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“Hedgehog” Proteins May Indicate Spread of Prostate Cancer

By Cheryl Simon Silver

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An estimated one in six prostate cancer tumors has the potential to spread to other parts of the body, but there is no way to tell which cancers are likely to spread. Researchers now report that activity of a protein signaling system known as Hedgehog may indicate which cancers are likely to metastasize and which are likely to remain localized.

Hedgehog and related signaling proteins promote the regeneration of tissue and in some cases the growth of cancers.

Philip A. Beachy of Johns Hopkins University School of Medicine in Baltimore and the Howard Hughes Medical Institute says the finding could eventually lead to diagnostic measures that would spare some men from unnecessary prostate removal. Removal of the prostate can cause side effects including sexual and urinary dysfunction.

Although the research, which appeared in Nature, is drawing attention, Beachy says it is not yet ready for the clinic.

About 230,000 men will be diagnosed with this year with prostate cancer, which follows only lung cancer as a cause of cancer death in men.

Beachy and colleagues compared activity levels of the Hedgehog signal in prostate tumors that had been surgically removed. They could detect some Hedgehog activity in three of the 12 removed glands with localized tumors.

In contrast, in the 15 tissue samples from metastatic prostate cancers, Hedgehog activity was 10 to 100 times higher than in the three localized tumors. It is not known yet whether the tumors with low Hedgehog activity have potential to spread beyond the confines of the prostate.

When the researchers activated the Hedgehog signal in genetically engineered normal prostate cells, and implanted them into mice, aggressive, lethal tumors formed, further suggesting the protein’s role in metastasis.

Standard therapy for metastatic prostate cancer cuts off testosterone temporarily, but the cancer comes back. The research may open new avenues for possible treatments. When the scientists blocked the activity of the Hedgehog protein with either an antibody or a natural plant compound called cyclopamine, they were able to change the course of the disease.

When highly aggressive prostate tumors were implanted in mice, a low dose of cyclopamine or the antibody extended the animal’s lifespan. At higher doses, cancers did not spread—they disappeared and did not grow back.

Beachy, whose main interest is in studying the Hedgehog protein and how it works, says that perhaps within a year a pathologist could develop a diagnostic test that would be based on samples from biopsied tissues.

A drug candidate will probably take at least several years, he says. Several drug companies are studying cyclopamine, and ways to develop compounds that mimic its ability to stop the Hedgehog signal that spurs replication of cancer cells.

Topical applications may be closer at hand, however: A team of Turkish researchers reported last spring that when a cream containing cyclopamine was applied to basal cell skin cancers, the treated tumors “regressed rapidly.”

The prostate findings join other reports in the last few years that link signals from the Hedgehog protein and another signaling protein called Wnt to so-called epithelial cancers. These include not only prostate cancers but cancers of organs including the skin, stomach, colon, and esophagus. Together, epithelial cancers account for 90 percent of cancers, and one third of cancer deaths.

Beachy and colleagues Sunil S. Karhadkar and David M. Berman, also of Johns Hopkins, published a separate essay in Nature recently in which they posit that high levels of Hedgehog activity may be a sign that the body’s ongoing quest to repair injured tissue has gone awry. The pathways are activated in response to injury, but get stuck in the “on” position.

“We are thinking of cancer in many settings as a persistent state of injury repair,” Beachy says.

Beachy, P.A. et al. Hedgehog signaling in prostate regeneration, neoplasia and metastasis. Nature advanced online publication, September 12, 2004.
Beachy, P.A. et al. Mending and Malignancy. Nature 431, 402. (September 23, 2004).

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