Scientists at Johns Hopkins
Kimmel
Cancer Center have identified a switched-off family of
genes that may prove to be a significant and early dent in
a colon cell's anti-cancer armor. The inactivated genes,
called SFRPs for secreted frizzled-related proteins, put
the brake on a pathway of cell-growth genes that is an
early step en route to cancer.
Because the way SFRP genes are altered--through the
attachment of so-called methyl groups--is reversible, the
findings, reported in the March 14 advance online edition
of Nature Genetics, also suggest potential
anti-cancer value in green tea and other compounds that
affect methylation.
"SFRP could be a great target for preventing cancer,"
said Stephen Baylin, Ludwig Professor of Oncology and
director for basic research at the Kimmel Cancer Center. A
cancer cell stops the SFRP gene's brake on cell growth by
attaching a methyl group to a specific portion of the gene
in a process called hypermethylation. Green tea and other
compounds are thought to block enzymes that control
methylation.
SFRP genes encode proteins that when secreted on the
cell's surface stop a chain reaction of cell growth
directed by the WNT gene. WNT stands for wingless type,
which, along with SFRP genes, gets its name from
characteristics of fruit flies with mutations in these
genes. The WNT gene pathway has long been linked to colon
cancer by scientists at the Kimmel Cancer Center and
elsewhere.
"Previously, we thought that mutations downstream of
the WNT gene were enough to trigger the cell to stay alive,
keep growing and develop into a tumor. Our key finding is
that the cell also may need to shut off SFRP genes to
become cancerous," Baylin said. When Baylin's team put
SFRPs back into colon cancer cells with inactivated SFRP
genes and mutations in the WNT pathway, the cells stopped
growing uncontrollably and died.
The research team also found that inactivation of SFRP
genes occurs in the earliest form of lesion, called an
atypical crypt foci (earlier than polyps or cancer).
Approximately 5 percent of these lesions become colon
cancers. "The colon cancer process may start by shutting
off SFRP genes, which allows the WNT pathway to stay on,
and these colon cells grow into atypical crypt foci,"
Baylin said. "Then, some of these early lesions may acquire
mutations in the WNT pathway that push the cell into growth
overdrive, failure to die properly and development into
polyps and, finally, cancer."
In addition to studying natural compounds, the
scientists will be investigating the prevention properties
of aspirin, non-steroidal anti-inflammatory drugs and other
drugs that block methylation to determine their effect on
SFRP genes.
This study was funded by the National Institute of
Environmental Health Services. Other participants in the
research from Johns Hopkins are Hiromu Suzuki, D. Neil
Watkins, Kam-Wing Jair, Kornel E. Schuebel, Yoshimitsu
Akiyama, Bin Yang and James G. Herman. The license to the
MSP technique used in this research belongs to
OncoMethylome. Baylin and Herman serve as consultants to
OncoMethylome and are entitled to royalties from any
commercial use of this procedure. The terms of this
arrangement are being managed by the Johns Hopkins
University according to its conflict-of-interest
policies.