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.
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,
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.
| “Manipulating the Hedgehog
signaling pathway may also offer a completely new way to treat metastatic
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.”