Researchers at Johns Hopkins have discovered that
cancers arising from epigenetic changes — in
this case, the inappropriate activation of a normally
silent gene — develop by becoming addicted to
certain growth factors.
Reporting online in the Dec. 11 Early Edition of the
Proceedings of the National Academies of
Sciences, the team shows that blocking this "addiction"
can greatly prevent cancer growth.
"If this is translatable to people, it could be really
exciting," said Andrew Feinberg, professor
of
medicine,
oncology and molecular biology and
genetics and director of the Epigenetics Center at
Johns Hopkins. "It means we might be able to do something
about at-risk cells before cancer develops,
and treat these cells biochemically and specifically rather
than using current drugs that are
nonspecific and kill everything in their path."
The gene for growth factor IGF-II (insulin-like growth
factor two) is one of several in the
human genome that is controlled by imprinting — where
one of the two copies of the gene is turned off,
depending on which parent it came from. Normally, the
IGF-II gene from your father is turned on and
the one from your mother is turned off. Loss of this
imprinting causes the activation of the maternal
copy, leading to activation of both copies of the IGF-II
gene, which has been associated with a
fivefold increased frequency of intestinal tumors in
people.
The Johns Hopkins team tested mouse cells with
imprinting intact, meaning that they have only
one copy of IGF-II activated, and compared them to cells
that had lost imprinting and have both
copies of IGF-II activated. They found that normally
imprinted cells respond to normal doses of
growth factor and recover within 90 minutes. However, cells
that had lost imprinting were activated
by the smallest doses and continued to stay activated for
more than 120 minutes.
Andre Levchenko, an assistant professor of biomedical engineering
at Johns Hopkins and co-
director of the study, said, "It's like they were on a hair
trigger, which was totally counterintuitive to
what we might have predicted. You would expect in cells
that have lost imprinting — and therefore have
twice the amount of gene product — that it would take
higher doses to activate the cell. In fact, the
cell becomes hypersensitized while having too much IGF-II
around."
The researchers then wondered if blocking the cells'
response to IGF-II could block cancer
growth in animals. Mice that develop colon cancer were
given a drug that specifically blocks a cell's
ability to respond to IGF-II. These mice developed 70
percent fewer precancerous lesions than mice
without treatment.
"Finding the molecular mechanism behind cancer
development allowed us to use a specific drug
to actually take care of these risky cells before the
animal developed cancer," Feinberg said. "It's
making us think about cancer prevention in a whole new
way."
The research was funded by the National Institutes of
Health and the Swedish Cancer
Research Foundation.
Authors on the paper are Atsushi Kaneda, Chiaochun
Wang, Raymond Cheong, Winston Timp,
Patrick Onyango, Bo Wen, Christine Iacobuzio-Donahue,
Levchenko and Feinberg, all of Johns Hopkins;
Rolf Ohlsson, of Uppsala University, Uppsala, Sweden; Rita
Andraos and Mark Pearson, of Novartis
Institute of Biomedical Research, Basel, Switzerland; and
Alexei Sharov, Dan Longo and Minoru Ko, of
the National Institute on Aging, Baltimore.
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