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TLR4 gene found to protect against tumor development

December 08, 2005

A new study finds that a gene which plays an important role in immune function, known as toll-like receptor 4 (TLR4), may also play a critical role in suppressing chronic lung inflammation and tumor development in mice.

"We know that chronic inflammation predisposes people to many types of cancer," says NIH Director Elias Zerhouni, M.D. "By using this new information we may be able to suppress chronic inflammation and reduce our Nation's cancer burden."

In the December 7, 2005 issue of the Journal of the National Cancer Institute, researchers at the National Institute of Environmental Health Sciences (NIEHS), a part of the National Institutes of Health, report that mice prone to lung cancer that had TLR4 removed or altered had 60 percent more tumors than mice that had intact receptors, illustrating a new protective role for this gene. There were no differences in overall tumor size or structure between the mice. TLR4 is part of what immunologists refer to as the "innate immune system" which acts as the body's first line of defense against harmful substances.

Researchers explain the immune system actually is comprised of two components or systems, the innate and the acquired. The innate system can be thought of as the way the body is naturally programmed to respond, forming the front line of defense against infection. The acquired depends on the development of antibodies and other systems to recognize pathogens and other foreign objects that might upset the body's ability to fight off diseases. Understanding more about how the innate system works will help inform how the more complex, acquired system works.

"We have recently learned a lot about TLR4, its different mutations, and the role they play in immunity," said David A. Schwartz, MD, the NIEHS Director, "but discovering this novel function of TLR4 in tumor biology may provide new therapeutic targets for many chronic diseases, including cancer."

"We can't attribute the number of tumors per mouse to TLR4 alone, but it accounts for a significant portion of it," said Steven Kleeberger, Ph.D., Chief, Laboratory of Respiratory Biology at NIEHS, where the research was conducted. The researchers administered a preservative known to cause lung inflammation to the mice to determine the role of TLR4 in inflammation. Primary tumor formation also was measured in mice known to have cancer. Mice with both functional and altered TLR4 were used in all protocols.

"TLR4 acts like a brake of a car," Kleeberger said. "If you take the brake or receptor away, you see more increases in tumor development, more inflammation and more mortality

Previous research indicated an association between chronic lung inflammation and lung cancer, but the mechanisms are not well understood. Chronic bronchitis and asthma, for example, are known to heighten the risk of lung cancer. Inflammation has been implicated as a contributing factor in several human cancers, including lung cancer. Therefore, researchers wanted to see if one of the well known receptors in the immune system, the TLR4, played a role in the development of cancer in an animal model.

"What we found is the innate immune system, particularly TLR4, plays a critical role in protecting against the development of tumors and chronic inflammation," said Alison Bauer, Ph.D., of NIEHS and lead author on the paper. "It suggests that targeting the innate immune system may be a useful tool in fighting a variety of human diseases, including cancer."

"This mouse model provides us with the rationale to ask whether the innate immune system might be involved in lung cancer in humans," said Dr. Schwartz. "We are clearly finding that a better understanding of innate immunity will provide us with new ways to fight off many diseases.\\\

NIH/National Institute of Environmental Health Sci