Some new basic science studies suggest breaches in the blood-brain barrier may be one reason some cancers are deadlier. The researchers found that blocking the activity of IL-6 at the blood-brain barrier increased the lifespan of fruit flies with cancer by 45%. The team also found that after 21 days, 75% of cancer-carrying lab mice treated with an IL-6 receptor blocker were alive, versus only 25% of untreated mice.
In a collaboration between the labs of UC Berkeley professors David Bilder, David Raulet, and Kaoru Saijo, the group also demonstrated that tumors in mice that release interleukin-6 (IL-6), make the blood-brain barrier leaky.
“It’s not just the breakdown of the blood-brain barrier that’s killing the animals,” Bilder said. “Flies can live for three or four weeks with a leaky blood-brain barrier, whereas, if they have a tumor, they die almost immediately when the barrier is compromised. So, we think that the tumor is causing something else to happen. Maybe it’s putting something in circulation that then gets through the broken barrier, though it could also be something going the other way, from the brain into the blood.”
Bilder and his colleagues have published their work on IL-6 disruption of the blood-brain barrier in the journal Developmental Cell, and he authored a review of the impact that fruit fly research has had on understanding tumor-host interactions that was published last month in the journal Nature Reviews Cancer.
“The IL-6 cytokine is known to cause inflammation. What’s new here is that this tumor-induced inflammation is actually causing the blood-brain barrier to open. If we interfere with that opening process but leave the tumor alone, then the host can live significantly longer and healthier with the same tumor burden,” Bilder said.
IL-6 plays other important roles in the body, so to benefit cancer patients, scientists would have to find a drug that blocks its action at the blood-brain barrier without altering its effects elsewhere.
One advantage of helping the host fend off a tumor’s effects on tissues far from the tumor site is that it could potentially reduce or even eliminate the need for toxic drugs typically used to treat tumors.
Beyond avoiding these side effects, targeting tumor cells “also selects for resistance in the tumor, because the tumor has genetic variability—a drug-resistant clone arises that will then cause cancer recurrence,” Bilder said. “But if you could target the host cells, they have a stable genome and are not going to gain resistance to these drugs. That’s our goal: to understand the ways that the tumor is affecting the host and attack the host side of the tumor-host dialogue.”
According to Bilder, scientists still are uncertain what causes death in many cancer patients. Cancer of the liver, for example, clearly destroys the function of an organ essential for life. However, other organs, like the skin or the ovaries, are less critical, yet people die from cancer in these sites, too, sometimes very quickly. And though cancers often metastasize to other organs—multiple organ failure is one of the main causes of cancer death listed by doctors—Bilder questions if that’s the whole story.
“Many human cancers are metastatic, but that doesn’t change the basic question: Why does the cancer kill?” he said. “If your tumor metastasized to the lung, are you dying because of lung failure or are you dying from something else?”
For that reason, he works with non-metastatic tumors implanted in fruit flies and mice and looks for systemic effects, not merely the effects on the tumor-containing organ itself.