NSAID drug protects against intestinal tumors in mice, despite poor diet and gene losses

April 18, 2005

Anaheim, Calif. -- In mouse models of intestinal cancer, use of an anti-inflammatory drug eliminated all of the cancer-causing risks produced by a high-fat Western-style diet - even when several genetic brakes to cancer formation were missing in the animals, say researchers from the Albert Einstein Cancer Center.

The investigators, who presented their findings at the 96th Annual Meeting of the American Association for Cancer Research, say that while the results do not yet have relevance for preventing human colon cancer, they do illustrate the interplay between genes and common nutritional and medicinal agents in development of cancer in the intestines.

The drug they tested, sulindac, was a highly effective chemoprevention agent, the researchers say, because it worked to induce expression of the p21 gene, which they found put a firm stop on tumor formation even though the mice were missing two key tumor suppressor genes (p27 and APC) and were fed a diet high in fat and low in calcium and vitamin D.

"It appears that p21 activation through sulindac offers protection against both a lack of tumor suppressor genes as well as poor diet," says the lead author, WanCai Yang, M.D., an assistant professor of medicine. While the drug is a NSAID (non-steroidal anti-inflammatory drug) and a COX-2 inhibitor, Yang believes its chemoprotective effects come via novel pathways that affect p21 expression.

The study builds upon a body of research conducted by Yang and Leonard Augenlicht, Ph.D., at the Albert Einstein Cancer Center that has used knockout mouse models to explore the role of genes and diet, including the finding that inactivation of the p21 gene accelerated tumor formation and that loss of this gene eliminated the ability of sulindac to inhibit tumor formation. Their earlier studies also showed that mice that lacked p27, another tumor suppressor gene, had a higher risk of developing tumors in both the small and large intestine.

Now, however, they have linked that risk to a high-risk diet. In the first part of the study, they found that mice lacking a p27 gene that were fed with a corn-oil rich diet (labeled AIN-76A, also low in calcium and vitamin D) formed tumors whereas knock-out mice fed with their regular chow (which was enriched with soybean oil) did not. And p27 knock-out mice given a Western diet, full of fat and lacking calcium and vitamin D, formed the most number of tumors.

The researchers then looked at the role that diet plays when expression of two tumor suppressor genes is reduced. The researchers mated mice that had only one APC gene to p27 positive or negative mice, producing variants with no p27 genes or one or two. The APC gene is responsible for an inherited colorectal cancer condition known as FAP (familial adenomatous polyposis), in which patients develop hundreds of potentially precancerous polyps.

They found that on the AIN-76A diet, loss of one APC gene but retention of the "wild-type" (normal) p27 genes was enough to induce tumor formation in 22 percent of the mice, but that number increased to 72 percent when one allele of the p27 gene was lost, and 93 percent when both alleles of the p27 gene were lost. But all of the knock-out mice variants developed tumors in both their small and large intestines when fed a Western-style diet.

"This showed that the diet overwhelmed any protective effect the p27 genes conferred," says Yang. "It not only increased tumor size and number, but also pushed the cancer into an invasive state."

Finally, they examined what happened when the knock-out mice were fed a Western diet enhanced with sulindac, an agent they had previously found help suppress tumor formation. To their surprise, none of the knock-out mice developed cancer.

"To us this means that as long as an animal can activate the p21 gene, this can have an overriding affect on suppressing tumor formation caused by either loss of other tumor suppressor genes or diet," says Yang. "We are testing this concept further, including exactly how the p21 gene gets activated."
-end-
Founded in 1907, the American Association for Cancer Research is a professional society of more than 24,000 laboratory, translational, and clinical scientists engaged in all areas of cancer research in the United States and in more than 60 other countries. AACR's mission is to accelerate the prevention and cure of cancer through research, education, communication, and advocacy. Its principal activities include the publication of five major peer-reviewed scientific journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. AACR's Annual Meetings attract more than 15,000 participants who share new and significant discoveries in the cancer field. Specialty meetings, held throughout the year, focus on the latest developments in all areas of cancer research.

American Association for Cancer Research

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.