KEY TO METASTAS IS
The Hedgehog Pathway

Karhadkar, Berman, and Beachy have linked Hedgehog activity to prostate cancer’s wanderlust. The cancer can spread only if the pathway goes with it.

It is the great mystery of prostate cancer: Like people, some cancer cells are better than others, and some are far worse. Some cancer cells don’t seem to do much; others quickly become dangerous, spread to sites far away from the original tumor, and eventually, if unchecked, ravage the body. Scientists have long sought to understand the difference between indolent and overzealous prostate cancer cells. What gives some cells the power to slip away and cause trouble? The Hedgehog pathway is as essential for cancer to live outside its home-base environment as oxygen is to a deep-sea diver.

Now, they think they’ve found at least one answer. The secret seems to be a common protein pathway, normally responsible for embryonic development of the lung, pancreas, prostate, part of the brain, and many other organs. The protein in question is called the Hedgehog protein (years ago, scientists discovered that when this protein was mutated in fruit flies, the insects were born with telltale, hedgehog-like prickles).

In breakthrough research, published in the journal Nature, Hopkins scientists have shown that the Hedgehog pathway is the key to metastasis—as essential for a cancer cell to live outside its home-base environment as oxygen is to a deep-sea diver. Even more exciting—these scientists have proven that they can block the pathway, and stop metastasis in its tracks.

The implications of this work are farreaching. “If we can use Hedgehog activity to predict whether a tumor will metastasize, we will have a great diagnostic tool, and we are testing this hypothesis,” says David Berman, M.D., Ph.D., assistant professor of pathology, urology and oncology. But Berman and colleagues Sunil Kahadkar, M.D., and Philip Beachy, Ph.D., professor of molecular biology and genetics and a Howard Hughes Medical Institute investigator, are aiming higher. “Manipulating the Hedgehog signaling pathway may also offer a completely new way to treat metastatic prostate cancer,” Berman says.

The pathway is not present in normal prostate cells, nor in most low- to middlegrade prostate cancer cells. But it’s very active in metastatic deposits; it’s also active in cancer cells of men who were thought to have localized prostate cancer, but who later developed metastases.

The investigators looked for detectable activity of the Hedgehog signaling pathway in prostate specimens from men with localized disease, and from men who died of metastatic cancer. They found Hedgehog activity in only three of 12 localized tumors— but in every one of the metastatic cancers, and at levels that were 10 to 100 times higher. In effect, they equated Hedgehog activity with cancer’s wanderlust— this suggest that the cancer can spread only if the pathway goes with it.

“Think of the soil and seeds,” explains Patrick C. Walsh, M.D. “The soil is the stroma of the prostate, and the cancer cells are the seeds. If these cells spread but lack the proper soil, they can’t survive. But if they can manufacture the Hedgehog protein, they can make the soil that they need— they can pack their lunch and take it with them.” The next part of the story involves oneeyed sheep. In the 1950s and 1960s, several generations of sheep in the western United States were born with only one eye—Cyclops sheep.

Their birth defect turned out to be caused by something their mothers were grazing on—a plant that was shown to contain a chemical called, appropriately, cyclopamine. When Beachy knocked out the gene that makes the Hedgehog protein in mice, they produced “Cyclops”offspring, as well. From this observation, he deduced and then demonstrated that cyclopamine must block the Hedgehog pathway.

In laboratory experiments on mice with aggressive prostate tumors, from cell lines established by Brady scientist John Isaacs, Ph.D., Kahadkar blocked the Hedgehog signal with daily injections of cyclopamine. Cyclopamine slowed or reversed the cancer’s growth, and prolonged the animals’ lives.

“It’s unbelievable,” says Walsh. “This work shows a whole new approach to treating advanced prostate cancer—take away the soil, and the cells die.”