Targeting Inflammation Emerges as a Strategy for Treating Cancer
, by Edward Winstead
In 1863, a German pathologist observed white blood cells in cancerous tissues. White blood cells are part of the body’s inflammatory response, which is activated to fight invaders, such as pathogens, and heal damaged tissue.
Based on his observation, the pathologist, Rudolf Virchow, proposed a new idea about the origins of cancer. Some tumors, he suggested, may start at sites of chronic inflammation—that is, places where inflammation persists after it is no longer needed.
His basic idea has stood the test of time. Chronic inflammation in certain parts of the body, such as the cervix or the colon, can increase the risk of cancer in those organs.
But Virchow’s observation marks just the beginning of a story about cancer and inflammation that is still being written.
Today, inflammation is considered a hallmark of cancer. Researchers are exploring the potential role of inflammation in many aspects of cancer, including the spread of the disease within the body and the resistance of tumors to treatment.
In the coming years, researchers hope to learn more about whether patients with cancer might benefit from treatments that target inflammation around tumors. Some early studies have yielded promising results.
"The numerous and diverse links between cancer and inflammation all present opportunities to develop therapies," said Michael Karin, Ph.D., of the University of California, San Diego, who studies mechanisms of inflammation.
Although much of the research on potential therapies is in the early stages, Dr. Karin predicted that “strategies to inhibit cancer-related inflammation will one day become a mainstay of modern cancer therapy.”
The complex relationship between cancer and inflammation
An inflammatory process begins when damaged tissues release certain chemicals, including histamines and prostaglandins. In response, white blood cells travel to the damaged tissues and produce substances that cause cells to divide and grow to rebuild tissue. The inflammatory process ends when the injury has been healed.
When inflammation occurs at the wrong times or becomes chronic, however, problems can arise. Many researchers describe inflammation as a double-edged sword.
“On the one hand, the immune system is constantly vigilant, monitoring the body for foreign invaders, such as pathogens,” said Stephen Hewitt, M.D., Ph.D., of the Experimental Pathology Laboratory in NCI’s Center for Cancer Research. “But on the other hand, inflammation that is not effectively controlled can potentially contribute to the development and growth of cancers.”
In some cases, tumor cells may take advantage of the inflammatory environment to actually exclude tumor-fighting immune cells.
The immune system is also on alert for threats from inside the body—that is, tumors. “Scientists have observed that there may be tumor cells in our bodies that we never know about, because the immune system is going out and killing those tumor cells,” said Dr. Hewitt.
What’s more, cancer treatments such as immunotherapy may kill cancer cells by activating some of the inflammatory processes used to fight pathogens. So, researchers have been studying the interplay between inflammation and immunotherapy, noted Dr. Karin.
In short, there is evidence that inflammation may both promote and constrain tumors. Over the past decade, researchers have used this knowledge to explore new treatments for cancer, including anti-inflammatory drugs.
A small clinical trial recently demonstrated the potential value of this approach. Researchers enrolled 24 patients with breast cancer that had spread to tissue near the breast, but not to other parts of the body (locally advanced), or that had spread to other parts of the body (metastatic).
The patients received chemotherapy plus an anti-inflammatory drug called L-NMMA, which blocks the production of nitric oxide, a molecule involved in inflammation.
The treatment regimen shrank the tumors in approximately half of the patients in the study. (Based on historical data, the researchers estimated that about a third of the patients would have responded to chemotherapy alone.) Three patients with locally advanced breast cancer had all signs of their cancers go away following treatment.
“We saw some remarkable responses in patients whom we did not expect to respond,” said lead investigator Jenny Chang, M.D., director of the Houston Methodist Hospital's Neal Cancer Center.
Her study was the first to test L-NMMA in patients with cancer. To learn more about how the anti-inflammatory drug worked in the body, the researchers studied the cells, molecules, and other structures surrounding tumors (the tumor microenvironment).
Their findings suggested that, by disrupting the production of nitric oxide, the drug helped reduce inflammation around the tumors. This seems to have made it possible for tumor-targeting immune cells to penetrate the tumors and kill the cancer cells, according to the researchers.
“In some chemotherapy-resistant breast cancers, inflammation is like a fortress around the tumor,” Dr. Chang said. “The microenvironment exudes pro-inflammatory proteins that make it impossible for immune cells to penetrate.”
But L-NMMA appeared to break down those barriers, even among patients who were not responding to other treatment options, she added.
Dr. Chang and her colleagues are planning an NCI-supported phase 3 clinical trial to test the drug in more patients. The study will include people with metaplastic breast cancer, a rare and often lethal form of the disease.
"Inflammation is a critical component of metaplastic breast cancer," said Dr. Chang.
"Timing is everything"
In a normal inflammatory response, immune cells produce chemicals that can kill a pathogen. These chemicals, known as reactive oxygen species, can also damage the DNA of normal cells, which increases the risk of mutations that could lead to cancer.
"Timing is everything," said Jennifer Kay, Ph.D., of the Silent Spring Institute, who studies how healthy cells become cancerous. "If the optimal timing of biological processes related to inflammation is altered, the chances of cancer occurring increase."
For instance, in the normal inflammatory response, the production of cells to replace injured tissue is normally delayed until reactive chemicals are no longer being produced. This sequence of events reduces the chances that replacement cells will sustain DNA damage, including cancer-causing genetic mutations, caused by reactive chemicals.
But during chronic inflammation, the production of reactive chemicals can overlap with the production of cells that restore injured tissue, Dr. Kay noted. This can potentially increase the risk of cancer.
The reasons inflammation starts when it is not needed or becomes chronic are not always clear. Some recent studies have focused on the failure of mechanisms that normally shut down inflammation at the appropriate times.
"Biology is complicated, because there’s a lot that goes into keeping a body healthy," Dr. Kay said. "Evolution has produced a vast network of tightly coordinated biological processes."
Many of these biological processes are interdependent, so disruptions to one pathway can have ripple effects elsewhere, potentially leading to uncontrolled inflammation, Dr. Kay added.
Learning how to manipulate the inflammatory system
At the University of Texas MD Anderson Cancer Center, researchers are investigating the molecular mechanisms of inflammation, including a protein involved in inflammation called STAT3.
"We are interested in learning how to manipulate components of the inflammatory system to improve the body's ability to fight tumors," said Stephanie Watowich, Ph.D., who directs the Center for Inflammation and Cancer at MD Anderson.
Abnormal levels of STAT3 activity have been linked to certain cancers, and drugs that inhibit the protein are being tested in people with cancer.
A growing body of evidence, including results from mouse studies, suggests that STAT3 inhibitors may have distinct and complementary effects: The drugs may prevent a tumor from growing while also enhancing the immune system’s ability to clear the remaining tumor cells, according to Dr. Watowich.
"That’s the hope with drugs that inhibit STAT3," Dr. Watowich said. Future research will explore whether blocking other proteins in immune cells could also improve the ability of those cells to clear tumor cells, she added.
New mouse models with functional immune systems
L-NMMA was originally developed to treat heart failure. Dr. Chang and her colleagues decided to test the drug, a nitric oxide synthetase inhibitor, in patients with cancer based in part on research in mice by NCI investigators.
A team led by David Wink, Ph.D., in NCI’s Center for Cancer Research studied drugs that inhibit nitric oxide, including L-NMMA, in new mouse models that had functional immune systems. Most mouse models used in cancer research have lacked normal immune systems.
The new models represent an important technology advance for studying cancer and inflammation, as the work on L-NMMA suggests, according to Dr. Hewitt.
"Having mice with functional immune systems allows us to dissect the molecular mechanisms involved in the interplay between the tumor and the immune system," said Dr. Hewitt.
Once the pilot study of L-NMMA had been completed, Dr. Chang’s team and the NCI researchers visualized the tumor microenvironments in the patients and the mice. In both species, prior to treatment with the drug, tumor-targeting immune cells appeared to be stuck outside the tumors, unable to infiltrate the cancers.
"The images were really remarkable," said Dr. Wink. "The way the immune cells oriented themselves relative to the tumor targets was strikingly similar between the species."
The investigators conducted additional studies to confirm their suspicions that inflammation had been preventing immune cells from killing cancer cells.
Tumor biopsies from patients who responded to L-NMMA showed increased levels of tumor-targeting immune cells and reduced levels of pro-inflammatory proteins, as did tumor biopsies from mice treated with the drug, the researchers found.
These results confirmed their view that L-NMMA helps to reduce inflammation and allow immune cells to infiltrate tumors, according to Dr. Chang.
“What we observed in the patients who responded was exactly what the mouse models had predicted would happen,” she said.
Putting knowledge to work for patients
Dr. Wink expects to see more studies testing combinations of drugs that target inflammation and other agents for treating cancer. “This is the new frontier,” he said.
More than 150 years after Rudolf Virchow’s observation, Dr. Wink continued, the time is right for a collaborative science project focused on inflammation. He envisions a comprehensive effort modeled on the Human Genome Project to describe the molecular components involved in inflammation.
“We now have the ability to map the nitty gritty of inflammation,” Dr. Wink said. “To find the Achilles’ heel of inflammation, we need to study all of the elements and the biological processes together.”
Dr. Karin agreed and issued a call to action.
“After several decades of fundamental research on inflammation and cancer, it’s time to put our knowledge to work for patients,” he said.