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Aug 23, 2012

A Target for Liver Inflammation and Cancer

  • A cell surface receptor involved in triggering liver inflammation could represent a new target for preventing or treating liver cancer, scientists claim. It’s long been suspected that chronic liver inflammation is associated with the development and metastasis of liver cancer, but to date, the mechanisms underlying this haven’t been uncovered. Studies in experimental mice by a team at Georgia Health Sciences University have now shown that knocking out the gene for the proinflammatory myeloid cell surface receptor TREM-1 on Kupffer cell macrophages rendered the animals far less susceptible to chemically induced liver inflammation and damage, and also to the development of liver cancer.

    Kupffer cells normally work to battle invading bacteria and other infections and destroy worn out blood cells. However, Anatolij Horuzsko, Ph.D., and colleagues have now found that under abnormal conditions such as liver damage due to environmental irritants or excessive alcohol, for example, TREM-1 is overexpressed, resulting in a chronic state of minor inflammation that subsequently triggers inflammatory cascades leading to uncontrolled liver cell damage and mutations, which eventually cause cancer.

    The researchers studies showed that diethylnitrosamine-treatment of wild-type mice was associated with marked overproduction of TREM-1 in Kupffer cells, leading to signs of liver damage within just days and the development of huge liver tumors within months. In contrast, the TREM-1-knockout animals demonstrated far less liver damage in response to DEN administration, and developed only very small, if any, tumors over the same time period. And when the knockout mice were given TREM-1-expressing Kupffer cells from wild-type mice, they rapidly became susceptible to the damaging effects of DEN.

    Further analysis indicated that knocking out TREM-1 in Kupffer cells led to downregulation of both the transcription and protein expression of IL-6, IL-1β, TNF, CCL2, and CXCL10, and in addition reduced activation of the p38, extracellular regulated kinase 1/2, JNKL, MAPK, and NF-κB signalling pathways. During the course of their studies they also identified HMGB1 as another potential target for liver therapy. The previously unknown activating ligand stimulates Kupffer cells to produce TREM-1 and set off the inflammatory process.

    The Georgia researchers hope their findings could lead to the development of new therapeutic approaches against a range of cancers. “TREM-1 could be a target for any inflammation-associated cancer,” Dr. Horuzsko suggests. “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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