Inflammation cuts both ways

Apr 6 2006

Inflammation cuts both ways. When invaded by an infectious agent, for example, the body calls on the forces of inflammation to fight and defeat the intruder.

But when the biochemical processes of the immune system are either misdirected or chronically turned on, inflammation can lead to adversity, including some forms of cancer.

For this reason, scientists are closely studying the link between inflammatory processes and tumor formation, while others are investigating anti-inflammatory drugs as a means to prevent and treat cancer, as seen by studies presented at the 97th Annual Meeting of the American Association for Cancer Research.

Antihistamine and Anti-inflammatory Drug Use Associated Differently for High-Grade Versus Low-Grade Gliomas: Abstract No. 486

Individuals who used antihistamines regularly for a six-month period or longer have nearly a three-fold greater risk of developing mid-grade brain tumors, and a two-fold risk of having low-grade tumors. Using anti-inflammatory medications helped protect against developing a deadly brain tumor called glioblastoma.

The researchers, led by Michael Scheurer, Ph.D., postdoctoral fellow in Cancer Prevention and Melissa Bondy, Ph.D., professor of Epidemiology, both at The University of Texas M. D. Anderson Cancer Center in Houston, cautioned that they are not implying that use of antihistamines causes brain tumors, but rather that these medications may be part of a complex milieu of factors that contribute to their development.

Scheurer and Bondy used combined data from two studies: the Harris County Adult Glioma Study and the Bay Area Adult Glioma Study, led by Margaret Wrensch, Ph.D. at the University of California, San Francisco. As part of the studies, participants were asked about their use of antihistamines and anti-inflammatory drugs.

They compared antihistamine and anti-inflammatory drug use in 830 brain tumor cases and 831 controls matched for age, gender and race. The tumors were analyzed by histologic type. The majority - 339 - were high-grade glioblastomas; 117 were mid-grade, or anaplastic astrocytoma; and 154 cases were low-grade.

The scientists found that regular, long-term antihistamine use was associated with an increased risk for developing anaplastic astrocytomas and low-grade brain tumors.

"To our knowledge, this report is the first time that anyone has looked at this particular relationship - the potential effects of antihistamines on the development of brain tumors in adults," said Scheurer. "It's apparent that some type of inflammatory response is playing some role in the development of brain tumors. We don't know exactly what that role is or the specific mechanisms, but we're on the road to finding out.

"This again points to the fact that brain tumors are caused by a combination of several environmental, endogenous and genetic factors," he said. "They are not related to one specific cause, but rather, to several that are interplaying with one another to create tumors. We're trying to figure out what those key factors and genes are and how they interact with one another."

Scheurer said several studies have reported that people with allergies or asthma have a lower risk of developing glioblastomas. One report showed that those who take non-steroidal anti-inflammatory drugs, or NSAIDs, also have a reduced risk for developing such high-grade tumors. He and Bondy focused on antihistamines because people who have allergies typically take antihistamines.

"We knew that the different types of tumors have different etiologies and different genetic characteristics and we wanted to see if there were differences in risk," Bondy said. Scheurer and Bondy are also looking at certain different variations of genes in individuals and how they respond to inflammatory processes in the brain. "We're hopefully looking at some genes related to inflammatory cytokines and we'll see how individual response to inflammatory stimuli may increase or decrease a person's risk of developing a brain tumor," Scheurer said.

Influence of Chronic Inflammation on Prostate Carcinogenesis: A Five-Year Follow-up Study: Abstract No. 1474

Researchers at Case Western Reserve University in Cleveland have evidence linking chronic inflammation in the prostate to a greater risk of developing prostate cancer. Results of repeat biopsies of prostate tissue over a five-year period from men who had abnormal serum prostate specific antigen (PSA) levels and/or digital rectal examinations (DRE) suggest that chronic inflammation may be a significant risk factor in the development of prostate cancer.

While connections between inflammation and cancer have been shown for some cancers, no one had shown a relation between chronic prostate inflammation and the development of prostate cancer, said Sanjay Gupta, Ph.D., assistant professor of urology at Case Western Reserve University in Cleveland, who led the work along with Greg MacLennan, M.D., associate professor of pathology.

Gupta and his co-workers examined the results of prostate needle biopsies from 177 men between ages 47 and 83 years who were at high risk for developing cancer based on either high PSA scores or abnormal DREs. Of the 177 men, 144 or 81 percent were found to have chronic prostate tissue inflammation.

The scientists categorized the biopsies based on pathology. They found that of the 144 cases, 15 percent (22/144) had only inflammation, 15 percent (22/144) had simple atrophy, 39 percent (54/144) showed PAH/PIA (post-atrophic hyperplasia and/or proliferative inflammatory atrophy, which indicate evidence of chronic inflammation) lesions, and eight percent, or 12/144, showed HGPIN - high-grade prostate intraepithelial neoplasia, which is a precursor to prostate cancer. About 20 percent, or 29/144, had cancer (adenocarcinoma) in the initial biopsies.

The researchers analyzed 84 subsequent biopsies performed within five years in patients who had initially shown chronic prostate inflammation. In the follow up, 29 new cancer cases were diagnosed: six occurred in patients in whom initial biopsies showed only chronic inflammation, 15 in patients with initial PAH/PIA lesions, along with eight in patients with chronic inflammation and other risk factors for cancer (high-grade prostate intraepithelial neoplasia and atypical small acinar proliferation that may have been cancerous).

In contrast, the researchers found only two cases - six percent - in the 33 patients without inflammation who went on to develop cancer, both of whom had other risk factors for cancer.

"We observed a significant association between serum PSA and the degree of chronic inflammation," said Gupta, which was expected based on previous findings.

"The first concern is, should patients with initial biopsies showing no malignancy but showing chronic inflammation be followed more closely and perhaps re-biopsied more frequently?" Gupta said.

Gupta's group plans future studies that will be similar in design, but have a larger number of subjects.

COX-2 Expression in Atypia: Correlation with Breast Cancer Risk: Abstract No. 2353

Women with atypical hyperplasia who also have high levels of the enzyme COX-2 in their breast tissue were more likely to develop breast cancer than women with lower levels of the enzyme.

According to Lynn Hartmann, M.D., professor of oncology at the Mayo Clinic College of Medicine in Rochester, Minn., about one million women a year have a breast biopsy with benign findings (sometimes called benign breast disease). One form of benign breast disease, atypical hyperplasia, or atypia, is characterized by abnormal cell growth and can be precancerous. Women with this condition have a four times greater risk of developing breast cancer.

Hartmann and her co-workers wanted to find out whether or not they could use molecular tools, such as COX-2 levels, to predict who among the group of women with atypia would develop breast cancer and develop ways to separate groups of women into high risk and normal risk. The COX-2, or cyclooxygenase-2, enzyme is produced by the body when there is inflammation and is also produced by precancerous tissues.

They took advantage of a tissue bank from the Mayo Clinic Benign Breast Disease Cohort, which includes several thousand women who, between 1967 and 1991, had a benign breast biopsy. Of this group, 235 women had atypical hyperplasia and tissue available for the study. Cancer follow-up information was available for all of these women. Hartmann and her co-workers determined the amount of COX-2 in these samples by staining immunohistochemistry methods. Forty-one of the 235 women with atypia developed breast cancer over roughly a 15- to 20-year period.

The research team found a significantly higher level of COX-2 in atypias of those women who went on to develop breast cancer than they did in control subjects. "Intense COX-2 expression," Hartmann said, "is associated with a significantly greater likelihood of a subsequent breast cancer in women with atypia. Specifically, for women with strong staining, their risk of breast cancer at 20 years was 31 percent, versus 14 percent for those with negative or weak staining."

She noted that increased COX-2 expression has also been seen in an early form of breast cancer called ductal carcinoma in situ, or DCIS. Hartmann said that COX-2 represents a potential target for chemoprevention. Her team plans to expand the test group and will continue to profile women with atypia who did and who did not develop breast cancer in an attempt to identify early predictors of risk.

Reduction in the Risk of Human Breast Cancer by COX-2 Inhibitors: Abstract No. 2352

Results of a five-year study have shown for the first time a significant reduction in risk associated with selective COX-2 inhibitors in human breast cancer.

Randall Harris, M.D., Ph.D., professor and director of the Center of Molecular Epidemiology in the College of Medicine and School of Public Health at The Ohio State University Medical Center in Columbus and his co-workers looked at the use of selective COX-2 inhibitors such as Vioxx and Celebrex between 1999 and 2004 and the incidence of breast cancer. They compared 323 breast cancer cases to 649 healthy controls and found a risk reduction of about 71 percent with the use of selective COX-2 blockers.

Harris was not surprised. "This was not a surprising result showing selective COX-2 inhibitors would have a significant effect in reducing the incidence of breast cancer," he said.

A number of studies have shown that people who regularly take non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen to treat conditions like arthritis, have lower rates of colorectal polyps, colorectal cancer, breast cancer and many other cancers. NSAIDs exert anti-inflammatory effects by blocking COX, or cyclooxygenase enzymes, which are produced by the body when there is inflammation and are also produced by precancerous tissues.

"The combined results of 20 human studies of aspirin and ibuprofen reflect an approximate 30 percent reduction in the risk for breast cancer, and animal studies have shown a profound effect by COX-2 blockers against a variety of cancers," he said.

Harris said that these results have implications for chemoprevention of breast cancer and other cancers. This particular study is a sub-study of four types of cancer, including prostate, lung and colon cancer. The researchers will release data at the meeting showing results consistent with the breast cancer findings.

"There's a lot of interest in the use of these compounds in therapy and prevention," Harris noted. "It will be important for investigators to look at these compounds in prospective and retrospective studies to see if these results are consistent." "We're concerned about potential side effects of these agents, and before making specific recommendations for their use, further studies are needed to determine if low dosages that cause no harm have consistent preventive effects against cancer," Harris said.

COX-2 inhibitors may also have effects in preventing other diseases, and his laboratory would like to explore their effects against cardiovascular and neurodegenerative diseases such as Alzheimer's disease. He hopes to continue to look at COX-2 blockers at sub-therapeutic doses in chemoprevention.

"We need to look at a broader spectrum of conditions related to the inflammatory cascade and modulating the cascade with these and other compounds."

Variants in the alpha-Methylacyl-CoA Racemase Gene and the Association with Advanced Distal Colorectal Adenomas in the Prostate, Lung, Colorectal and Ovarian Screening Trial: Abstract No. LB-344

Researchers have shown that a particular version of a gene that enhances ibuprofen's anti-inflammatory effects also makes it more effective in preventing the development of potentially precancerous polyps in the colon.

Sarah Daugherty, research fellow at the National Cancer Institute and doctoral candidate at Johns Hopkins Bloomberg School of Public Health and her colleagues looked at seven variants of the gene for alpha-methylacyl-CoA racemase, or AMACR. This protein metabolizes branched chain fatty acids, cholesterol metabolites and enhances the activity of ibuprofen.

The AMACR protein is overexpressed in some cancers such as prostate, colon and precancerous colorectal adenomas, or polyps, though it is expressed very little in normal tissues. According to Daugherty, no one had examined the association between AMACR variants and colorectal adenomas or cancer.

The research team identified 725 white men and women between ages 55 and 74 who had participated in the multicenter, National Cancer Institute-supported Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and who had a sigmoidoscopy that showed a suspicious polyp in the distal colon that was confirmed by a follow-up exam. These participants were compared to 729 control subjects who had a sigmoidoscopy showing no polyps. All subjects completed questionnaires that asked about ibuprofen use and each provided a blood sample.

The scientists looked at the seven gene variants among the two groups. They found that four of seven variants were associated with an increased risk for advanced distal colorectal adenomas. The frequency of these variants was higher among those with polyps than among controls.

The researchers also compared ibuprofen use among the two groups. Studies have shown that non-steroidal anti-inflammatory drugs such as ibuprofen can reduce the risk of adenomas and colorectal cancer.

"We found that regular use of ibuprofen had a slight protective effect in the development of advanced distal colorectal adenomas - a 20 percent reduction in risk, which was not statistically significant," Daugherty said.

When they looked further at the association between ibuprofen use and colorectal adenomas, they found that a subgroup of individuals who had two copies of one variant showed a statistically significant reduction of nearly 70 percent in the risk for developing adenomas. Among the other individuals who did not have this genotype, regular use of ibuprofen had little effect on risk of colorectal adenomas.

"Our data are the first to show a link between these genotypes and effectiveness of ibuprofen in protecting against adenomas," Daugherty said. She noted that previous research in animals has shown that AMACR modifies a component of ibuprofen that enhances its chemopreventive effects.

"This is the first study to corroborate the biological data at a statistical level in humans," she said.

Her team's results need to be verified in other populations, she said. "While our results are statistically suggestive that there is an association between these variations in the gene and colorectal adenomas, there needs to be biological follow-up so we know the functional relevance of these markers."

Daugherty said that before AMACR can be used for any potential clinical application, more study is needed to verify the findings and determine relationships to ibuprofen dose, duration and timing.