Cancer Cachexia May Arise From Defects in Protein Signaling

NEW YORK (Reuters Health) – Cancer cachexia may be due to defects in protein signaling that lead to muscle wasting, studies in mice and patient samples suggest.

“Our findings show that as cancer progresses, the close working relationship that normally exists between motor nerves and muscle fibers – through their interaction at the neuromuscular junction – becomes impaired,” Dr. Paul Gregorevic of the University of Melbourne in Australia told Reuters Health by email.

“When muscle fibers no longer receive the signals they seek from motor nerves, the processes that control muscle fiber size and activation become affected,” he explained. “Left unchecked, these impairments lead to muscle wasting and failure to effectively produce the force on demand that we require to live well.”

“These findings…could help to explain why many people with common cancers become increasingly frail and develop complications that reduce their survival,” he said. “The disturbance of muscle-nerve interaction could help to explain why (they) may display more weakness than their quantity of muscle mass would predict.”

“This concept is also important because muscle fibers deprived of motor nerve signals tend to respond poorly to interventions designed to stimulate cell growth,” he added. “As such, it is tempting to speculate that the impairment of muscle-nerve communication may help to explain why some experimental agents trialed for cancer cachexia have struggled to achieve desired improvements in strength and physical performance.”

As reported in Science Translational Medicine, Dr. Gregorevic and colleagues investigated the mechanisms that contribute to cachexia in advanced cancer in a series of experiments in mice and in 79 patient samples. They found that the activity of bone morphogenetic protein (BMP), which normally suppresses protein breakdown, was abnormally low in mice with cancer cachexia.

However, restoring BMP activity with genetic techniques or with the antiviral drug tilorone slowed the muscle mass loss.

Mechanistically, the team found that BMP activity declined in the mice because of because of cancer-mediated factors including Activin A and IL-6, which trigger the expression of the BMP inhibitor Noggin in muscle; this blocks the actions of BMPs on muscle fibers and motor nerves, subsequently causing disruption of the neuromuscular junction, denervation, and muscle wasting.

The researchers also observed defects in BMP signaling and degeneration of neuromuscular junctions in the patient samples.

“Collectively, these findings present interventions that promote BMP-mediated signaling as an attractive strategy to counteract the loss of functional musculature in patients with cancer,” the authors conclude.

Dr. Gregorevic said, “It is important to remember that the biology underlying cancer cachexia is highly complex and that a host of different mechanisms contribute to (its) development in ways that vary between individuals based on their cancer type, unique genetic traits and prior health history.”

“We still have more to learn,” he said. “But we suggest that monitoring for biochemical and functional signs of the biological mechanisms that contribute to impairment of neuromuscular function could be considered as part of an overall plan to develop better ways to personalize interventions for people, and to monitor their wellbeing.”

Dr. Daniel Marks, senior associate dean for research at the Oregon Health and Science University School of Medicine in Portland and a member of the Board of Directors of Endevica Bio, which is developing a drug for cachexia, commented in an email to Reuters Health, “This is a rigorous and compelling study performed by a collaboration between the labs of thought leaders in muscle biology.”

“This study provides an interesting new angle on muscle wasting in cancer cachexia, and the data suggest that the connection between nerves and muscles are disrupted early in the course of cancer cachexia,” he noted. “Most muscle biology has focused on mechanisms of protein loss in the muscle cell itself, and far less attention has been given to the connection between nerves and muscles.”

“If confirmed,” he added, “these studies point toward a new avenue for treatment of this debilitating condition.”

That said, he noted that some aspects of cachexia in humans, including anorexia, fatigue and neurocognitive clouding, might be expected to worsen with the use of tilorone, since these are side effects of the drug.

Further, he said, “this study did not address pathology in the cardiac muscle. Wasting occurs in the heart in cancer cachexia, but the heart does not have the same kind of innervation as skeletal muscle, so it is not clear what the impact of this therapeutic pathway would be on the health of the heart.”

“It is difficult to study every aspect of cachexia simultaneously,” Dr. Marks said, “and it is likely that combination therapies will be needed to treat this complex condition.”

SOURCE: Science Translational Medicine, online August 4, 2021.

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