Calming Chronic Inflammation

Every cancer patient who has waited for a pathology report owes a grudging debt to Rudolf Virchow. The 19th-century German physician brought pathology into the modern scientific era, laying the foundation for this critical discipline. Now, another of his insights is potentially reshaping how we understand and treat cancer.

In 1863, two decades after the discovery of white blood cells, Virchow identified them in a sample of cancerous tissue. Long before we even conceived of DNA, he suggested that chronic inflammation might foster the development of cancer. Over the past 20 years, researchers have been homing in on his prescient observation.

White blood cells are the foot soldiers in the body’s immune system, mustered to points of injury or infection. There are many types of these cells, and, while they have different capabilities, they work together to produce that warm, red, painful and sometimes puffy feeling called inflammation.

While inflammation is the body’s approach to biologic defense and repair, evidence increasingly suggests that too much of a good thing—inflammation—could inadvertently aid and abet the growth, survival and ultimate metastasis of cancer cells. Inflammation might not cause cancer—there needs to be genetic damage for cancer to get started. But as immune cells fight infection and repair damage, they build blood vessels. Once a tumor is born, inflammation might pave the way for its growth and metastasis.

Cancer patients often feel betrayed by their body, and inflammation seems a likely part of the conspiracy. Chronic inflammation-related cancers include those of the bladder, colon, esophagus, liver, lung, mouth, ovary, pancreas, stomach and lymph system. For instance, patients with a history of inflammatory bowel disease are thought to be two to six times more likely to develop colorectal cancer. Inflammation and cancer are both complex phenomena, so it’s difficult to draw broad conclusions from any one example. But understanding inflammation might also give us a powerful lever for treating cancer and controlling recurrence. Drug developers are now using the chemical clues of inflammation to design new treatments and prevention strategies. Those aren’t market ready yet, but in the meantime, research suggests that survivors of cancer who work to control their own inflammation levels might live longer, healthier lives.

Inflammation has many points of origin. The chemicals in tobacco smoke inflame the delicate cells in the lining of the lungs. Disrupted sleep or sleep deprivation is associated with a rise in the level of inflammatory molecules in the body, while physical exercise might help reduce them. Certain foods might increase inflammation in both the digestive tract and elsewhere, and obesity and the “metabolic syndrome” it can cause are both accompanied by markers of inflammation.

A significant source of inflammation is stress. Stress is a normal part of life and activates the immune system. However, when stress becomes chronic, the immune system can’t get a break to catch up with damage and major inflammation can occur. And regardless of whether stress is psychological or biological, its effect is the same: It can contribute to a variety of health problems.

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“All patients with cancer endure a lot of stress,” explains Judith Payne, program director of nursing research at the University of Wisconsin Hospital and Clinics in Madison, Wis. They must first contend with the diagnosis and its attendant uncertainty, followed by the challenge of making complex medical choices. Then, the treatments and side effects can be stressful. And a cancer diagnosis can bring many other issues to the forefront—employment challenges, family conflicts, financial concerns. To patients caught in the middle, it might seem like a perfect storm.

The link between stress and inflammation is hardwired in the body’s emergency response system, often called the fight-or-flight response. Most people know it as that little kick of adrenaline when a squirrel darts out in front of a moving car. But it’s not just adrenaline that gets released: a cocktail of hormones and neurotransmitters flood the body, activating body systems that might be needed to survive, including the genes that control inflammation.

“What we’ve learned from 2 million years of evolution is that if you’re in fight-or-flight mode for a long time, the odds that you’re going to get injured are actually pretty good,” says Steven Cole, a professor at the David Geffen School of Medicine at the University of California, Los Angeles, who is also an investigator at the Cousins Center for Psychoneuroimmunology. “So, stressful situations are great times to amp up this inflammatory biology to combat injuries.”

Back when humans were running around the savannah, fleeing lions, tripping over rocks, the body’s fight-or-flight response offered genuine protection. Now, instead of predators, it’s the guy who steals the parking space or the mail carrier delivering a stack of medical bills. “In the world we’re living in now, that [fight-or-flight response] doesn’t do us any good,” Cole says. “All of us have periodic stress. It’s unavoidable and not unhealthy. However, it can become toxic when you live stress as a lifestyle.”

Cole says living with so much stress “is like adding fertilizer to the growth process for the cancer.” The science is pretty clear—multiple studies link chronic stress to the progression of established malignancies. But can a doctor attack the stress-related inflammation with a prescription pad?

“That is the $64,000 question at this point,” says Cole. The most honest answer is: Researchers aren’t sure. Evidence from large-scale epidemiologic studies suggests that the regular use of anti-inflammatory medications, such as aspirin, could well reduce cancer. In studies involving animal subjects and looking at specific diseases, results seem promising. But drawing more precise conclusions has been difficult, with studies slowed by the Vioxx (rofecoxib) recall that engulfed anti-inflammatory research in 2004.

How do people even know if their body is experiencing systemic levels of inflammation? While there are lab tests that can track the alphabet soup of the body’s inflammatory compounds—IL-1beta, IL-8, TNF-alpha, CRP—there is little consensus yet on what these levels might mean. And it’s unlikely a health insurer will pay for them.

Chronic stress if a major cause of inflammation, so reducing stress could improve health outcomes.

Survivors should discuss inflammation-lowering strategies with their doctor.

The possible exception is CRP, or C-reactive protein. People who have heart issues might already be monitoring their CRP levels. CRP is a general marker of inflammation that rises when the overall level of inflammation in the body rises, and in some studies, high levels are associated with a risk of cancer or cancer recurrence. Interpreting high CRP levels is still a matter of some debate, but Cole argues it’s the best measure of generalized inflammation currently available. And because chronic inflammation is a cross-cutting risk factor—affecting cancer, cardiovascular disease and diabetes—it’s wise to pay it heed. Most doctors are willing to order it tested. “If you’re in a place where you’re at high CRP for months and months, your [health] risk really is materially changed, and it’s worth thinking hard about what you’re going to do to address that,” Cole says.

The preponderance of evidence points to chronic inflammation as a bad guy, yet research hasn’t forged a clinical weapon. “People often expect medication when they go to a doctor,” Payne says. “From a pharmacological standpoint, there are not a lot of options for treating chronic inflammation.”

But survivors of cancer do have options. “Diet, exercise, stress management, sleep—all of these play a role,” Payne says. And exercise is primary in improving sleep and energy levels during and after cancer treatment. “It really does improve certain symptoms,” she says, particularly fatigue.

By helping patients and survivors sleep, exercise has a naturally anti-inflammatory effect, because when the sleep cycle breaks down, inflammation creeps up.

All of us have periodic stress. It's unavoidable and not unhealthy. However, it can become toxic when you live stress as a lifestyle.

Exercise can also help control weight, Cole adds, and inflammation is driven by fat. One major way that obesity, or even just being overweight, contributes to disease is that fat tissue fosters the active growth of the immune cells that manufacture inflammatory compounds. “If you want to make a big difference in your risk of cancer, maintain a healthy body weight, make sure that you’re physically active on a regular basis, and as much as possible, minimize your engagement with long-term chronic stress,” he advises.

And he adds, a bit chagrined, consider meditation. “I am not into meditation at all; it drives me crazy,” he admits. But he analyzes a lot of data and says he can’t ignore the benefits. “I’ve got to tip my hat to meditation in general, and mindfulness meditation in particular,” he says. “I haven’t gotten a meditation study yet that didn’t have a pretty clear indication of positive biological impact.”

Lifestyle changes, such as exercising more or adopting a meditation practice, can be difficult, Payne acknowledges. And she, like many in the medical community, is convinced that we’ve only begun to tap the potential benefits from a better understanding of inflammation. “I believe that recurrence can be prevented,” she says. It’s a bold statement, and she knows that science hasn’t yet found a way to do so. But she believes there is a high probability that it will. “We’re going to need more rigorous research,” she cautions. Stay tuned.