NIDCD Scientists Discover Inflammation’s “One-Two Punch” in Promoting Cancer

The relationship between cancer and inflammation—the immune system’s response to infection, irritation, or injury—is a bit like that between the chicken and the egg. The two seem to occur together, but scientists aren’t really sure which comes first or whether one causes the other.

A recent discovery by a team of researchers led by NIDCD intramural scientist Carter Van Waes, M.D., Ph.D., his colleagues in the tumor biology section of the head and neck surgery branch at the NIDCD, and scientists at SUNY Buffalo and the U.S. Food and Drug Administration (FDA) in Bethesda, Md., could help shine a welcome light on this quandary. The finding is the first to show that inflammatory factors produced during the development of head and neck tumors play an active role in coordinating a series of cellular events that allow cancer cells to grow and multiply unimpeded. Their findings are published in the September 20 early online edition of Cancer Research.

Head and neck squamous cell tumors are the most common cancers that affect voice and speech, but treatment options are limited and usually involve surgery, radiation, or both. Finding alternative treatments that are less intrusive and could potentially keep tumors from returning is driving explorations into particular genes and their family members that function as tumor suppressors or oncogenes.

The p53 gene is often called the “guardian of the genome” because its activities revolve around protecting and repairing damaged DNA in cells. It has such a strong hold over the genome’s health it can even order cells to self-destruct if their damage is too severe. It shouldn’t be a surprise then that mutations in p53 that deactivate its powers are at the root of many cancers. In fact, researchers estimate that the p53 gene is mutated in 40 percent or more of the people who develop head and neck cancers.

Fortunately, p53 has siblings—p63 and p73 among them—that appear to be in the same business and should be able to rally and step in when mutations in p53 cause the protein to lose its ability to keep cancer cells at bay. But they don’t. Why this doesn’t happen has puzzled many researchers, including Dr. Van Waes and his collaborators.

Their research led them to look at one of the primary signaling mechanisms of the immune system—tumor necrosis factor (TNF)—which is produced when tumor cells begin to grow and is a major mediator of cancer-related inflammation. They were especially interested in TNF’s relationship with a gene called NF-kappa beta (NF-κB), which was known to turn on several oncogenes that help cancer cells survive and multiply.

Using cultured squamous cells, DNA markers, and sophisticated gene assay technology, Dr. Van Waes and his collaborators were able to witness the series of events that turns p53 family members from heroes into villains.

It turns out that TNF leads off the transformation with a signal to the NF-κB protein, telling it to bind to p63, which inactivates its sibling, p73. TNF coordinates a kind of “one-two punch,” by switching on one protein that promotes cancer growth, and switching off another family of proteins that prevent tumor growth. This leaves the cells defenseless against cancer proliferation.

TNF has already caught the interest of some drug developers, who have created drugs that either inhibit its synthesis or its function. Some have already been tested in trials and shown to inhibit cancer growth. But Dr. Van Waes and his team’s discovery adds new sites of gene and protein activity, where other interventions might also work. Their research is continuing as they study a group of candidate drugs that can inhibit TNF and the signaling that activates the NF-κB protein, while switching p73 back on.

In the future, either drugs or other therapeutics that block this mechanism could be combined with radiation or with chemotherapy drugs to which the cancers would be more sensitive. The good news is that by understanding this new switch, and figuring out how to turn it off, we could also find our way to better and more successful cancer therapies.
NIDCD scientists discover inflammation’s “One-Two Punch” in promoting cancer