Studies highlight role of inflammation in cancer

Apr 18 2007

Can reducing inflammation keep cancer at bay? Two novel studies presented at the 2007 Annual Meeting of the American Association for Cancer Research that examine use of common anti-inflammatory agents suggest this might be the case.

One large study found that women who regularly use aspirin developed fewer cancers than women who did not, while another, conducted in mice and now being confirmed in an analysis of breast cancer patient records, discovered a link between asthma and an increased risk of cancer metastasis to the lungs.

Both studies offer hope that managing inflammation can help control cancer.

Association of aspirin and non-aspirin NSAIDs with cancer incidence and mortality in a large prospective cohort study: Abstract 3400

Regular aspirin use was associated with lower cancer incidence and cancer mortality, but non-aspirin non-steroidal anti-inflammatory drug (NSAID) use was not, according to one of the largest studies ever conducted to look at the impact of these agents on overall cancer risk. Aspirin was also associated with a lower risk of dying from coronary heart disease, while NSAIDs were not.

Among 22,507 cancer-free postmenopausal women who participated in the Iowa Women's Health Study and provided information on aspirin and NSAID use, those who said they regularly used aspirin had a 16 percent reduced risk of developing cancer more than a decade later, as well as a 13 percent reduced risk of dying from cancer over this same time period, compared to women who did not use aspirin. But there was no statistically significant impact on cancer incidence or mortality among women who used non-aspirin NSAIDs, compared to those who did not, say researchers from the Mayo Clinic, in Rochester, Minnesota.

The researchers also looked at whether smoking status had any impact on the potential preventive effects of aspirin and found that while these agents were associated with lower cancer incidence and mortality among former and never smokers, the same apparent benefits were not seen among active smokers.

These study results do not mean, however, that women should throw away their NSAIDs or pick up a bottle of aspirin, says the study's lead author, Aditya Bardia, M.D., M.P.H. "This is just one study," he says. "However, it does provide provocative evidence that regular aspirin use may play a role in preventing the most common chronic diseases in western countries, namely cancer and heart disease."

The different impact of aspirin compared to other NSAIDs was somewhat surprising, the researchers say. "While chemically different, these agents share at least one similar mechanism of action so you might have expected them to have comparable effects," says Jon Ebbert, M.D., the senior author on the study.

Specifically, aspirin and other NSAIDs reduce inflammation through inhibition of cyclooxygenase (COX) enzymes. These enzymes are responsible for the formation of prostaglandins, which can drive inflammation and possibly stimulate cancer development in a number of organ sites, Dr. Ebbert said.

Previous studies have evaluated whether aspirin or other NSAIDs prevent specific cancers, such as breast cancer. "But this study is unique because we were able to evaluate comprehensive endpoints such as total cancer incidence and cancer mortality, which are more clinically relevant outcomes for patients," Dr. Bardia said.

While the researchers note that one of the weaknesses of this study was that the women were given only a single survey of aspirin and non-aspirin NSAID use, it also had many strengths including the prospective cohort study design, relatively long follow-up (up to 12 years) on a large number of participants, during which time many developed (3,487) and died (1,193) from cancer. The authors were also able to adjust the results for a large number of lifestyle factors, and found little evidence that these other factors could explain the aspirin and cancer associations observed in this study.

Chronic allergen provocation results in a significant increase in the rates of lung metastasis that is dependent on induced pulmonary inflammation: Abstract 2553

An intriguing study, conducted in mice and supported by an ongoing examination of breast cancer patient records, suggests a link between the pulmonary inflammation seen in asthma and increased risk of lung metastasis.

The study, conducted by researchers at Mayo Clinic Arizona, suggests that breast cancer patients who have asthma could reduce their risk of cancer spread by using readily available inhaler medications.

"A link between pulmonary inflammation and lung metastasis would not only have significant effects on patient diagnosis and care, but will also immediately affect the way breast cancer patients are treated," said Anna Taranova, M.D., a senior research fellow in the laboratory of James Lee, Ph.D. at Mayo. "Those with asthma might be able to reduce their risk of lung metastasis, and increase their survival, with aggressive corticosteroid treatment."

Furthermore, the findings could prove to be relevant to asthma patients diagnosed with other cancers that metastasize to the lungs, according to Dr. Taranova.

"We suspect that the relationship between lung inflammation and metastasis will not be limited to breast cancer patients," Dr. Taranova said.

The researchers say these results, along with findings from their other recent research, offer a biological link: activation of cells that line blood vessels is required both for the movement of pro-inflammatory white blood cells into lung tissue (as occurs in asthma) and for the movement of circulating cancer cells from the blood into lung tissue.

In this study, mice were exposed to an aerosolized allergen commonly used in mouse asthma studies and then were injected with melanoma cells. Three other groups of mice were also studied: control mice; mice that received the human corticosteroid allergy and asthma therapeutic agent budesonide after exposure to the allergen; and mice treated with an antibody to eliminate CD4+ T cells before exposure to allergen. (CD4+ T cells orchestrate immune responses to allergens and are largely responsible for the lung inflammation that occurs in asthma.) Metastasis was continually assessed in all groups.

The researchers found that allergen-induced pulmonary inflammation was associated with an almost 400 percent increase in lung metastasis in the mice. But in mice treated with either an antibody to deplete CD4+ T-cells or budesonide to reduce their allergic lung inflammation, the rate of metastasis fell to that seen in mice that were not exposed to allergen. "The treatments wiped out the increases in the rate of metastasis induced by allergic inflammation, reducing the observed rates of metastasis to those found in mice that never experienced the allergen," Dr. Taranova said.

The researchers are now working with epidemiologists at Mayo Clinic Rochester to determine if breast cancer patients with lung metastasis had higher than normal rates of asthma. To date, they have found "productive and provocative results," Dr. Taranova says: over 20 percent of women with breast cancer who developed lung metastasis also appear to have had a previous diagnosis of asthma. The typical frequency of asthma occurrence in U.S. women is, at most, eight percent, she said.

"Our long term goal is to continue this detailed retrospective study of breast cancer patients, eventually translating these studies into a multi-center prospective examination of cancer patients," Dr. Taranova said. "We want to define the specific parameters that link lung metastasis and pulmonary disease."

The researchers say that many questions need to be answered, including whether asthmatics who regularly use anti-inflammatory corticosteroids experience a side benefit of reduced risk for lung metastasis, and whether people who have allergies, but not asthma, are at the same risk.

Dr. Taranova believes these findings are surprising, as the researchers originally suspected that patients with asthma would have limited lung metastasis. "However, as in most things in science, we have learned much more from studies disproving our flawed hypotheses than from studies confirming our preconceived ideas," she said.