In experiments with mice, a team of scientists from
the United States, Sweden and Japan has discovered that
having a double dose of one protein is sufficient to change
the normal balance of cells within the lining of the colon,
thereby doubling the risk that a cancer-causing genetic
mutation will trigger a tumor there. Roughly 10 percent of
people have this double protein dose as well.
In the Feb. 24 online version of Science, the
researchers report that mice engineered to have a double
dose of insulinlike growth factor 2, or IGF2, developed
more so-called precursor cells within the lining of the
colon than normal mice. When these mice also carried a
colon cancer-causing genetic mutation, they developed twice
as many tumors as those with normal IGF2 levels.
"Both clinically and scientifically, this discovery
should expand attention in colon cancer research to earlier
events, situations [that are] present well before tumors
appear," said the study's leader, Andrew Feinberg,
professor of medicine and director of the Center for
Epigenetics in Common Human Disease at Johns Hopkins.
"In the mice with a double dose of IGF2, everything is
pretty normal except for the extra precursor cells," said
Christine Iacobuzio-Donahue, assistant professor of
pathology and oncology. "But when the genetic mutation is
present too, we found a clear cost for what otherwise
appears to be a benign effect of extra IGF2."
The team's analysis of colon tissue samples from a
dozen or so Johns Hopkins patients with suspected colon
cancer suggests that IGF2's effect in people may be
similar. A larger study of samples from patients with and
without suspected colon cancer is under way, Feinberg
In the mice — as well as in about 30 percent of
colon cancer patients and 10 percent of the general
population — the extra IGF2 stems not from a genetic
problem, or mutation, but from an "epigenetic" problem that
improperly turns on the copy of the IGF2 gene that should
Unlike most genes, the copy of IGF2 that should be
silent depends on which parent it came from, a situation
called genomic imprinting. For IGF2, the copy inherited
from the mother is always supposed to be turned off.
In the mice and in some people, however, cells lack
the epigenetic "marks" that sit on the DNA and keep the
maternally inherited copy turned off. As a result, cells
make a double dose of the IGF2 protein and are said to have
"loss of imprinting" of IGF2.
Although Feinberg and others have already noted an
association between loss of imprinting of IGF2 and colon
cancer in people, the current experiments were designed to
find out whether the loss of imprinting is involved in
cancer's development or just in its progression.
"Most researchers, including me, expect epigenetic
differences to influence progression — whether a
tumor would grow slowly or quickly, or whether it would
spread," Feinberg said. "But, in this case, our results
show that loss of imprinting of IGF2 contributes to colon
cancer's development in the mice; it doesn't cause tumors
directly, but it creates an environment which is ripe for
cancer to start."
Because precursor cells in the colon's lining had been
identified as a likely starting point for tumors, Feinberg
and his team tossed a cancer-causing genetic mutation into
the mix. The IGF2 mice were crossed with mice carrying a
mutation in a gene called APC, which had been tied to colon
cancer by researchers studying families with excessive
growths, or polyps, in the colon.
Mice with extra IGF2 and the APC mutation developed
twice the number of tumors as mice with the mutation but
whose IGF2 levels were normal. The tumors grew at the same
rate in both sets of mice, suggesting that more tumors get
started in the mice with extra IGF2, Feinberg noted.
"In the mice, loss of imprinting of IGF2 roughly
doubles the risk that the genetic mutation will cause a
tumor," said postdoctoral fellow Atsushi Kaneda. "Double
the risk may not seem like much, but this loss of
imprinting is common."
The researchers' mice mirror two situations in people
because the double dose of IGF2 was accomplished in two
ways. One set of mice, obtained from Shirley Tilghman at
Princeton, has a double dose of IGF2 because they are
missing another gene, H19, whose sequence overlaps the
region that usually shuts off one copy of IGF2. As a
result, these mice lack H19 and have double IGF2.
To isolate the effect of the extra IGF2, Rolf Ohlsson
at the Uppsala University in Sweden developed a set of mice
missing only the control region for IGF2; their H19 gene
was intact. These mice likely mimic the 30 percent of colon
cancer patients and 10 percent or so of the human
population who have loss of imprinting of IGF2.
Only the Princeton mice have been crossed with the APC
mice. Both the Princeton and Swedish mice have the extra
precursor cells in the lining of the colon, suggesting the
effect on cancer development would be similar.
Co-author Dan Longo, of the National Institute on
Aging, noted that the mice with both double IGF2 and the
APC mutation should be a useful animal model to evaluate
the impact of colon cancer prevention strategies, including
dietary interventions and targeted drugs.
The researchers were funded by the National Cancer
Institute, the National Institute on Aging, the Uehara
Memorial Foundation and the Swedish Cancer Research
Foundation. Authors on the paper are Kaneda, Feinberg,
Iacobuzio-Donahue, Takashi Sakatani and Sten de Boom Witzel
of Johns Hopkins; Mark Carter, Minoru Ko and Dan Longo of
the National Institute on Aging; Hideyuki Okano of Keio
University School of Medicine, Tokyo; and Ohlsson of