Tumors Disrupt the Blood-Brain Barrier at a Distance

Tumors Disrupt the Blood-Brain Barrier at a Distance
Shoring up the tissues that separate neurons and other brain cells from the circulatory system in fruit flies and mice can prolong life in the presence of a tumor.

A major objective of most cancer treatments is to kill or, at the very least, halt tumor development. A new research appearing in Developmental Cell on September 7th hints to a supplementary approach to address Zika: strengthening the blood-brain barrier (BBB). The researchers discovered that tumors in the body may damage the BBB, which can be resolved by maintaining the integrity of the BBB. This significantly improved the health of both fruit flies and mice while tumor development continued. Wu-Min Deng, who studies tumorigenesis in Drosophila at Tulane University School of Medicine and was not involved in the study, asserts that “[breaking] the blood-brain barrier is at least one of the causes of death” in animals with cancer. The work found that “this happened, on average, 2 days after [breaching] the blood-brain barrier and [creating] blood [vessels in the brain]” in the mice and rats the researchers studied. He says that it “serves as a powerful tool to address a lot of tough issues in cancer biology.” To investigate whether the tumor-BBB interactions are consistent throughout vertebrates, his team partnered with colleagues at Berkeley who are specialists in melanoma tumors in mice. Here, too, cancer activated an IL-6–dependent BBB degradation through a cancer-induced IL-6 response. The mice were less ill when IL-6 signaling was inhibited.

Julia Cordero, a cancer biologist at the University of Glasgow in Scotland who did not participate in the research, tells The Scientist that the mice experiments hold the intriguing prospect that “the pathways discovered in flies may have relevance to human disease.” As she also notes, animal models of cancer with tissue-specific tumors—in addition to the experimental work being done here with injected melanoma cells—will probably further explore this “pioneering Drosophila research.” Bilder’s work suggested that tumors produce more cytokines when compared to healthy tissue. This suggested that they use mice as a model for studying cancer, and mice had previously shown an increase in cytokines after cancerous tumors were surgically implanted in them. The broader significance of this finding is therefore unclear. “We definitely hope it encourages doctors who have not looked at the blood-brain barrier in patients,” he says, adding that “we also hope that it will show that the inflammation caused by cancer, which is already well recognized, has a greater effect on other organs than previously thought.”

Natasha O’Brown, who researches the blood-brain barrier in zebrafish at Harvard Medical School and did not participate in the study, believes the study’s “clever approach to think about the blood-brain barrier” merits consideration. One unanswered issue is: “Will the breakdown still be there if you induce with a tumor and then remove it?” She also points out that understanding the extent to which tumor removal may reverse any harm will be important to the health of people, and that various signaling pathways have a natural tendency to reinforce themselves, making it significant to know the potential for repair in human tumors. Bilder is especially concerned in understanding the mechanisms that lead to mortality after BBB impairment. “The tumor may be producing something in the bloodstream that is then traveling to the brain and damaging it,” he adds. “But it is also possible that the opposite occurs. A component exiting the brain may be causing death.”

David Bilder and his UC Berkeley team have used Drosophila models to investigate cancer for two decades. “We’ve got a fly here that could be a model for studying how tumors grow and the impact they have on the host,” he says. “And one of the students came to the lab a couple of years ago who was really interested in how we could make that fly into a better model by looking at it both ways. It’s not only the study of the tumor; it’s the study of the whole organism. And this was quite an exciting prospect, particularly because that young student went on to produce a master’s thesis project, which involved identifying this little muscle cell, the fruit fly muscle cell, as the model that the entire project is based on.” Bilder, together with Alejandra Figueroa-Clarevega, discovered that malignant tumors produce a protein that messes with insulin signaling in fruit flies, leading to cachexia, a condition that is characterized by massive fat and muscle loss and that is often deadly for cancer patients. The latest study, which was inspired by the work, uses a fly to investigate how a tumor affects the host in distant bodily locations, with lead researcher Jung Kim, a postdoc in the Bilder lab, exploring those options. Kim, Bilder, and others used nonmetastatic, malignant tumors that grew when they transplanted tissue expressing the activated oncogenes Ras and aPKC into wildtype adult flies. These tumors were fatal to the mice; animals that had noncancerous tissue transplants lived for half the normal fly lifetime, on average. The researchers found that these tumors cause inflammation in the flies and activate the JAK/STAT signaling pathway in the flies’ glial cells.

Flies have a blood-brain barrier, or BBB, comprising glia that keeps Drosophila’s hemolymph in their system from getting into their brain. The researchers injected a dye into the hemolymph to confirm if the BBB was still intact. Flies with tumors, they discovered, absorbed the color, whereas controls did not. The group’s next effort targeted a cytokine known as interleukin 6 (IL-6), which may signal through JAK/STAT pathways in graft or host tissue. Additionally, the IL-6 orthologs found in graft or host tissue were knocked out. The researchers were pleased with the results of the experiment since flies that had cancer did not have their blood brain barrier break down, and as a result, survived longer. When the glia were activated in the absence of a tumor, the glia stimulated JAK/STAT signaling, which then led to increased BBB permeability and death. However, this occurred over a longer period of time than mortality in flies with tumors. According to the scientists, these results point to cytokines that tumor cells generate resulting in inflammation and BBB breakdown that eventually kill the host. The “remarkable” consequences of maintaining the BBB in flies. “In the presence of a tumor, they are surviving longer,” Bilder says.

Categories: Clinical