CU Researchers Make Cancer Discovery

Doctors knew that Helicobacter pylori, the same bacterium that causes ulcers, can also lead to stomach cancer. But a team led by the Columbia University Medical Center now knows why—and may be able to apply that knowledge to wider cancer prevention and treatment.

A report published Nov. 4 in the journal Cancer Cell by a team of scientists led by CUMC’s Timothy Wang shows that H. pylori causes cancer by spurring excessive inflammation, lending further support for what Wang said is a growing consensus in the scientific community that inflammation is a factor in many types of cancer. “Certainly the idea that inflammation promotes the growth and progression of cancer is now pretty well accepted in the field,” Wang said.

Under normal circumstances, the inflammatory response is an important weapon against disease. When certain cells in the immune system sense the presence of an invader, they call for backup by releasing chemicals called cytokines. These cytokines spread through the body to let the rest of the immune system know where the problem is. Soon other immune cells, responding to the cytokines, arrive on the scene and help eliminate the troublemakers.

But too much inflammation can be harmful. If the inflammation continues for too long, nearby cells are often unable to cope with the stress. Over time, these stressed-out cells may become less vigilant against the subtle damage that leads to cancer.

So scientists already had good reason to suspect that H. pylori, since it causes harmful inflammation of the stomach, had some role to play in stomach cancer. What they didn’t know was precisely how the bacterium exerted this effect. Inflammation is a very complex process that involves many different cells and cytokines, any one or combination of which could have been responsible for H. pylori’s link to cancer.

Following up on evidence from previous research, Wang’s team had a hunch that a single cytokine, called IL-1β, might be involved. They infected mice with a bacterial cousin of H. pylori, but also gave the mice a drug that specifically counteracts the effects of IL-1β. Sure enough, these mice did not develop stomach cancer. Researchers also used genetic engineering techniques to create mice whose stomachs released excessive amounts of IL-1β. The researchers saw that these mice had very high rates of stomach cancer, even in the absence of bacterial infection, further confirming the conclusion that IL-1β is a primary cause of stomach cancer.

On their own, these would be significant findings. Stomach cancer is the second most common cancer worldwide, so other researchers will soon follow up to see whether anti-IL-1β drugs could effectively treat the later stages of the disease, which are hard to tackle with conventional treatments.

But the researchers were also able to discover the precise mechanism by which IL-1β leads to cancer, and in doing so may have uncovered a wider link between the immune system and cancer.

Wang’s team followed the trail of IL-1β to a mysterious type of immune cell known as the MDSC. “The MDSC, I thought, was one of the important links we picked up in this paper,” he said.

Scientists already knew that MDSCs betray the body by helping existing tumors grow larger. They help the tumor slide under the radar of the immune system, which would otherwise eradicate it. They also help the tumor feed itself by persuading the body to grow new blood vessels in the area. What Wang’s team discovered is that the MDSCs are involved in the early stages of cancer as well.

“We are the first group to really prove or show that they can probably play a role in cancer initiation,” Wang said. “So our paper was all about the beginnings of cancer—that is, there was no cancer, and then there was cancer.” And when the researchers looked at the early stages of inflammation that would later lead to cancer, they saw that the MDSCs were there, present at the scene as the crime was about to occur.

The discovery that MDSCs may be involved in the birth of cancer is a major find. If scientists can figure out how to control the activity of MDSCs, they might be able to work out a general strategy for preventing cancer. Although the researchers had success in using anti-IL-1β drugs to suppress MDSCs, the drugs are too powerful and expensive to use as a preventative measure.

“You certainly don’t want to go around giving infusions of IL-1β receptor antagonists [one class of anti-IL-1β drug] just to prevent cancer in patients who don’t have any disease,” Wang said. But he expressed hope that further study of MDSCs might yield safe and effective ways both to treat advanced cancer, and to prevent it from occurring in the first place.

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