Cachexia, which is characterized by the progressive loss of skeletal muscle mass, affects up to 80% of patients with advanced cancer. It seriously reduces quality of life and is estimated to be responsible for ∼25% of deaths in these patients. Therapeutic strategies to prevent muscle wastage are limited and the underlying mechanisms are unclear. Now, Zhou and colleagues provide evidence to suggest that the activin receptor type 2B (ACVR2B) signalling pathway is important in cancer cachexia and show that blockade of ACVR2B signalling with a soluble decoy receptor prevents, and even reverses, muscle wastage. Furthermore, it prolongs survival in several mouse models of cancer cachexia.

ACVR2B mediates the signalling of several ligands in the transforming growth factor-β superfamily, including activin A and myostatin. High levels of activin A have previously been shown to enhance gonadal tumour growth and to cause a cachexia-like syndrome in mice deficient in inhibin (a protein that opposes the activities of activin). By contrast, myostatin is a known negative regulator of muscle growth.

To investigate whether signalling in the ACVR2B pathway directly causes cancer cachexia the authors evaluated the effects of a soluble ACVR2B–Fc construct termed sACVR2B in colon 26 (C26) tumour-bearing mice, in inhibin-deficient mice and in nude mice bearing human melanoma or ovarian carcinoma xenografts. Treatment with sACVR2B reversed weight loss and muscle loss, and thereby extended survival in the tumour-bearing animals. Importantly, sACVR2B had no effect on tumour growth in the C26 model, indicating that the survival benefit was not due to reduction of the tumour.

The study also provides new evidence of cardiac muscle atrophy in cancer models, which was completely blocked by sACVR2B, suggesting that amelioration of cardiac muscle atrophy also contributed to the observed survival benefits. However, the mechanism by which sACVR2B prevents cardiac atrophy in the tumour-bearing mice was not clear and needs further investigation.

For skeletal muscle, the authors show that sACVR2B has multiple effects. It sequesters activin A and myostatin and prevents the induction of other atrophy-related ligases, such as atrogin 1 (also known as FBXO32) and MURF1 (also known as TRIM63), by blocking the induction of the upstream regulator SMAD2. Moreover, sACVR2B is able to promote the growth of a population of stem cells that are present in skeletal muscle. Overall, this could explain how treatment with sACVR2B can restore muscle mass in tumour-bearing mice to levels that equal or even surpass that of control mice. The causal role of activin A in the development of anorexia in cancer cachexia was also confirmed, although how it regulates food intake is unclear.

In summary, the study shows the importance of the relationship between muscle loss and survival in cancer, and indicates that blockade of the ACVR2B pathway could be a promising strategy for treating cancer cachexia. It also highlights the potential for investigating such strategies in other diseases involving muscle wasting, such as HIV infection and heart failure.