Johns Hopkins researchers have discovered a possible
way to distinguish lethal metastatic prostate cancers from
those restricted to the walnut-size organ.
If future studies show their test — measuring
the level of activity of a signaling pathway called
Hedgehog — can predict which prostate cancers will
spread, the results could revolutionize decision-making
processes for prostate cancer patients, the researchers
say.
Most prostate cancers grow slowly, making "watchful
waiting" a common alternative to immediate surgical removal
of the prostate. However, there's no sure-fire way to tell
whose cancer will stay put in the gland and whose will be
aggressive and spread, a development that despite
aggressive treatment is usually fatal.
In the Sept. 12 advance online edition of
Nature, the Johns Hopkins researchers report that
only three of 12 localized prostate tumors obtained at
surgery had detectable activity of the Hedgehog signaling
pathway. In contrast, all 15 samples of metastatic prostate
cancers, donated at patients' deaths, had Hedgehog
activity, which was 10 to 100 times higher than the highest
levels seen in localized tumors. It remains to be seen
whether Hedgehog activity in localized cancers will predict
the ability to be metastatic.
The Hedgehog pathway produces a well-known growth and
development signal during embryonic and fetal stages. It is
also active in some cancers, including prostate, pancreatic
and stomach cancers and the brain tumor medulloblastoma,
but the researchers' study is believed to provide the first
evidence of its role in cancer's spread.
"If we can use Hedgehog activity to predict whether a
tumor will metastasize, we will have a great diagnostic
tool, but manipulating the Hedgehog signaling pathway may
also offer a completely new way to treat metastatic
prostate cancer," says David Berman, assistant professor of
pathology,
urology and
oncology at Johns Hopkins. "Right now nothing works
very well — you can help temporarily by cutting off
testosterone, but the cancer always comes back."
In experiments with mice, fellow Sunil Kahadkar showed
that blocking the Hedgehog signal with daily injections of
either a natural plant compound called cyclopamine or an
antibody slowed and even reversed growth of highly
aggressive rat prostate tumors implanted into the animals.
Without treatment, the aggressive cancers, from a
collection established by Johns Hopkins' John Isaacs,
killed the animals within 18 days. A low dose of
cyclopamine gave the animals an extra week to 10 days, but
at a higher dose, these aggressive cancers not only didn't
metastasize, they actually disappeared and didn't
return.
In a similar set of experiments using human prostate
cancers implanted into mice, treatment with cyclopamine
also caused those tumors to regress and not return —
even months after treatment was stopped, the researchers
report.
"Cyclopamine may not itself become an anti-cancer
drug, in part because it's already in the public domain
— it's been known since the mid-1960s as the cause of
one-eyed sheep in the western U.S.," says Philip Beachy,
professor of molecular
biology and genetics in Hopkins' Institute for Basic
Biomedical Sciences and a Howard Hughes Medical Institute
investigator. "But our finding that cyclopamine inhibits
Hedgehog signaling has provided the basis for drug
companies' very active efforts to develop new mimics of
cyclopamine."
Right now, prostate cancer is evaluated largely by
levels of prostate specific antigen circulating in the
blood. However, the ranges associated with various
potential diagnoses — noncancerous growth, cancer and
aggressive cancer — are fairly rough guides. And even
under a microscope, aggressive prostate cancer doesn't
always look appreciably different from its wallflower
counterpart.
In sharp contrast, levels of Hedgehog activity weren't
even close between still-localized tumors removed during
prostatectomies and those from lethal metastatic prostate
cancers, which were collected as part of a research program
run by G. Steven Bova, assistant professor of pathology, to
try to figure out what makes them so deadly.
To investigate Hedgehog's role in metastasis,
Karhadkar genetically engineered normal prostate cells to
activate their Hedgehog signal. These cells then grew
unchecked and formed aggressive tumors when implanted into
mice, he found. He also discovered that triggering Hedgehog
activity in a low-metastasizing rat prostate cancer line
made it metastasize aggressively.
"Hedgehog isn't just making these cells grow and
divide more; the signal is really converting them from
being indolent to being highly invasive and dangerous,"
Beachy says.
Exactly how the Hedgehog signal is involved in other
cancers, including pancreatic and stomach cancers and
medulloblastoma, a childhood brain cancer, is still being
worked out. Critical in normal embryonic development, the
signal is supposed to be turned off when cells take on the
"grown-up" identity of a differentiated cell type.
Karhadkar, Beachy and Berman — and a growing
number of other scientists — point to the involvement
in cancer of embryonic proteins and pathways like Hedgehog
as evidence that aggressive cancer in particular might form
not by accumulation of genetic errors in regular cells but
because a smaller number of errors occurs in a more
primitive cell, what might be called a "stem cell," in the
tissues. And it would be these "cancer stem cells" —
transformed versions of the tissue's normal stem cells
— that metastasize and travel through the body to
form new tumors in distant places.
"Perhaps aggressive prostate cancers get started from
a more primitive prostate cell or from a different
initiating lesion than do prostate cancers that don't
metastasize," Beachy says. "It's an idea we're
exploring."
The research was funded by the National Institutes of
Health, the Prostate Cancer Foundation and the Howard
Hughes Medical Institute. Authors on the paper are
Karhadkar, Bova, Nadia Abdallah, Surajit Dhara, Anirban
Maitra, John Isaacs, Berman and Beachy, all of Johns
Hopkins; and Dale Gardner, of the U.S. Department of
Agriculture's Poisonous Plant Research Laboratory.