Although the experience of a fruit fly dying of cancer may appear to be worlds apart from that of a human with a life-threatening tumor, researchers at the University of California, Berkeley, are seeing parallels that could lead to new strategies to extend the lives of cancer patients.
Research on fruit flies is already leading to a novel anti-cancer technique that differs from the traditional goal of eradicating the tumor or malignant cells. Instead, the study implies that attacking the cancer’s harmful compounds could boost survival rates and enhance patient health.
“It’s a tremendously complementary way of thinking about therapy,” said David Bilder, a molecular and cell biology professor at UC Berkeley. “Rather of destroying the tumor, you’re attempting to assist the host in dealing with its repercussions.”
Jung Kim, a postdoctoral fellow in Bilder’s lab, recently discovered that tumors in fruit flies release a chemical that disrupts the blood-brain barrier, allowing the two environments to mix — a formula for disaster in a variety of disorders such as infection, trauma, and even obesity. Kim and Bilder later established, in partnership with UC Berkeley professors David Raulet and Kaoru Saijo’s labs, that tumors in mice that release the same chemical, interleukin-6 (IL-6), also cause the blood-brain barrier to leak.
By limiting the cytokine’s influence on the barrier, scientists were able to lengthen the longevity of both fruit flies and mice with malignant tumors.
“Inflammation is known to be caused by the cytokine IL-6. The fact that this tumor-induced inflammation is causing the blood-brain barrier to open is novel. If we stop that opening process but leave the tumor alone, the host can live much longer and be much healthier with the same tumor burden “According to Bilder.
Because IL-6 has other vital functions in the body, scientists would have to develop a medication that blocks its action at the blood-brain barrier without affecting its effects elsewhere. However, he believes that such a medicine could help human cancer patients live longer and be healthier.
Bilder’s team discovered six years ago that tumors in fruit flies also release a chemical that prevents insulin’s effects, suggesting a possible explanation for cachexia, the tissue wasting that kills one-fifth of all cancer patients. Several labs across the world are now looking into this work.
One benefit of assisting the host in fending off the effects of a tumor on tissues remote from the tumor site is that it may lessen or even eliminate the requirement for harmful medicines commonly used to suppress malignancies. Such medications are also harmful to the patient, as they kill both healthy and malignant cells.
Beyond these negative consequences, targeting tumor cells “also selects for resistance in the tumor, because the tumor has genetic variability — a drug-resistant clone emerges, causing cancer recurrence,” he explained. “However, if you can target the host cells, they will have a stable genome and will not develop resistance to these medications. That is our goal: to figure out how the tumor affects the host and tackle the host side of the tumor-host conversation.”
Bilder and colleagues published their findings on IL-6 disruption of the blood-brain barrier in the journal Developmental Cell this week, and he co-authored a review of the influence of fruit fly research on understanding tumor-host interactions in the journal Nature Reviews Cancer last month. Their work on cachexia was published in Developmental Cell in 2015.
What causes cancer patients to die?
According to Bilder, experts are still unsure what causes many cancer patients to die. Cancer of the liver, for example, plainly degrades the function of a vital organ. Other organs, such as the skin and the ovaries, are less important, but individuals die from cancer in these areas as well, and sometimes very fast. Despite the fact that malignancies frequently spread to other organs — multiple organ failure is one of the leading causes of cancer death, according to doctors — Bilder doubts that this is the whole picture.
“Many human tumors are metastatic, but it doesn’t change the fundamental question: why do malignancies kill?” he stated. “Are you dying of lung failure or something else if your tumor metastasized to the lungs?”
As a result, he studies non-metastatic cancers implanted in fruit flies and mice, looking for systemic effects rather than just those on the tumor-bearing organ.
Cachexia, or the inability to retain weight, is a systemic consequence of cancer that leads to muscular atrophy even when the patient is receiving intravenous nutrition. While Bilder revealed one probable cause for tissue atrophy — tumours emit a molecule that stops insulin from storing energy in the body — other scientists have discovered additional compounds secreted by malignancies that may also be responsible.
Breach of the blood-brain barrier, like cachexia, could be another long-distance impact of tumors. The researchers discovered that inhibiting IL-6 activity at the blood-brain barrier enhanced the lifetime of cancer-ridden flies by 45 percent. Although laboratory mice must be terminated before they suffer and die from experimental cancer, the researchers discovered that after 21 days, 75 percent of cancer-carrying mice treated with an IL-6 receptor blocker remained alive, compared to only 25% of cancer-carrying mice who were not treated.
“It’s not simply the blood-brain barrier that’s killing the animals,” Bilder explained. “When the blood-brain barrier is disrupted, flies can live for three or four weeks, yet when the barrier is compromised when they have a tumor, they die practically instantly. As a result, we believe the tumor is causing something else to occur. Perhaps it’s circulating something that then passes through the damaged barrier, however it might also be something flowing in the opposite direction, from the brain to the blood.”
Bilder has discovered more cancer-producing compounds in flies, which he believes are linked to edema (bloating caused by excess fluid retention) and excessive blood clotting, which causes vein blockage. Cancer is commonly accompanied by both of these disorders. Other researchers have discovered a relationship between tumor-produced fly compounds and anorexia (a loss of appetite) and immunological dysfunction, both of which are hallmarks of many malignancies.
According to Bilder, cancer research in fruit flies has significant advantages over cancer research in other mammals such as mice and rats. For one thing, researchers can track flies right up until they die, allowing them to figure out what causes death. Researchers are unable to allow vertebrates to suffer due to ethical considerations, so research animals are terminated before they die naturally, impeding a complete understanding of the cause of death. Tumor size is employed as a proxy to measure an animal’s chance of survival in these studies.
“We’re ecstatic about the possibility of looking at survival and life span directly,” he said. “We believe this is a major blind spot that has prevented scientists from answering questions about how the tumor kills people outside of its localized growth. That isn’t to suggest that tumor size isn’t deceiving, but fruit flies provide a different perspective on cancer.”
Fruit fly investigations can encompass hundreds of individuals, whereas most cancer studies in rats involve only a few dozen animals. This increases the statistical significance of the data. Fruit flies are also quick to reproduce and have short natural life spans, allowing for faster research.
Although fruit flies and humans are only distantly related, these flies — Drosophila melanogaster — have played an important role in the understanding of tumor growth factors and oncogenes in the past. Fruit flies may now be crucial in gaining a better grasp of cancer’s systemic impacts.
“Not only do flies have tumors that look like human tumors, which we first observed 20 years ago,” he explained, “but we’re also seeing that the host response has amazing similarities in cachexia, coagulopathies, immunological response, cytokine release, and all of these things.” “I believe it is a superrich region (the tumor-host response in fruit flies). Our goal is to raise awareness of the field and encourage others to join it, both from a fly’s perspective and from a cancer biology and clinician’s standpoint.”