Chronic
inflammation combines with DNA methylation, a process that closes
against cancer genes, to promote the development of colorectal cancer,
scientists at the University of Texas MD Anderson Cancer Center report
today in the advance online publication of the journal Nature Medicine.
Connections
teams of two separate effects can eventually lead to a better
combination therapies to treat and prevent colorectal cancer.
In
animal experiments, researchers found that prostaglandin E2, a chemical
that promotes inflammation, accelerate the development of colorectal
cancer by shutting down genes that suppress tumors and repair damaged
DNA. They
also found that while both as an anti-inflammatory drug or a
demethylating agent reduces the size and number of tumors in mice with
colorectal cancer, the strongest response occurs when both drugs are
used together.
"We've
known that chronic inflammation increases cancer risk and progression
of the disease," said senior author Raymond DuBois, MD, Ph.D., provost
and executive vice president at MD Anderson. "We
have also known that tumor suppressor genes are silenced in human
colorectal cancer, however, no one has made a molecular link between
inflammatory mediators and changes in gene expression or silencing of
genes through DNA methylation affects on .."
Potential cancer preventionTwo
drugs used in animal experiments - an anti-inflammatory agent celecoxib
(known commercially as Celebrex ®) and the demethylating agent
azacitidine (Vidaza ®) - are both approved for human use.
"One
of the potential applications of our research will be clinical trials
for patients who are at particularly high risk for developing colorectal
cancer, such as those with a genetic predisposition, to see whether
treatment with these agents would reduce their risk," said DuBois.
Prostaglandin E2 and methylationProstaglandin E2 (PGE2) is a lipid mediator that is found at high levels at sites of inflammation where immune cells merge. DuBois
and colleagues to find a correlation between the levels of PGE2 and a
class of enzymes called DNA methyltransferases, which attach a methyl
group (one carbon atom with three hydrogen atoms) to the promoter
regions of genes, blocking gene expression.
"We
found that PGE 2 levels correlated with levels of two
methyltransferases, DNMT1 and DNMT3, in human colorectal cancer
specimens," said DuBois.
Subsequent experiments showed PGE2:* Directly elevated levels of both enzymes methylating in three human cell lines of colorectal cancer;* Improved silencing by methylation of tumor suppressor gene CNR1 and DNA repair gene MGMT;*
Methylation also expanded from a variety of other DNA repair genes, the
most important and MLH1 silencing CDKN2B, a DNA mismatch repair.
PGE 2 protective silence genes in mice
Treating mice that were genetically altered to develop intestinal tumors with increased PGE2:
* The level of gene expression in tumor cells methyltransferase;
* Methylation of four tumor suppressor genes, which reduces the expression of messenger RNA and associated protein levels in tumor cells, and
* The size and number of precancerous polyps.
Giving them demethylating agent azacitidine rats reversed the effect of PGE 2 on tumor growth and the silencing of tumor suppressor genes and DNA repair.
Mice treated with azacitidine alone experienced a 60 percent decline in tumors, and those treated with celecoxib alone, 77 percent reduction in tumors. Treatment with both drugs simultaneously reducing the number of tumors by 93 percent. All three regimens also reduced the average tumor size, but the combination therapy caused the largest decrease, cutting by half the size of the tumor.
Seen in human colorectal cancer the same correlation
The researchers found that various processes were observed in mice - such as the promotion of inflammation by PGE2 and other inflammatory agents called PTGS2, methlytransferases DNMT1 and DNMT3B, and methylation CNR1, MGMT and MLH1 - all positively related to human colorectal cancer, as well.
"This study mice makes us optimistic that we can extrapolate our data to help humans treat," said DuBois. "Improved understanding of the role of PGE 2 in cancer development and regulation of DNA methylation may provide a basis for developing combination therapies to treat patients with the target group, and to prevent cancer from occurring or recurring in high-risk groups."
