~ Scientists Spot Cancer's 'Shield'

HealthDay, 05-11-06

THURSDAY, May 11 (HealthDay News) -- U.S. scientists say they've discovered a key mechanism by which cancer cells evade detection and destruction by the immune system.

The finding could lead to drugs that effectively rob tumors of the protected environment they need to survive and thrive.

A molecule called interleukin-23 (IL-23) "creates an environment that's just not acceptable to normal immune surveillance. Healthy immune cells that could kill the tumor can't get in there because of this -- it's almost a shield around the tumor," explained study co-author Robert Kastelein, a distinguished research fellow at the Schering-Plough Research Institute in Palo Alto, Calif., part of the Schering-Plough pharmaceutical company.

He and his colleagues published their findings in the May 11 issue of Nature.

The California team has for years focused its efforts on the connection between chronic inflammation of tissues and cancer.

"This association has been observed for over 100 years," noted senior study author Dr. Martin Oft, senior principal scientist at the institute. He pointed out that sites of chronic inflammation -- such as stomachs affected by ulcers or bowels plagued by Crohn's disease -- are also at high risk for cancer.

Pro-inflammatory molecules called cytokines are intimately involved in these processes, and literally thousands of scientific papers have been written about one such cytokine, interleukin-12 (IL-12).

But about five years ago, Kastelein's lab discovered that IL-12 was structurally linked to a second, then-as-yet-undiscovered cytokine, IL-23.

"Slowly, we began to realize that the chronic inflammatory [role] that had been assigned to IL-12 actually needed to be assigned to IL-23," he said.

Besides rewriting the textbooks on IL-12, the finding suggested IL-23 might have a role to play in promoting cancer.

In their latest study, the researchers attempted to induce cancer in mice genetically engineered to lack either IL-12 or IL-23.

"It turns out that the animals that did not have IL-23 were now protected from tumors," Oft said. "We tried to induce tumors in those mice and they did not get them."

Normal mice developed cancers at expected rates, and mice lacking IL-12 actually got more cancers than expected, suggesting that IL-12 -- once considered a cancer villain -- might actually counterbalance IL-23 to help ward off malignancy.

According to the California team, the evidence now points to the pro-inflammatory cytokine IL-23 as the "missing link" connecting inflammation and cancer.

But how does it do so? The researchers pointed out that the body's immune system is constantly on the alert for rogue cancer cells, killing them wherever they are found.

However, in other experiments, Oft and Kastelein found that high production of IL-23 kept immune system "killer" T-cells away from malignant cells, allowing cancer the space and time it needed to grow.

On the other hand, suppressing IL-23 brought T-cells flooding back to the tumor site, where they got busy hunting down cancer cells.

The bottom line: "If you happen to have chronic inflammation, and IL-23 is fueling that inflammation, your level of immune surveillance is limited," Oft said. "It's a devastating blow to the surveillance of cancer."

The discovery of IL-23's crucial role in this process may pump new life into the search for an effective immune-targeted anti-cancer therapy, the researchers said. In fact, Oft said, "we found that if you knock out the receptor for IL-23, animals have a much better chance to control tumor growth. That was very promising."

Kastelein said his team is "going full steam ahead" with animal studies that should expand on the IL-23-cancer link. The ultimate goal is the development of immune-based anti-cancer therapies.

"One of the key things that's missing now in terms of tumor treatments is how we can use the immune system to attack a tumor," he said. "The problem has been tumor penetration -- nobody has been able to effectively change the tumor environment so that your immune system, which should be able to take care of cancer, can actually do that."

But, according to Oft, the idea now is to suppress or otherwise manipulate IL-23 to "ramp up the immune system" and allow T-cells access to vulnerable cancer cells.

"We're very upbeat about potential applications further [down the line] in clinical trials," he said.

For more on the causes of cancer, head to the U.S. National Cancer Institute.

For the latest health news & Health-Life Services like tools, calculators, & a physician locator, go to www.healthday.com.

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