Gene activity in prostate cancer is reminiscent of
that in the developing fetal prostate,
providing further evidence that all cancers are not equal,
Johns Hopkins researchers report. The
finding could help scientists investigate how to manipulate
the genetic program to fight a disease
whose biology remains poorly understood despite more than
half a century of investigation.
Decades ago, researchers noticed that cancers often
display many of the same "forever young"
features seen in healthy embryonic organs during their
early development: fast growth, evasion of
aging and death, recruitment of blood vessels to grow more
tissue, lots of movement and invasion of
Though researchers noticed these similarities as far
back as the 1920s, the sophisticated
technology necessary to test the relationships between
development and cancer didn't exist until
recently, said David Berman, associate professor of
urology at the Johns
Hopkins School of Medicine.
In a new study published online Sept. 15 in
Oncogene, Berman and his team used new gene-
profiling technology to compare the normally developing
prostate in mice to human prostate cancers.
The work took advantage of extensive existing knowledge
about prostate development in mouse
Male mice develop prostate glands in response to
androgens — male hormones that include
testosterone — during day 17 of a 21-day gestation.
An absence of androgen in female mice causes the
cells in the same area to develop into a vagina and
urethra, but females can grow prostates if they are
artificially supplied with androgen.
To kick-start prostate development on a precisely
timed schedule, the researchers gave
pregnant mice androgen shots on day 16 after conception,
sending male hormone circulating through
the mothers' bloodstreams to their developing litters. A
second group of pregnant mice were injected
with an inactive solution for comparison.
Using mouse gene chips that catalog nearly every gene
in the mouse genome, the researchers
probed to see which genes were turned on in the urogenital
areas of developing female mice six and 12
hours after they were exposed to androgen. They also
compared these mice to normally developing
females (not exposed to androgen) and males (which make
their own androgen).
Their gene-profiling results showed that the pattern
of activity of genes presumed to be
turned on and off by androgen exposure changed dynamically
over time. At six hours after injection,
693 genes responded to androgen, mostly by turning off. A
little later on, at 12 hours, 177 genes
responded, mostly by turning on. By 48 hours, on and off
responses were approximately equal, with
829 genes responding to androgen.
"Our pet theory is that these developmental genes may
be first turning off normal female
development in response to androgens and then turning on
prostate development," Berman said. "And
when we looked closer at the nature of these genes, we
found that many are involved in cell survival,
growth and movement, which are behaviors seen in cancer
cells, so we probed further to see if these
genes could be directly linked to prostate cancer."
By comparing the list of mouse genes to genes whose
human counterparts are known to be
involved in prostate cancers, the researchers found that
many of these developmental genes appear to
be turned on or off in prostate cancers, especially the
more aggressive types and at critical transition
points during cancer progression. Moreover, Berman said,
the same genes that appear to cause cells to
divide, move and change shape to form the prostate in a
developing fetus also seem to be reactivated
in prostate cancer cells, potentially causing them to
divide, move and spread.
"We've identified the programs that form the prostate
in the embryo and found them to be
remarkably similar to those that form tumors in prostate
cancer patients," Berman said. "Since
prostate development is reproducible, genetically and
pharmacologically tractable, and reflects the
entire spectrum of human prostate cancer progression, this
gives us a new roadmap for better
understanding this particular cancer and identifying new
prostate cancer-specific treatments."
These studies were funded by the Evensen Family,
Passano and Patrick C. Walsh Prostate
Cancer foundations, and the National Institutes of
Edward M. Schaeffer and Luigi Marchionni led the
laboratory and analytic work. Other
researchers who participated in this study are Zhenhua
Huang, Brian Simons, Amanda Blackman,
Wayne Yu and Giovanni Parmigiani.