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Researchers identify distinctive signature for metastatic prostate cancer

s, as well as researchers at other institutions, have found that in some cancers, this pathway has escaped the normal control mechanisms and helped spur uncontrolled cell proliferation. These include cancers arising in organs of the gastrointestinal tract, such as the stomach, pancreas, esophagus and biliary tract.

According to Beachy, since all these cancers arise in organs of endodermal origin, it seemed reasonable to test whether activation of the Hedgehog pathway might similarly drive the development of prostate cancer, which also arises from endodermal tissues.

In their initial studies, Beachy and his colleagues established that the Hedgehog pathway was, indeed, active in cultures of human metastatic prostate cancer cell lines. Blocking Hedgehog signaling with cyclopamine, a drug discovered by Beachy's group that targets another protein in the pathway, Smoothened, inhibited growth of these cell lines. Furthermore, they showed that when the tumor cells were introduced into mice, cyclopamine caused a permanent regression of the tumors.

"We interpreted the finding in mice to mean that we had probably killed tumor stem cells responsible for propagating the cancers," said Beachy. "This finding led us to explore the role that the Hedgehog pathway might play in the function of normal progenitor cells."

To study the relationship of the Hedgehog pathway to normal prostate stem cells, the researchers performed experiments in mice in which they eliminated the male hormone, androgen, causing regression of the prostate. Normally, restoring androgen causes the prostate to regenerate. However, the scientists were able to block this regeneration by giving the animals cyclopamine or a Hedgehog-neutralizing antibody.

In additional studies of cultures of cells that closely resemble these prostate progenitor cells, the researchers found that switching on the Hedgehog pathway caused them to proliferate and form tumors when implanted into mice. <
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Contact: Jennifer Michalowski
michalow@hhmi.org
301-215-8576
Howard Hughes Medical Institute
13-Sep-2004


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