Navigation Links
Inflammatory mediator promotes colorectal cancer by stifling protective genes
Date:1/22/2012

HOUSTON - Chronic inflammation combines with DNA methylation, a process that shuts down cancer-fighting genes, to promote 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.

The team's connection of these two separate influences eventually may lead to better combination therapies for treating and preventing colorectal cancer.

In animal experiments, researchers found that prostaglandin E2, a chemical that promotes inflammation, accelerates the development of colorectal cancer by shutting down genes that suppress tumors and repair damaged DNA. They also found that while either an anti-inflammatory drug or a demethylating agent reduced the size and number of tumors in mice with colorectal cancer, the most powerful response occurred when both drugs were used together.

"We've known that chronic inflammation increases the risk of developing cancer and progression of disease," said senior author Raymond DuBois, M.D., Ph.D., provost and executive vice president at MD Anderson. "We've also known that tumor-suppressing genes are silenced in human colorectal cancer. However, nobody had made a molecular connection between these inflammatory mediators and changes in gene expression or silencing of genes through affects on DNA methylation."

Cancer prevention potential

The two drugs used in the animal experiments - the anti-inflammatory agent celecoxib (known commercially as Celebrex) and the demethylating agent azacitidine (Vidaza) - are both approved for human use.

"One potential application of our research would be a clinical trial for patients who are at extremely high risk for developing colorectal cancer, such as those with a genetic predisposition, to see if treatment with these agents would decrease their risk," DuBois said.

Prostaglandin E2 and methylation

Prostaglandin E2 (PGE2) is a lipid mediator found at high levels at sites of inflammation where immune cells are aggregating. DuBois and colleagues looked for correlations between levels of PGE2 and a class of enzymes called DNA methyltransferases, which attach methyl groups (one carbon atom joined to three hydrogen atoms) to the promoter region of genes, blocking gene expression.

"We found that levels of PGE2 correlate with levels of two methyltransferases, DNMT1 and DNMT3, in human colorectal cancer specimens," DuBois said.

Subsequent experiments showed PGE2:

  • Directly increased levels of both methylating enzymes in three human colorectal cancer cell lines;
  • Increased the silencing by methylation of the tumor-suppressor gene CNR1 and the DNA repair gene MGMT;
  • Also expanded methylation of a variety of other DNA repair genes, most importantly silencing CDKN2B and MLH1, which repairs DNA mismatches.

PGE2 silences protective genes in mice

Treating mice that are genetically altered to develop colon tumors with PGE2 increased:

  • Levels of the methyltransferase gene expression in tumor cells;
  • Methylation of the four tumor-suppressing genes, which reduced the expression of their corresponding messenger RNA and protein levels in tumor cells; and
  • Size and number of precancerous polyps.

Giving those mice the demethylating agent azacitidine reversed the effect of PGE2 on tumor growth and on the silencing of tumor-suppressing and DNA repair genes.

Mice treated with azacitidine alone experienced a 60 percent reduction in tumors, and those treated with celecoxib alone, a 77 percent tumor reduction. Treatment with both drugs in tandem cut the number of tumors by 93 percent. All three regimens also reduced the average size of tumors; however, the combination therapy led to the greatest decrease, cutting the size of tumors by half.

Same correlations evident in human colorectal cancers

The researchers found that various processes observed in mice - such as inflammation promotion through PGE2 and another inflammatory agent called PTGS2, methlytransferases DNMT1 and DNMT3B, and the methylation of CNR1, MGMT and MLH1 - are all positively associated in human colorectal cancer, as well.

"These mouse studies make us optimistic that we can extrapolate our data to help treat humans," DuBois said. "Improved understanding of PGE2's roles in cancer progression and the regulation of DNA methylation may provide the basis for developing combination therapy to treat targeted groups of patients, and to prevent cancer from occurring or recurring in high-risk groups."


'/>"/>
Contact: Scott Merville
smerville@mdanderson.org
713-516-4855
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

Related medicine news :

1. Inflammatory Bowel Ups Risk for Blood Clots
2. NIH grant will create behavioral health registry for pediatric inflammatory bowel disease
3. Prozac and Celexa exhibit anti-inflammatory effects
4. Physician's Pain Relief Cream Includes Patented Anti-inflammatory in New Formula
5. Feedback loop explains inflammatory effect on intestinal lining
6. Study Details Machinery of Immune Protection Against Inflammatory Diseases Like Colitis
7. Two New Phytochemicals with Anti-Inflammatory Activity Found in Noni Fruit
8. New research reinforces anti-inflammatory properties of tart cherries
9. First Annual Observance of World IBD Day Draws Awareness to Growing Global Incidence of Inflammatory Bowel Disease
10. POP ROCK BAND Honor Society Drummer Advocates for Inflammatory Bowel Disease Patients on Capitol Hill in Conjunction with World IBD Day
11. Crohn's & Colitis Foundation National Event Helping Women Manage Inflammatory Bowel Disease: Two Women Physician Experts and Researchers in IBD on Interactive Webcast/Teleconference
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/13/2017)... Vegas, Nevada (PRWEB) , ... October 13, 2017 , ... ... 7® Hemp CBD Oil utilizing Purzorb™ technology. Applying the Purzorb™process to full spectrum CBD ... dose required and providing a CBD form that can be easily incorporated into liquid ...
(Date:10/13/2017)... (PRWEB) , ... October 13, 2017 , ... The Visiting ... Day Market. Featuring a collection of specialty vendors and unique items from across the ... and quality-focused health and wellness services offered by the VNA. The boutique will ...
(Date:10/13/2017)... ... October 13, 2017 , ... Coveros, a ... has been awarded a contract by the Center for Medicare and Medicaid Services ... accelerate the enterprise use of Agile methodologies in a consistent and high value ...
(Date:10/12/2017)... ... ... Planet Fitness, one of the largest and fastest growing franchisors and operators ... location in Covington, LA at 401 N. U.S. Highway 190, in January of 2018. ... in the Holiday Square shopping center. Its location allows it to serve both Covington ...
(Date:10/12/2017)... ... 12, 2017 , ... Information about the technology: , Otomagnetics ... enable prevention of a major side effect of chemotherapy in children. Cisplatin and ... For cisplatin, hearing loss is FDA listed on-label as a dose limiting toxicity. ...
Breaking Medicine News(10 mins):
(Date:10/12/2017)... , Oct. 12, 2017 AVACEN Medical ... the company with their  2017 New Product Innovation Award ... on extensive primary and secondary medical device market research by ... through its first-to-market OTC, drug-free pain relief product, the AVACEN ... approach to treating fibromyalgia widespread pain. ...
(Date:10/12/2017)... -- West Pharmaceutical Services, Inc. (NYSE: WST), ... administration, today announced that it will release third-quarter 2017 ... 26, 2017, and will follow with a conference call ... a.m. Eastern Time. To participate on the call, please ... is 94093362. A ...
(Date:10/11/2017)...  Caris Life Sciences ® , a leading innovator ... precision medicine, today announced that St. Jude Medical Center,s ... (POA) as its 17 th member. Through participation ... Cancer Institute will help develop standards of care and ... making cancer treatment more precise and effective. ...
Breaking Medicine Technology: