Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

Abstract

Muscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation of cachexia, thus affecting quality of life and overall survival in cancer patients. Pre-clinical studies have shown that blocking activin receptor type 2 (ACVR2) or its ligands and their downstream signaling can preserve muscle mass in rodents bearing experimental cancers, as well as in chemotherapy-treated animals. In tumor-bearing mice, the prevention of skeletal and respiratory muscle wasting was also associated with improved survival. However, the definitive proof that improved survival directly results from muscle preservation following blockade of ACVR2 signaling is still lacking, especially considering that concurrent beneficial effects in organs other than skeletal muscle have also been described in the presence of cancer or following chemotherapy treatments paired with counteraction of ACVR2 signaling. Hence, here, we aim to provide an up-to-date literature review on the multifaceted anti-cachectic effects of ACVR2 blockade in preclinical models of cancer, as well as in combination with anticancer treatments.

Keywords: activins; cancer cachexia; chemotherapy; mortality; multi-organ; muscle wasting; myostatin; survival; tumor.

Figure 1

Hypothesis of causality between cancer cachexia and death. Dashed lines indicate inferred mechanisms requiring further investigation. Images were adapted from https://smart.servier.com (accessed on 23 February 2021).

Figure 2

A simplified illustration of intracellular signaling induced by binding of myostatin or activins to their receptor activin receptor type 2B (ACVR2B). Cell membrane and DNA images were adapted from https://smart.servier.com (accessed on 23 February 2021) (Modified from Reference [135]).

Figure 3

Simplified cartoon showing tumor-driven alterations potentially rescued by blocking ACVR2 or its ligands. Various factors modulate the treatment response, including tumor type, chemotherapy regimen, diet, physical activity, as well as specificity and timing of ACVR2 or its ligand inhibition. Some of the effects are stronger and more consistent than others and some organ effects may occur at least in part through rescuing muscle wasting. Organ images were obtained from https://smart.servier.com (accessed on 23 February 2021).