Cancer-associated cachexia is a severe tissue wasting syndrome. Alleviating the loss of adipose and skeletal muscle tissue would help improve the quality of life of patients who are affected by this syndrome and potentially improve disease outcome. Three recently published studies have identified underlying mechanisms of tissue wasting in early and advanced disease, raising the prospects of therapy options.

Credit: Lara Crow/Macmillan Publishers Limited

Two reports studied tissue wasting in pancreatic ductal adenocarcinoma (PDAC), using mouse models with activation of Kras and loss of p53 function (KP mice). Parajuli, P., Kumar, S. et al., who published in Developmental Cell, analysed muscle tissue loss in advanced PDAC and found that the transcription factor TWIST1 was required for skeletal muscle cachexia observed in KP mice older than 12 weeks, following overt PDAC formation. TWIST1 was induced in skeletal satellite cells, which triggered a paracrine protein degradation programme in myofibres. Muscle TWIST1 expression was also increased in mouse models of colorectal and lung cancer, and melanoma. In colorectal and lung cancer patients with cachexia, muscle TWIST-1 expression was increased. Activin A, a transforming growth factor-β (TGFβ) family member, induced TWIST1 in vitro, and TWIST1 induced the muscle degradation enzymes MuRF1 and Atrogin1 in mice. TWIST1 activity could be inhibited by the BET inhibitor JQ1, which led to a reversal of muscle cachexia and prolonged survival of KP mice.

Danai, L. V., Babic, A. et al., who published their findings in Nature, analysed tissue wasting during early stages of PDAC formation in KP mice and showed that loss of adipose and skeletal muscle tissue occurs by 6 weeks of age, before the frank onset of PDAC. Loss of adipose tissue was specifically linked to reduced exocrine pancreatic function rather than a systemic factor. While dietary supplementation with pancreatic enzymes reduced adipose tissue wasting in KP mice, it surprisingly also reduced the survival of KP mice — raising doubts about whether adipose tissue wasting was causally linked to reduced survival in PDAC patients. Indeed, in a population of 782 PDAC patients, adipose or skeletal muscle tissue wasting was not associated with reduced survival.

Loss of adipose tissue was specifically linked to reduced exocrine pancreatic function

The third study looked at metastatic cancer-induced cachexia. In mouse models of metastatic breast, colon and lung cancer, muscle overload with the heavy metal zinc increased muscle tissue wasting by blocking muscle cell differentiation and promoting myosin heavy chain loss. Wang, G., Biswas, A. K., Ma, W. et al., who published their results in Nature Medicine, showed that metastatic disease in their models was accompanied by reduction in body weight and loss of muscle tissue. The cachectic muscle tissue showed upregulation of the metal-ion transporter ZRT- and IRT-like protein (ZIP14). ZIP14 was upregulated in cachectic patients, and induced in vitro in response to inflammatory cytokines. ZIP14 mediated zinc influx and muscle cachexia, and was dispensable for tumour growth in mice.

Tumour-dependent changes in protein breakdown and inflammation contribute to and promote cachexia in advanced disease, in which cachexia is common and often associated with poor prognosis. In PDAC, the syndrome can develop even before frank cancer onset owing to functional organ impairment and defective nutrient catabolism. While cachexia might not be linked to patient survival across cancer types and/or stages, the lower quality of life associated with this syndrome necessitates further studies into therapeutic options.