Researchers from the Georgia Health Sciences University Cancer Center have identified a gene that disrupts the inflammatory process in liver cancer. Experimental mice without this gene lack a pro-inflammatory protein called TREM-1, and the lack of this gene can keep mice from getting liver cancer when exposed to carcinogens. The study, published in the journal Cancer Research (a journal of the American Association for Cancer Research), could lead to the development of drugs that target TREM-1, said Anatolij Horuzsko, PhD, an immunologist at the GHSU Cancer Center and principal investigator of the study. “We’ve long believed that chronic inflammation plays an important role in the initiation of cancer and also in its progression and metastasis.” We have studied the molecules that control the inflammatory response to gain a better understanding of this process,” Horuzsko said. One of the important trigger receptors for the inflammatory process is TREM-1. TREM-1’s role in promoting inflammation is also useful in fighting viral or bacterial infections and maintaining normal tissue function. But as Horuzsko’s group found, TREM-1 replicates like crazy under abnormal conditions – such as alcoholic liver injury or other stimulants. In a chronic, low-level inflammatory state, TREM-1 can lead to the development of other inflammatory conditions; this leads to more damage, increased cell replication and can produce mutant cells. Replication of these mutant cells can lead to cancer. During the 14-month study, Horuzsko and his team used mice to collect data on the role of TREM-1 in liver cells and to discover potential treatments. Because a mouse has a lifespan of roughly three years, the study mimicked a progression similar to 20-30 years of human liver cancer. Two groups of mice – one group knocked out of the TREM-1 gene – were exposed to the diethylnitrosamine carcinogen, or DEN, which is found in tobacco, chemicals and other products. Within just 48 hours of DEN injection, control mice began to show signs of liver cell damage and death and had high expression of TREM-1 in liver Kupffer cells. These particular hepatocytes are normally responsible for killing bacteria and destroying senescent red blood cells. After eight months, these mice developed large liver tumors. But the mice with the knockout TREM-1 gene remained healthy, with very little change after eight months, and the tumors were small, if any. The only difference between the two groups was the appearance of TREM-1 in the liver Kupper cells. Horuzko’s group hopes that their findings and the potential cancer treatments associated with TREM-1 will be equally applicable in other cancers. “TREM-1 could be a target for any cancer associated with inflammation,” Horuzsko said. “In the future, we will be able to see drugs that target TREM-1 in vivo. We’re already working in that direction.” In their research, the Horuzsko group also identified another potential target for drug therapy, a product of hepatocyte injury and death – HMGB1, a previously unknown activating ligand or mediator that stimulates Kuffer cells to produce TREM-1 protein and initiate the inflammatory process. Dr. Samir N. Khleif, director of the GHSU Cancer Center, said, “Advanced drug therapy for cancer is an evolving area of research, and immunotherapy is an important part of our goals.” Research like Dr. Horuzsko’s is leading the way in discovering targeted therapies that will become our standard of care in the future. When we open the door to new scientific discoveries, we can provide better care for patients and families suffering from cancer.