Dousing the Flames

From Paths of Progress Fall/Winter 2014

Why Inflammation May Blaze a Trail for Cancer

by Robert Levy

Almost from the time of their debut under a microscope, cancer cells were found to have some unexpected company.

In 1863, when German pathologist Rudolf Virchow looked at malignant tissue through his microscope, he saw the cancer cells were mixed with a throng of white blood cells, which are part of the body's inflammatory response to infection and injured tissue. Surprised to find tumor cells intermingling with cells that ought to be their fiercest enemy, Virchow asked whether inflammation might actually contribute to cancer.

Over the next century and a half, scientists would confirm what Virchow could only hypothesize. But that is hardly the end of the matter. As researchers have diagrammed the body's disease-fighting system in increasing detail, they've come to realize that the connection between cancer and chronic inflammation is not a one-way affair, but a tangle of interdependence and exploitation, of cooperation and antagonism — a vicious biological circle. If inflammation had a Facebook page, it would list its relationship status with cancer as "Complicated."

As the give-and-take between cancer and chronic inflammation has become clearer, so, too, have the opportunities for disrupting it — both to treat cancer and reduce the risk of some tumors getting started. At Dana-Farber, investigators are studying how lifestyle changes that reduce obesity — a trigger for inflammation — can impede cancer development. Others are tracking the flow of signals between cancer cells and inflammatory agents to identify cut-off points that can be targeted by drug therapy.

"We think that chronic inflammation can play an important role in the development and progression of cancer," says Charles Fuchs, MD, MPH, director of the Center for Gastrointestinal Oncology at Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC). "As we discover the molecular pathways that link them, we're developing additional therapies that can target inflammation — and improve patient outcomes."

First Responders

Inflammation is the body's way of responding to tissue damage. When bacteria or other infectious agents enter the body, or when chemical irritants find a way in, they're met by a burly crew of white blood cells called neutrophils and monocytes which have no fondness for foreigners. The white blood cells shower the intruders with caustic chemicals, gouge holes in their surface, or gobble them whole. This microscopic melee produces the redness, heat, swelling, and pain familiar to anyone who has skinned a knee or had a sore throat.

As critical as the onset of inflammation — as important as the prompt detection, identification, and demolition of the invaders — is the winding-down process. After the enemy has been defeated or devoured, signals order the white cells to leave the damaged area and re-enter the bloodstream. Remaining too long in fighting mode could result in damage to nearby, healthy tissue.

On rare occasions, however, the battle ends in stalemate rather than victory. If the inflammatory response can't clear the infectious agent or chemical irritant, a kind of ineffectual siege occurs, in which the inflammation lingers but accomplishes little. It is this type of persistent, chronic inflammation — associated with diseases such as ulcerative colitis, inflammatory bowel disease, and Crohn's disease — that increases the risk of cancer.

Evidence of a link between chronic inflammation and cancer is perhaps strongest in the digestive tract. "In virtually every type of GI cancer that we see, there is a chronic inflammatory condition that is a risk factor for it," Fuchs says. Examples are numerous: inflammatory bowel disease is a risk factor for colon cancer; gastritis, an inflammation of the stomach lining due to infection with the bacterium Helicobacter pylori (h. pylori), raises the risk of stomach cancer; Barrett's esophagus, an inflammatory-like condition of the esophagus tube due to backflow of stomach acid, often precedes esophageal cancer; and viral hepatitis increases the chance of liver cancer development. In each case, it is inflammation of many years' duration that poses a cancer risk, Fuchs notes, not the temporary inflammation that occurs as wounds heal.

Multiple studies have shown that anti-inflammatory drugs such as aspirin can reduce the risk of developing colon cancer, and of the cancer recurring after it's been treated. Fuchs and his colleagues have shown that this effect stems from its ability to block a key enzyme called COX-2. In another study, his team found a way to identify colon cancer patients who are most likely to benefit from aspirin therapy.

Molecular Chess

Dana-Farber's Glenn Dranoff, MD, has studied the basic mechanics of inflammation's relationship with cancer. In mice born with a genetic risk for certain cancers, he and his colleagues discovered an elaborate interplay of action and reaction.

"We found that chronic inflammation sets up conditions that tumors thrive under, because they learn to adapt to factors that are present in that situation and use them for their own benefit," Dranoff remarks. "The abnormal production of these factors can enhance tumor cell survival, as well as the ability to invade other tissue and grow blood vessels.

"But we also discovered that chronic inflammation can block the ability of the immune system to restrain tumor growth," he continues. Chronic inflammation, in other words, enables cancer growth in two ways:

1. by providing chemicals that tumor cells exploit for their own selfish purposes; and
2. by tamping down the immune system response that normally would attack the cancer.

Many scientists now believe that chronic inflammation is often necessary for full-blown, invasive tumors to emerge. Cells that acquire genetic mutations may begin to grow out of control and drift in the bloodstream to other parts of the body, but only when they have access to the rich chemical broth of the inflammatory response do they become truly malignant.

This dynamic helps explain why cigarette smoking is so closely tied to lung cancer, Dranoff notes. "There's a buildup of toxic substances in the lungs that damages tissue. When these toxins aren't removed — as often happens when people continue to smoke — a state of chronic inflammation can follow. The inflammatory response itself can produce tissue damage, which spurs even more inflammation. Early-stage cancer cells in the lungs may take advantage of this situation."

The cancer-inflammation relationship is more complex than even this description suggests. Studies indicate that tumor cells not only respond to the inflammatory state, they can actually instigate it, generating even more of the substances that tumor cells crave.

There's also evidence that inflammation not only affects already-existing cancer cells but can, in some instances, cause mutations that help normal cells become cancerous.

Dousing the Fire

Dana-Farber scientists are studying several strategies for depriving cancer cells of the biochemical boost they receive from chronic inflammation.

Jennifer Ligibel, MD, of the Susan F. Smith Center for Women's Cancers at Dana-Farber, is leading several studies that evaluate how increased exercise and weight loss affect inflammatory indicators in breast and other cancer patients. Obesity and inactivity are both linked to increased inflammation and to an increased risk of developing breast cancer. Ligibel wants to better understand how lifestyle changes can influence inflammation and subsequent cancer risk, with the ultimate goal of designing studies to test the impact of weight loss and increased exercise on cancer risk and development.

Kornelia Polyak, MD, PhD, is studying samples of normal mammary (breast) tissue from thin and obese mice. The samples have been "scored" to indicate how much inflammation is present. Polyak and her colleagues will study how the level of inflammation affects "progenitor" cells, which are forerunners of cells that line the milk ducts, and are thought to be where breast cancer often originates.

Explorations of the inflammation-cancer link aren't limited to breast cancer. DF/BWCC's Nikhil Munshi, MD, for example, has found that people with inflammatory diseases such as rheumatism, colitis, and ulcerative colitis have two to three times the normal chance of developing the blood cancer multiple myeloma. One reason, he discovered, is that immune system cells called T helper 17 (Th17) cells are overabundant in myeloma tissue. He also found that these cells produce a protein called interleukin-17 (IL-17) and other inflammatory proteins, raising the prospect that drugs that block IL-17 could stop or slow the development of myeloma. A clinical trial of one such drug for patients with relapsed myeloma is planned for this fall.

Meanwhile, Dana-Farber researcher Constantine Mitsiades, MD, PhD, has shown that inflammatory agents in myeloma's "microenvironment" — the web of cells around the tumor tissue — can influence how the cancer responds to various drugs. The interactions between myeloma and its neighboring tissue are so important to the survival of myeloma cells, Mitsiades says, that precision therapy for the disease will need to take account not only of the specific mutations within the cancer cells but also the makeup of the cells' microenvironment.

Another project is exploring inflammation's role in certain malignant and non-malignant blood disorders. In a newly launched study, patients with very early stages of chronic lymphocytic leukemia, myelodysplastic syndrome, and Waldenström's macroglobulinemia (a rare form of lymphoma) will periodically answer health questionnaires that will help researchers pinpoint what causes the disease to progress. "We'll ask patients about any infections they've developed, their exercise habits, weight, and other conditions such as rheumatoid arthritis that could be related to inflammation," says DF/BWCC's Irene Ghobrial, MD, who is co-leading the project.

Researchers agree that lifestyle changes and carefully targeted medicine offer the best way of severing cancer's pipeline to the inflammatory response. Rudolf Virchow would most likely approve.

Paths of Progress Fall/Winter 2014 Table of Contents