Silencing the TREM-1 Gene Protects Mice from Developing Liver Cancer

Blocking the activity of the proinflammatory enzyme TREM-1 (triggering receptor expressed on myeloid cells) protected mice from developing chemically induced liver cancer.

The relationship between TREM-1 and chronic inflammatory responses had already been established in studies on bacterial infection. Excessive inflammation owing to bacterial infections leads to tissue damage and septic shock. Inflammatory responses to microbial products were shown to be amplified by a pathway mediated by TREM-1. TREM-1 is an activating receptor expressed at high levels on neutrophils and monocytes that infiltrate human tissues infected with bacteria. Furthermore, it is upregulated on peritoneal neutrophils of patients with microbial sepsis and mice with experimental lipopolysaccaride (LPS)-induced shock. Blockade of TREM-1 protected mice against LPS-induced shock, as well as microbial sepsis caused by live Escherichia coli. These results demonstrated a critical function of TREM-1 in acute inflammatory responses to bacteria and implicated TREM-1 as a potential therapeutic target for septic shock.

In the current study investigators at the Georgia Health Sciences University (Augusta, USA) showed that in a mouse model chronic inflammation due to the expression of TREM-1 expressed by liver Kupffer cells was a crucial factor in the development and progression of liver cancer.

The study involved two groups of mice: a normal control group and a genetically engineered group in which the TREM-1 gene had been removed. All the animals were exposed to the cancer-causing agent diethylnitrosamine (DEN). Results published in the August 15, 2012, issue of the journal Cancer Research revealed that within 48 hours of DEN injection, the control mice showed signs of liver cell injury and death and high levels of TREM-1 expression in the liver's Kupffer cells. These mice developed massive liver tumors within eight months. The modified mice remained healthy following injection of DEN and produced at most a few very small tumors after eight months. The only apparent difference between the two groups was the appearance of TREM-1 in the Kupffer cells of the normal mice.

"We have long suspected that chronic inflammation is a very powerful tool in the initiation of cancer, and also in the progression or metastasis of cancer," said senior author Dr. Anatolij Horuzsko, professor of immunology at Georgia Health Sciences University. "We looked at the molecules that control inflammatory responses to gain a better understanding of how this process works. One important triggering receptor for inflammation is TREM-1. TREM-1 could be a target for any inflammation-associated cancer. In the future, we could use a drug to target TREM-1 in the body. We are already working in this direction."

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