Can fruit fly research help improve cancer patient survival?


Cross-section of a fruit fly brain showing how substances seep in from the blood (green) after cytokines from a distant tumor break the barrier between the bloodstream and the brain. Blocking the cytokine improved the health and survival of both fruit flies and mice with cancer and could do the same for human cancer patients. (Image by Jung Kim)

The experience of a fruit fly dying of cancer may seem worlds apart from that of a person with a life-threatening tumor, but researchers at the University of California, Berkeley, are finding similarities between the two that could lead to ways to extend the life of cancer patients.

Fruit fly research is already pointing to a new anti-cancer strategy that differs from the traditional goal of destroying tumor or cancer cells. Instead, the research suggests, attacking the destructive chemicals the cancer secretes 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 cell biology at UC Berkeley. “They 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 the Imagery, recently discovered that tumors in fruit flies release a chemical that disrupts the barrier between the bloodstream and the brain, mixing the two environments – a recipe for catastrophe in numerous diseases, including infections, Trauma and even obesity. Working with the laboratories of UC Berkeley professors David Raulet and Kaoru Saijo, Kim and Bilder subsequently showed that tumors in mice that release the same chemical, a cytokine called interleukin-6 (IL-6), also cross the blood-brain barrier leak.

More importantly, they were able to extend the lifespan of fruit flies and mice with malignant tumors by blocking the cytokine’s action on the barrier.

“The IL-6 cytokine is known to cause inflammation. What is new is that this tumor-related inflammation actually leads to the opening of the blood-brain barrier. If we disrupt this opening process but leave the tumor alone, the host can live significantly longer and healthier with the same tumor burden, ”said Bilder.

David Bilder, Jung Kim and Kaoru Saijo are sitting at a desk with a computer

Postdoc Jung Kim, lead author of the new study, flanked by David Bilder, Professor of Molecular and Cell Biology, and Kaoru Saijo, Assistant Professor of Molecular and Cell Biology. (UC Berkeley photo by Mark Khoury)

IL-6 plays other important roles in the body. To help cancer patients, scientists would have to find a drug that blocks its action at the blood-brain barrier without changing its action elsewhere. But such a drug could potentially extend the life and health of human cancer patients, he said.

Six years ago, the Bilder team found that tumors in fruit flies also release a substance that blocks the action of insulin, which provides a possible explanation for the tissue atrophy called cachexia, which kills a fifth of all cancer patients. This work is now being studied by numerous laboratories around the world.

One advantage of helping the host ward 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 normally used to combat tumors . Such drugs also harm the patient by killing healthy cells as well as cancer cells.

In addition to these side effects, the targeting of tumor cells “also selects for resistance in the tumor, since the tumor has genetic variability – a drug-resistant clone is created which then causes the cancer to recur,” he said. “But if you could target the host cells, they will have a stable genome and will not develop resistance to these drugs. That is our goal: to understand how the tumor affects the host and attacks the host side of the tumor-host dialogue. “

Bilder and his colleagues published their work on the disruption of the blood-brain barrier by IL-6 in the journal Developmental Cell last week, and he authored a recent review of the impact of fruit fly research on understanding tumor-host interactions in months the journal Nature Reviews Cancer. Her cachexia paper was published in Developmental Cell in 2015.

What actually kills cancer patients?

According to pictures, scientists are still unsure of what leads to death in many cancer patients. Liver cancer, for example, clearly destroys the function of a vital organ. However, other organs such as the skin or the ovaries are less critical, but even here people sometimes die very quickly from cancer. And while cancer often metastasizes to other organs – multiple organ failure is a major cause of cancer death cited by doctors – Bilder asks if that’s the whole story.

Diagram showing how distant tumors in mice and flies leak brains

In fruit flies (top row) and mice (bottom row), cytokines (yellow arrow) released by distant tumors (red mass) break a barrier that normally protects the brain. These leaks allow molecules circulating in the blood to enter the brain, as evidenced by the green dye that has diffused through the barrier (middle column). The right column shows brains from flies and mice without tumors, which have 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 lungs, will you die of lung failure or 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 tumor-containing organ itself.

A systemic effect of cancer is cachexia, the inability to maintain weight resulting in muscle wasting even when the patient is given intravenous feeding. While pictures discovered one possible reason for this – cancers release a chemical that prevents insulin from storing energy in the body – other scientists have found additional substances that cancer releases and may also be responsible for tissue atrophy.

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

“It’s not just the breakdown of the blood-brain barrier that kills the animals,” said Bilder. “Flies can live with a leaky blood-brain barrier for three or four weeks, while when they have a tumor they die almost instantly when the barrier is compromised. So we think the tumor is causing something else. Maybe it circulates something that then penetrates the broken barrier, but it could also be something that goes the other way, from the brain to the blood. “

Graphic showing how tumors and stress affect the blood brain barrier, including words

The blood-brain barrier usually prevents substances circulating in the blood from entering the brain through cellular connections and potentially causing damage. Tumors and other injuries like stress, infection, or a high-fat diet create chemicals that cause inflammation that affects the junction and leaks the brain. One such chemical is the cytokine interleukin-6, which acts through the STAT signaling pathway. (Graphic courtesy of Developmental Cell)

Bilder found additional carcinogenic chemicals in flies that have been linked to edema – bloating from excessive fluid retention – and excessive clotting, which leads to clogged veins. Both diseases often accompany cancer. Other researchers found that fly chemicals produced by tumors are linked to anorexia – loss of appetite – and immune deficiency, which are also symptoms of many cancers.

Pictures said studying cancer in fruit flies had several advantages over models of cancer in other animals such as mice and rats. For one, researchers can track flies to death to find out what is actually causing mortality. Ethical concerns prevent researchers from making vertebrates suffer. Therefore, research animals are euthanized before they naturally die, preventing a full understanding of the ultimate cause of death. In these animals, the tumor size is used as a proxy to assess an animal’s chance of survival.

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

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

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

“Not only can flies get tumors that resemble human tumors, which we described 20 years ago, but we now see that the host response has remarkable similarities in terms of cachexia, coagulopathies, immune response, cytokine production, and all of those things.” . “I think it (the tumor-host response in fruit flies) is a super-rich area. We hope to draw attention to this area and to win other people over to the work, both from the perspective of the flies and from the perspective of cancer biology and the clinic. “

The co-authors of the new paper are postdoc Hsiu-Chun Chuang from UC Berkeley, doctoral student Natalie Wolf and former doctoral student Christopher Nicolai. The work was supported by the National Institutes of Health (GM090150, GM130388, AI113041, HD092093).



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