March 07, 2003
Steve Mitchell, Medical Correspondent
United Press International
Scientists said Thursday they discovered blocking a molecule thought to play a role in cancer could prevent inflammation from occurring in mice, a finding that could lead to treatments for tumors, arthritis and other autoimmune disorders.
The researchers found knocking out the gene for a substance called HIP-1 -- which plays a role in activating the immune system -- stopped inflammation in its tracks, Randall Johnson, a molecular biologist at the University of California, San Diego, who headed the study, told United Press International.
"If we do things to the animals to induce inflammation ... nothing happens," Johnson said. "They don't get arthritis, they don't get inflammation."
"There are all sorts of places where you get inflammation you don't want," Johnson said. "If we could put an instant stop to that I think that could be tremendously beneficial," he said, adding it could be useful for treating conditions such as septic shock and arthritis, and autoimmune disorders such as lupus and multiple sclerosis.
In addition, several pharmaceutical companies currently are attempting to develop anti-cancer drugs that block HIF-1 because it also appears to play a role in several types of cancer.
White blood cells -- components of the immune system that help fight off infection -- are often drawn to sites of injury because damaged tissues register low oxygen levels.
The cells, which normally circulate in the oxygen-rich blood, have the ability to switch their metabolism from a high-oxygen environment to a low-oxygen or oxygen-free situation so they can generate energy and survive in a hypoxic situation. HIF-1 controls this process.
Johnson's group found knocking out the HIF-1 gene blocked the ability of white blood cells -- called macrophages -- and neutrophils that are involved in inflammation to function in a low-oxygen environment, thereby preventing the inflammation response.
"I think it's a major advance," Dr. Howard Franklin Bunn, a professor of medicine at Harvard Medical School in Boston who reviewed the study for cell, told UPI.
"It shows really beautifully ... that the adaptation of white blood cells to low oxygen levels is critical for their function" and is dependent on HIF-1, Bunn said.
This has implications for understanding normal function of the body as well as disease. HIF-1 is found throughout the body and may play a role in several disorders, he said.
In the March 7 issue of the journal Cell, Johnson and his colleagues describe their research with genetically modified mice. They bred mice with specific markers around a genetic coding for the HIF-1 molecule with other mice that expressed an enzyme in their macrophages and neutrophils that recognized the markers.
The enzyme cut out the gene but only in the macrophage and neutrophil cells, preventing those cells from functioning in low-oxygen injury sites and causing inflammation.
As the researchers then observed, the genetically altered mice failed to exhibit an inflammation response after being exposed to noxious substances or conditions that induced inflammation in normal mice. The modified animals also did not develop arthritis symptoms such as joint inflammation after exposure to treatments known to cause arthritis, Johnson said.
The findings could lead to new drugs that block HIF-1 in order to treat arthritis and other inflammatory conditions, he said. "Lots of (pharmaceutical) companies are trying to develop drugs against HIF-1 to prevent tumor growth ... but these could be potent anti-inflammatories," Johnson said.
Bunn agreed the findings could help researchers synthesize drugs to target HIF-1, but he noted the medications would need to be tailored to specific conditions as well as specific tissues in the body. In some cases, such as cancer, it might be desirable to suppress HIF, while in other cases, such as heart disease or wound healing, increasing HIF levels could be beneficial, Bunn said.
Johnson noted inhibiting the immune system cells "under normal circumstances ... would not be a good thing." This is because it would limit the immune system's ability to fight off infection and thus make patients vulnerable to diseases. Such possibilities must be taken into consideration when developing drugs that could block HIF-1, he said.
The findings could have implications for treating cancer, he said. An inherited disorder in which people have a mutation in the HIF-1 gene that causes overexpression can lead to cancer and is thought to be due to an excessive inflammatory response caused by the overexpression of HIF-1, Johnson explained.
In addition, "a lot of tumors are not only sites themselves of fairly low oxygen but also massive inflammation," he said. It is unclear whether the inflammation is beneficial or detrimental, so his group is now conducting additional experiments in which they will knock out HIF-1 and see how it affects tumor growth.
Copyright 2003 by United Press International