Drs. Anatolij Horuzsko (from left) and Juan Wu look at the molecules
that control inflammatory responses to gain a better understanding of how chronic
inflammation is linked to cancer
Researchers at the Georgia Health Sciences University Cancer Center have
identified a gene that disrupts the inflammatory process implicated in liver
cancer.
Laboratory mice bred without the
gene lacked a pro-inflammatory protein called TREM-1 and protected them from
developing liver cancer after exposure to carcinogens.
The study, published in Cancer
Research, a journal for the American Association for Cancer Research, could
lead to drug therapies to target TREM-1, said Dr. Anatolij Horuzsko, an
immunologist at the GHSU Cancer Center and principal investigator on the study.
"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 Horuzsko. "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's role in promoting
inflammation is useful in cases such as battling viral or bacterial infections
and in maintaining normal tissue function. But as Horuzsko's team discovered,
in abnormal conditions—such as liver damage due to alcohol abuse or other
irritants—production of TREM-1 goes haywire. A chronic, low-level state of
inflammation is produced as TREM-1 leads to the development of other
inflammatory agents, which causes more damage, increases cell production and
creates mutated cells. These mutated cells then reproduce—planting the seeds
that can lead to cancer.
During the 14-month study,
Horuzsko and his team used mouse studies to gather data on the effect of TREM-1
in the liver cells and identify potential sources for therapies. Because a
mouse's life span is about three years, the length of the study mimicked a
similar 20- to 30-year cancer progression of liver cancer in humans.
Two sets of mice—one with the
TREM-1 gene removed—were exposed to the cancer-causing agent
diethylnitrosamine, or DEN, which is present in tobacco smoke, chemicals and
other products. Within just 48 hours of DEN injection, the control mice were
already showing signs of liver cell injury and death and high levels of TREM-1
expression in the liver's Kupffer cells. These specialized liver cells normally
destroy bacteria and worn-out red blood cells. Eight months later, these mice
also showed massive liver tumors.
But the mice with the gene
removed remained healthy, showing very few changes—and very small, if any,
tumors after eight months. The only difference between the two groups was the
appearance of TREM-1 in the Kupffer cells.
Horuzko's team hopes the
findings—and their potential in TREM-1-related cancer treatment—will be
applicable to other cancers as well. "TREM-1 could be a target for any
inflammation-associated cancer," said Horuzsko. "In the future, we
could use a drug to target TREM-1 in the body. We are already working in this
direction."
Horuzsko's team also identified
another potential target for drug therapy during the study—a product of liver
cell injury and death called HMGB1. HMGB1 is a previously unknown activating
ligand, or agent, that stimulates Kupffer cells to produce the TREM-1 protein
and start the inflammatory process.
"Advanced drug therapies for
cancer are a growing field of research, and immune therapies are an important
part of our mission," said Dr. Samir N. Khleif, Director of the GHSU
Cancer Center. "Studies like Dr. Horuzsko's are leading the way to
identify targeted therapies that will become our future standards of care. As
we open the door to new scientific discoveries, this enables us to provide
better care to patients and families with cancer. "
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