Tumors Disrupt the Blood-Brain Barrier at a Distance

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The goal of most cancer therapeutics is to eliminate or at least stop the growth of malignant cells. A study published September 7 in Developmental Cell points to a possible complementary strategy: reinforcing host defenses, specifically the blood-brain barrier (BBB). The authors found that tumors in the body can disturb the BBB and that interfering with this disruption seems to improve host health in both fruit flies and mice, even as tumor growth continues.

This work “shows that [breaking] the blood-brain barrier is at least one of the causes of death” in animals with cancer, says Wu-Min Deng, who studies tumorigenesis in Drosophila at Tulane University School of Medicine and was not involved in the study. It’s “a very good example of how the fly model can be used to answer some very difficult questions in cancer biology,” he adds.

For the past two decades or so, David Bilder’s group at the University of California, Berkeley, has leveraged Drosophila models to better understand cancer. Then, “maybe eight or nine years ago, a really spectacular student came to the lab, who got very interested in the idea of that we could use the fly not only as a model for studying how tumors grow, but also how tumors affect the host,” he tells The Scientist.

In 2015, that student, Alejandra Figueroa-Clarevega, and Bilder showed in fruit flies that malignant tumors make a protein that disrupts insulin signaling, leading to so-called cachexia, a breakdown of fat and muscle and subsequent extreme weight loss, which is linked to death in many human cancer patients. The work inspired current Bilder lab postdoc Jung Kim, who led the new study, to use the fly to explore other ways in which a tumor affects a host at distant sites in the body.

Kim, Bilder, and colleagues started by transplanting tissue that expresses the activated oncogenes Ras and aPKC into wildtype adult flies, where the tissue formed malignant, nonmetastatic tumors. These tumors killed the animals within a few weeks—about half the lifespan of flies that received a noncancerous tissue transplant. The researchers determined that these tumors activate the JAK/STAT signaling pathway—a readout of inflammation—throughout the flies and particularly in glial cells.

The BBB in flies is made of glia that protect the brain from the open circulation of hemolymph, the circulatory fluid in Drosophila. The researchers checked whether the BBB was intact by injecting a dye into the hemolymph. They found that the dye got into the brains of flies with tumors but not the brains of controls.

Next, the team knocked out the fly orthologs of interleukin 6 (IL-6), a cytokine that can activate JAK/STAT signaling; the receptor that the IL-6 orthologs bind to; or STAT itself in graft or host tissue. When they did that, the breakdown of the blood brain barrier didn’t happen in the flies with cancer, and the insects lived longer. Activation of JAK/STAT signaling in the glia in the absence of a tumor also led to an increase in BBB permeability, followed by eventual death, though it happened much more slowly than in flies with tumors. All together, the authors conclude, these findings indicate that cytokines produced by the tumor lead to inflammation and disruption of the BBB, which ultimately kills the host. 

The effects of preserving the BBB in flies are “really remarkable. They’re living longer in the presence of a tumor,” Bilder tells The Scientist. 

In flies and mice, cytokines released from tumors in the body cause cell junctions that normally protect the brain from circulating molecules to open up, shown here by the diffusion of a tracer dye.

Jung Kim, Hsiu-Chun Chuang, David Bilder

To explore if the interactions between tumors and the BBB are conserved in vertebrates, his group joined forces with collaborators at Berkeley who have expertise in mice with melanoma-derived tumors. They found that here, too, cancer triggered an IL-6–dependent BBB breakdown. When IL-6 signaling was blocked, the mice got less sick. 

The mouse work raises “the exciting possibility that the mechanisms identified in flies may have implications to human disease,” Julia Cordero, a cancer biologist at the University of Glasgow in Scotland who did not participate in the study, writes in an email to The Scientist.

She adds that experiments evaluating the BBB in mouse models of cancer that develop tissue-specific tumors—an extension of the work with injected melanoma cells, as the authors have done here—“are likely to follow up from this pioneering Drosophila study.” Bilder explains that they chose the mouse model they did because the tumors had been shown to upregulate the cytokine they’d implicated in the fly, so it’s not clear how broadly this finding will apply across other types of cancer. At the same time, “many cancers are known to cause significant systemic inflammation, so we certainly hope it inspires clinicians who have not looked at the blood-brain barrier in patients” to do so, he says. 

This study is “a clever way to think about the blood-brain barrier,” says Natasha O’Brown, who studies the BBB in zebrafish at Harvard Medical School and did not participate in the work. One open question is: “If you induce with a tumor and then took the tumor out, will the breakdown still be there?” Many of these signaling pathways get started and then are self-reinforcing, she adds, so knowing how much of the damage is reversible upon tumor removal could be relevant to human health.

Figuring out the particular factors that cause death after the BBB is damaged is a priority for Bilder. “It’s probably something that the tumor is creating in circulation, that’s then getting into the brain to hurt it,” he says, “but we also can’t rule out that it goes the other way”—that is, that a factor leaving the brain is what causes death.

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