it's very tough with manipulation of expression of a single cellular gene and has never been done before, to my knowledge to cause a primary human cell to become a cancer," said Beachy. "And that suggests that perhaps we have identified the right prostate target cell and activated the right pathway to trigger cancerous growth."

To relate their findings to the metastatic process, the researchers tested samples of metastatic prostate cancer from men who had died of the disease. They found a uniformly high level of Hedgehog activity in these tissues, compared to benign prostate tissue samples. The researchers also found high levels of Hedgehog pathway activity in rat prostate cancer cells known to be actively metastatic.

In contrast, cells that were not metastatic showed low levels of activity. In particular, said Beachy, their experiments showed that pathway activation in metastatic cancers depended on the expression of Smoothened suggesting that gene may be "a focal point of regulation in tissue regeneration and tumorigenesis."

They also found they could convert low-metastatic cells into highly metastatic tumors by activating the Hedgehog pathway. "We actually found we could interconvert the two kinds of cell lines in mice," said Beachy. "Whereas the high-metastatic lines were normally rapidly lethal in the mice, we could prolong survival essentially indefinitely by giving them cyclopamine. And when we activated Hedgehog in the low-metastatic lines, they became highly lethal," he said.

HHMI investigator Matthew Scott, a developmental biologist who has studied the Hedgehog pathway at Stanford University, noted that Beachy's "study is very thoroughly done and holds great promise in the search for new treatments for human disease. Quite possibly only some of the cells in a tumor "tumor stem cells" have the especially dangerous property of unlimited growth, so the search for ways to i
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
13-Sep-2004


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