Cancer cachexia, or the wasting syndrome, is a catastrophic condition that causes dramatic and involuntary loss of muscle mass, fat and weight, alongside extreme fatigue, anorexia and anemia in patients with cancer.1 This severe stress reduces the body’s ability to respond to treatments, worsening prognosis and drastically accelerating death.
“More often than not, if you have two patients that have the exact same stage of disease, pathology of disease, but one of those cancers figured out how to promote wasting in the body, [that person] will live half as long as the other person,” said Puneeth Iyengar, a radiation oncologist at Memorial Sloan Kettering Cancer Center.
Cachexia affects approximately 50 to 80 percent of patients with cancer and is the primary cause of death in 30 percent of patients. Yet, robust remedies for the condition are lacking. “We don’t know enough about [cancer cachexia] biology. It’s a very complex problem,” Iyengar said.
In a recent study published in Nature Communications, a team of researchers at Cold Spring Harbor Laboratory (CSHL) shed light on the neural mechanisms driving this condition.2 The findings revealed novel targets that could inform the development of therapies that improve the quality of life for patients suffering from the condition.
Cancer cells modulate the surrounding tissue and distant organs through the molecules they secrete. One such multifunctional messenger, interleukin-6 (IL-6), is a key driver of cancer cachexia. Many patients with the condition exhibited elevated blood levels of the cytokine. Studies in rodents suggest that excess IL-6 can affect brain-controlled physiological reactions like the urge to eat or fever. However, it was unknown whether IL-6 activates receptors in the brain to trigger cachectic symptoms.
The study began with an impromptu collaboration between cancer biologist Tobias Janowitz and neuroscientist Bo Li, both at CSHL. Li recalled that, despite multiple conversations in which Janowitz suggested collaborating to explore the brain’s role in cachexia, he was unsure how he could contribute; he was skeptical about how a rodent model could help decode such a complex physiological problem involving a syndrome of symptoms. However, after observing that mice with cachexia exhibited increased levels of IL-6 in their blood, followed by classical cachexia symptoms such as anorexia and dramatic weight loss, Li became convinced of their potential.
The first thing Li and the team tested was where IL-6 travels and acts in the cachexia model mice. They injected both healthy and cachectic mice with IL-6 tagged with a molecular marker and examined their brains three hours later. To their surprise, in the entire brains of both healthy and cachectic mice, they found IL-6 only in one region: area postrema (AP), a brainstem structure. Using the neuronal activity marker Fos, the team observed that the IL-6 injection increased the activity of AP neurons and cells in brain regions connected to the AP, including areas of the hypothalamus and the amygdala. A subset of the activated AP cells were previously shown to cause nausea and cancer cachexia in mice.3
When the research team injected IL-6 into the bloodstreams (pink) of healthy (top row) and cachectic mice (bottom row) they detected it only in one brain region, the AP.
To determine if cancer alone could increase AP neuron activity, the team turned to a colon cancer mouse model. Following tumor formation, IL-6 levels increased in the AP. A few days later, the research team observed a rise in the number of active neurons in the AP followed by heightened activity in the connected brain regions. Only after these changes occurred did cachexia manifest.
Once the condition sets in, it can quickly wreak havoc; Li and his team noted that some mice lost 10 percent of their bodyweight in a single day. To alleviate these symptoms, the researchers affixed a miniature pump to the heads of the mice and delivered antibodies against IL-6 to the cerebral spinal fluid. The treatment successfully reduced cachexia symptoms both when given at a late stage of the disease and before the tumor developed. Mice that received the infusion ate more food, drank more water, lost less weight, and lived longer than the untreated mice. The antibody also dampened neuronal hyperactivity in the AP and its connected regions.
“The thing that surprised me the most was that our manipulation in a small brain area, with not that many neurons in there, in a very severe condition, can actually make the animal survive much longer,” Li said. To causally demonstrate that AP neurons drive cachexia the team used a CRISPR/dCas9 system to dampen levels of Il6ra, the IL-6 receptor gene, in these cells and inoculated the mice with tumor cells two weeks later. Not only did these mice exhibit less neuronal activity in the AP, but they also showed fewer cachectic symptoms relative to mice with normal levels of the gene. These results confirmed that high levels of IL-6 in cancer can send the AP network into hyperdrive, activating a cascade of symptoms that result in the development of the wasting syndrome. The team observed the same results in mouse models of pancreatic ductal cancer and Lewis lung carcinoma.
Next, Li wants to determine whether human patients exhibit similar cachexia-induced changes in AP activity. He is also interested in mining the data to develop better and more specific therapies to treat the condition.
“People feel that maybe it’s almost hopeless to cure cachexia. But, if we can even minimize cachexia symptoms, that will give the patient the opportunity to undergo the standard therapy for cancer and have a better chance for survival,” said Li.
