Fruit fly research helps uncover new anticancer strategies

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The experience of a fruit fly dying of cancer may seem like a far cry from that of a human with a potentially fatal tumor, but researchers at the University of California at Berkeley find commonalities between the two that could lead to ways of prolonging the life of cancer. the patients.

Research on fruit flies is already pointing to a new anticancer strategy separate from the conventional goal of destroying tumor or cancer cells. Instead, research suggests that launching an attack on the destructive chemicals that cancer rejects could increase survival rates and improve patient health.

“It’s a really complementary way of thinking about therapy,” said
David Bilder, professor of molecular and cellular biology at UC Berkeley. “You are trying to help the host deal with the effects of the tumor, rather than killing the tumor itself.”

Jung Kim, a postdoctoral fellow at Bilder’s lab, recently discovered that tumors in fruit flies release a chemical that compromises the barrier between the bloodstream and the brain, leaving the two environments to mix – a recipe for disaster in many diseases, including infections, trauma and even obesity. In collaboration with the labs of Professors David Raulet and Kaoru Saijo of UC Berkeley, Kim and Bilder subsequently demonstrated that tumors in mice that release the same chemical, a cytokine called interleukin-6 (IL- 6), also make the blood-brain barrier leaky. .

Most importantly, they were able to prolong the lifespan of fruit flies and mice with malignant tumors by blocking the effect of the cytokine on the barrier.

“The IL-6 cytokine is known to cause inflammation. What’s new here is that this tumor-induced inflammation actually causes the blood-brain barrier to open. If we interfere with this opening process but leave the tumor alone, then the host can live much 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 should find a drug that blocks its action at the blood-brain barrier without altering its effects elsewhere. But such a drug could potentially extend the lifespan and lifespan of cancer patients, he said.

Six years ago, Bilder’s team discovered that tumors in fruit flies also release a substance that blocks the effects of insulin, providing a potential explanation for the atrophy of tissues called cachexia that kills a fifth. of all cancer patients. This work is now being explored by many laboratories around the world.

One of the benefits of helping the host fend off the effects of a tumor on tissues far from the tumor site is that it could potentially reduce or even eliminate the need for toxic drugs typically used to control tumors. These drugs also harm the patient, killing healthy cells as well as cancer cells.

Beyond these side effects, targeting tumor cells “also selects resistance within the tumor, because the tumor has genetic variability – a drug resistant clone appears which will then cause the cancer to recur,” he said. declared. “But if you could target the host cells, they have a stable genome and are not going to develop resistance to these drugs. This is our goal: to understand how the tumor affects the host and to attack the host side of the tumor-host dialogue.

Bilder and his colleagues published their work on
IL-6 disruption of the blood-brain barrier last week in the newspaper Development cell, and he wrote a examining the impact of fruit fly research on understanding tumor-host interactions which was published last month in the journal Nature Reviews Cancer. Their cachexia work published in 2015 in Development cell.

What Really Kills Cancer Patients?

Scientists still don’t know what causes the deaths of many cancer patients, Bilder said. Liver cancer, for example, clearly destroys the function of an organ that is essential for life. However, other organs, such as the skin or the ovaries, are less critical, but people also die from cancer in these sites, sometimes very quickly. And although cancers often metastasize to other organs – multiple organ failure is one of the leading causes of cancer death documented by doctors – Bilder wonders if that’s the whole story.

In fruit flies (top row) and mice (bottom row), cytokines (yellow arrow) released by distant tumors (red mass) break down a barrier that normally protects the brain. These leaks allow molecules circulating in the blood to invade the brain, as shown by the green dye that has diffused through the barrier (central column). The right column shows brains of flies and mice without tumors, which show no brain leaks. (UC Berkeley photo by Jung Kim and Hsiu-Chun Chuang)

“Many human cancers are metastatic, but that doesn’t change the basic question: why does cancer kill? he said. “If your tumor has metastasized to the lung, are you dying from lung failure or are you dying of something else?” “

For this reason, he works with non-metastatic tumors implanted in fruit flies and mice and looks for systemic effects, not just effects on the organ containing the tumor itself.

One of the systemic effects of cancer is cachexia, the inability to maintain weight, which results in muscle wasting even when the patient receives intravenous nutrition. While Bilder discovered a possible reason for this – cancers release a chemical that prevents insulin from storing energy in the body – other scientists have found additional substances released by cancers that may also be responsible. tissue atrophy.

Like cachexia, breaches in the blood brain barrier can be another long-range effect of tumors. In the new study, researchers found that blocking IL-6 activity at the blood-brain barrier increased the lifespan of flies with cancer by 45%. Laboratory mice must be euthanized before suffering and dying from experimental cancer, but the team found that after 21 days, 75% of mice with cancer treated with an IL-6 receptor blocker were alive, compared to only 25% of untreated cancer mice. .

“It’s not just the breakdown of the blood-brain barrier that kills animals,” Bilder said. “Flies can live 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 the tumor is causing something else. Maybe it puts something in circulation that then goes through the broken barrier, although it could also be something that goes the other way, from the brain to the blood.

Bilder has found other carcinogenic chemicals in flies that it’s linked to edema – bloating due to excessive water retention – and excessive blood clotting, which leads to clogged veins. Both conditions frequently accompany cancer. Other researchers found that the fly chemicals produced by the tumors were linked to anorexia – loss of appetite – and immune dysfunction, which are also symptoms of many cancers.

Bilder said the study of cancer in fruit flies offers several advantages over models of cancer in other animals, such as mice and rats. On the one hand, researchers can follow the flies until they die, in order to determine what is really causing the mortality. Ethical concerns prevent researchers from allowing vertebrates to suffer, so research animals are euthanized before they die naturally, preventing a full understanding of the ultimate cause of death. For these animals, the size of the tumor is used as an indicator to assess an animal’s chances of survival.

“We are incredibly excited about the potential to look directly at survival and lifespan,” he said. “We think this is a real blind spot that has not allowed scientists to answer questions about how the tumor kills outside of its local growth. That’s not to say the tumor size is misleading, but fruit flies provide us with a complementary way to examine what cancer is doing. “

And while most rodent cancer studies involve only a few dozen animals, fruit fly experiments can involve several hundred individuals, improving the statistical significance of the results. Fruit flies also reproduce quickly and have a short natural lifespan, which allows for faster studies.

Bilder recognizes that fruit flies and humans are only distantly related, but in the past these flies – Drosophila melanogaster – have played a key role in the understanding of tumor growth factors and oncogenes. Fruit flies could also play a key role in understanding the systemic effects of cancer.

“Not only can flies get tumors that look like human tumors, which we described 20 years ago, but we are now seeing that the host response has remarkable similarities in cachexia, coagulopathies, response immune, cytokine production, all of those things, “he said. noted. “I think (the tumor-host response in fruit flies) is a very rich area. Our hope is to bring attention to the field and attract others to work in it, both from a fly point of view and from a cancer biology and clinician point of view.

Reference: Kim J, Chuang HC, Wolf NK et al. Tumor-induced disruption of the blood-brain barrier promotes host death. Development cell. 2021. doi: 10.1016 / j.devcel.2021.08.010

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