Tumours activate neurons to trigger appetite loss

Blocking a population of neurons in the brain could help treat anorexia and weight loss caused by cancer.

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The same neurons that help the brain respond to painful stimuli are also responsible for causing a loss of appetite in people with cancer. The discovery could lead to new treatments for people suffering from cancer-induced weight loss and anorexia.

“It’s pretty clear that people with cancer often die, not necessarily because the tumour is causing organ malfunction, but because they lose a lot of body weight. Loss of appetite is a large part of that,” says Carlos Campos, from the University of Washington in Seattle, US, who led the study. “If you can treat the weight loss that is a consequence of the loss of appetite, you improve the ability to prolong life and hopefully have a longer time frame to treat the tumour.”

The neurons behind cancer-related anorexia are located at the junction of the brain stem and the midbrain, in a small anatomical structure known as the lateral parabrachial nucleus (PBN). Campos and his colleagues decided to focus on these neurons after previously showing that their activation in otherwise healthy mice could make them lose their appetites.

Notably, the PBN neurons express a small protein known as calcitonin gene-related peptide (CGRP). This neuropeptide is the target of several drugs currently in late-stage clinical development for the treatment of migraines. According to Campos, these same drugs might prove useful for restoring appetite in cancer patients.

To test the role of these CGRP-expressing neurons in cancer-induced appetite changes, Campos and his team implanted lung cancer cells in one set of mice genetically altered another set of mice to spontaneously develop intestinal cancer. They showed that CGRP-expressing neurons in the PBN were pathologically active in response to the tumours in both sets of mice.

The researchers also injected an engineered virus into the brains of all the mice, allowing them to selectively inactivate the CGRP-expressing neurons at will. In this way, they showed they could prevent or reverse signs and symptoms of anorexia and weight loss, depending on when they silenced the neurons.

In addition to boosting appetite, blocking the CGRP-expressing neurons also reversed signs of lethargy, anxiety and malaise in the mice. If the same could be done with a drug in patients, “that would have huge implications for quality of life,” says Campos.

References

Campos, C. A., Bowen, A. J., Han, S., Wisse, B. E., Palmiter, R. D. & Schwartz, M. W. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nature Neuroscience 20, 934-942 (2017).

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