Research Profile - Restoring inflammation's tarnished reputation

Inflammation – it's usually cast as the bad guy. But that might be too simple an interpretation. Sometimes inflammation can be a good thing in cancer. The problem is, we don't know when or why.

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Dr. Rama Khokha thinks inflammation has been given a bum rap.

"I think there's an overemphasis on how bad inflammation is," she says. "Understanding inflammation more fully is needed. It may not be bad in every case."

Dr. Khokha is a cancer researcher at the Ontario Cancer Institute. She's been investigating TIMP3, a gene that regulates inflammation and plays a role in cancer development. TIMP3 belongs to a small family of genes, with only four members. But these four genes together regulate metalloproteinases, a large family of proteins that regulate inflammation onset through cytokines.

It's long been recognized that inflammation can be a significant contributor to cancer development. In Dr. Khokha's research, though, she's found that the relationship is a bit more murky.

She has developed mice that don't have the TIMP3 gene. If you induce inflammation in these mice, they "super-respond" without TIMP3 to regulate and dampen inflammation and have a highly inflammatory response.

If, indeed, inflammation is tied to cancer development, the cancer should just take off, says Dr. Khokha. So they induced different kinds of cancer in these mice and watched to see the cancer grow. And in some cancers, this did happen, as expected. But surprisingly, the mice were resistant to some other kinds of cancer.

"We think that the resistance is a direct result of the absence of TIMP3," she says.

So now Dr. Khokha and her team are trying to figure out exactly which metalloproteinases TIMP3 is working on when it inhibits cancer and which it is working on when it encourages the disease. This knowledge could lead to the elucidation of promising new targets for treatment.

The targets are especially promising because, unlike many other genes, TIMP3 works outside the cell. That means you don't have to deliver the treatment into each cell; it's enough to deliver the treatment to the tissue environment in which the cancerous cells are found.

It's not quite that easy though, Dr. Khokha says. Because TIMP3 can both inhibit and encourage cancer growth, you have to ensure that you're aiming at the right place.

Still, Dr. Khokha has high hopes for the potential her research holds for developing a new way to target cancer. It's time, she says. The science has progressed since the field of TIMP3 and metalloproteinases was in its infancy, about 15 years ago. At that time, many companies made metalloproteinase inhibitors, but they didn't work and had some harmful side effects.

"The whole field was quite daunted," says Dr. Khokha. "But this field was tapped too early for cancer treatment. First we need to understand the basic functioning."

Understanding the most fundamental function of this family of genes has driven Dr. Khokha's research, in the firm belief that, if we can understand that better, then we can systematically go about targeting the right things.

The Study

It is now recognized that inflammation can significantly contribute to cancer development. Dr. Rama Khokha and her team have established that the TIMP3 gene regulates inflammation and that its loss can promote or inhibit different cancers. She is working to precisely determine the mechanism by which TIMP3 regulates inflammation, affecting cancer development. They are investigating how TIMP3 regulates the activity of inflammatory cytokines, including tumour necrosis factor at the local and whole-body level, using mice lacking TIMP3.

"I think there's an overemphasis on how bad inflammation is. Understanding inflammation more fully is needed – it might not be bad in every case."