Dr. Lorne Brandes: Preventing liver cancer by blocking inflammation
Published Wednesday, September 5, 2012 10:24AM EDT
Scientists have long known that chronic inflammation underpins the development of cancer. The first recognized example was scrotal cancer in chimney sweeps.
In 1775, British surgeon, Sir Percivall Pott, discovered that it developed as a result of chronic progressive inflammation of the skin of the scrotum caused by exposure to coal tars present in chimney soot. Not only did Pott identify the first environmental carcinogen, he provided a way to prevent the cancer by the simple act of daily bathing.
Now, two centuries later, we know that chronic inflammation increases the risk of many types of cancer.
For example, patients with inflammatory bowel disease (IBD), such as Crohn’s and ulcerative colitis, are significantly more likelythan healthy individuals to develop colon cancer. A bacterium, called Fusobacterium nucleatum, found in a majority of biopsiesof inflamedintestinal tissue from patients with IBD, has also been identifiedin human colon cancer specimens, but not in normal bowel tissue. These provocative findings suggest that chronic Fusobacterium infection could be linked to both IBD and bowel cancer.
Even if such a link was ultimately proven, it would not be unique. There are already several known examples where chronic viral or bacterial infections result in tissue inflammation that directly causes, or contributes to, the development of cancer: human papilloma virus (HPV) and cervical and oral/anal cancers; hepatitis B and C virus and primary liver cancer; mononucleosis (Epstein Barr) virus and lymphomas/nasopharyngeal cancer; and Helicobacter pylori bacteria and stomach cancer/gastric lymphoma.
Yet, to establish a link between chronic inflammation and cancer is one thing; to understand the underlying mechanism(s) through which inflammation leads to cancer is quite another.
Now, in a paperjust published in Cancer Research, a group of scientists led by immunologist, Dr. Anatolij Horuzsko at Georgia Health Sciences University Cancer Center in Augusta, have made an important discoverythat not only opens the door to that understanding, but may have the potential to prevent liver and other cancers.
How? By potently blocking inflammation triggered by a specialized receptor, called TREM-1, present on our white blood cells.
First, some background. Normally, when our infection-fighting white cells (called neutrophils) are confronted by bacteria, TREM (Triggering Receptor Expressed on Myeloid Cells)-1 receptors on their outer walls are activated, sending out signals that unleash a cascade of inflammatory chemicals that help destroy the invaders. But, in addition to killing the bacteria, those same chemicals also cause tissue inflammation, resulting in unpleasant symptoms that we all know: pain, heat, swelling and redness at the site of the infection.
Once the infection resolves (often with the help of antibiotics), TREM-1 quiets down, the inflammatory response subsides, and everything returns to normal. However, as we will see, elevated levels of TREM-1 accompanying persistent inflammation are another matter.
In describing the theory leading up to his teams’ experiments, Dr. Horuzsko explains, "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. 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.”
So, to test the hypothesis that TREM-1 may influence the development of liver cancer by promoting inflammation, the researchers first injected a carcinogen, called diethylnitrosamine(DEN), into two groups of mice: normal controls, and those that had been genetically engineered to remove the gene that makes TREM-1.
What did they observe? Within 48 hours of the DEN injection, livers in the control mice all showed signs of acute inflammation and injury; many liver cells died. These changes were accompanied by high levels of TREM-1 in Kupffer cells(specialized liver cells that, like the blood’s white cells, release inflammatory chemicals in response to chemicals, viruses and bacteria). Moreover, the control mice all developed massive liver tumours within eight months.
In contrast the mice lacking the TREM-1 gene remained healthy. Their livers showed very little evidence of acute inflammation or tissue damage after the DEN injection; by eight months, only a few mice had developed liver tumours and, in those that did, the tumours were very small.
According to Dr. Horuzsko, the only difference between the two groups was the level of TREM-1 in the livers’ Kupffer cells: high in the control mice and low in the group lacking the TREM-1 gene.
"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," Dr. Horuzsko said in his institution’s press release.
My opinion? I agree with Dr. Horuzsko. This is a very promising new lead that, if as effective in humans as it is in mice, may ultimately lead to cancer prevention on a wide scale.