A Different Path for Harnessing TRAIL

For two decades, researchers have been trying to exploit the apoptosis-inducing protein TRAIL as a cancer therapy. Now two studies reveal how tumors exploit TRAIL to spur inflammation that fosters their growth, suggesting that blocking the protein might be more effective.

TRAIL kills cancer cells by activating receptors on their surface. Researchers have developed several approaches to stimulate these receptors—and some potential drugs, such as the monoclonal antibody mapatumumab (GlaxoSmithKline), made it into clinical trials, but none worked very well. Some evidence suggests, however, that TRAIL can also benefit cancer cells, possibly by promoting production of proinflammatory cytokines. Both new studies delve into the mechanism behind this effect.

In the first study, Seamus Martin, PhD, and Conor Henry, PhD, of Trinity College in Ireland, discovered that stimulating TRAIL receptors triggered the formation of a signaling complex that contains caspase-8 and FADD. FADD is an adaptor protein, whereas caspase-8 can promote or prevent apoptosis, depending on the situation. When this signaling complex assembles, Martin and Henry found, it prompts cells to switch on NF-κB, triggering release of proinflammatory molecules such as IL6 and IL8. In turn, these molecules attract neutrophils and monocytes that may boost inflammation in the tumor. Through this mechanism, Martin says, tumor cells orchestrate a wound-healing response that permits them to survive and proliferate.

In the second study, Henning Walczak, PhD, of University College London in the UK, and colleagues also found that TRAIL prompts caspase-8 and FADD to join a signaling complex that spurs the release of tumor-aiding cytokines. In addition, the researchers provided in vivo data showing that deleting FADD reduced the number of tumors in mice with non–small cell lung cancer. Using data from The Cancer Genome Atlas, Walczak's team determined that in patients with lung adenocarcinomas, TRAIL levels correlated with levels of cytokines, such as CD33 and CCL2, that indicate an inflammatory, protumor environment.

The results of the studies indicate that “molecules like TRAIL might be acting as important drivers of tumor inflammation,” says Martin. “The tumor is using a molecule that normally would be used to kill it.” How TRAIL switches between its protumor and antitumor roles isn't clear, Martin says, but tumors may have a way to make sure they escape death: Many of them carry a mutant version of caspase-8 that can bind to FADD but doesn't induce apoptosis.

The study is not a “death blow” to the efforts to uncover potential treatments to stimulate TRAIL, says Thomas Griffith, PhD, of the University of Minnesota in Minneapolis, who wasn't connected to the research. However, it does demonstrate that “serving as a tumor death–inducing agent is not TRAIL's sole purpose.” Douglas Green, PhD, of the St. Jude Children's Research Hospital in Memphis, TN, adds that, “these papers may help to explain why the trials [of TRAIL stimulation] failed, and point the way towards new approaches to TRAIL therapy.” –Mitch Leslie