Research

RESEARCH

Cachexia is a wasting syndrome associated with elevated basal energy expenditure and loss of adipose and skeletal muscle tissues. It accompanies many chronic diseases including renal failure and cancer and is an important risk factor for mortality. About half of all cancer patients suffer from cachexia which is the direct cause of at least 20% of all cancer deaths1,2. Patients with pancreatic and gastric cancer have the highest frequency of weight loss at over 60-80% while the incidence of weight loss in patients with lung, colorectal, or head and neck cancer is above 50%3-5. Cachexia reduces the quality of life and causes frailty in patients. It leads to a poor response to chemotherapy, prevents patients from receiving further treatment, and negatively influences survival.

Cachexia in cancer and other chronic diseases remains a major unmet medical need6. The impact of cachexia on the survival of cancer patients is dramatic, however, the mechanisms underlying the progressive weight loss remain elusive and an effective therapy to block cancer cachexia is not available1,7. Cachexia is often considered to be an unfortunate consequence of cancer and gets less scientific attention than it deserves. However, it’s now becoming increasingly appreciated that cancer management should involve combined anti-tumor and anti-cachexia therapies, which would have synergistic effects on enhancing response rates and improving quality of life4,7.  There is urgent need for understanding the underlying molecular mechanisms and identification of new players and novel therapeutic approaches.

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Figure 1: Atrophy of white adipose tissue is  associated with emergence of beige cells and the  browning of the tissue. Tumor-driven depletion  of fat depots is not due to a drop in number of fat  cells but a decrease in lipid stores.

Energy Wasting in Adipose Tissue

Although cancer cachexia is frequently linked to reduced food intake and anorexia, it is fundamentally different from malnutrition. Cachexia-driven weight loss is not reversed by nutritional supplementation8. Rather, tumour-induced metabolic inefficiency and futile metabolic activities mediate wasting. Increased thermogenic activity of adipose tissue has been shown to contribute to the accelerated energy expenditure associated with cachexia and the resultant weight loss9. Increases in brown fat mass and activity were described in mouse models of cancer cachexia and in certain cachectic cancer patients10-16.

Brown fat burns lipids to generate heat through a process called adaptive thermogenesis, which involves the mitochondrial uncoupling protein UCP1. White fat depots are also known to harbor pockets of UCP1-expressing thermogenic cells, called beige cells, that can be stimulated via a process termed browning17. In white adipose tissue, tumors cause enhanced lipolysis and browning through promoting emergence of thermogenic beige cells (Figure 1). Tumor-driven increase in thermogenic activity of adipose tissue contributes to energy wasting and the loss of fat mass.

Skeletal Muscle Atrophy

Concomitant to the loss of fat tissue, tumors also cause atrophy of skeletal muscle fibers, which is evident from their decreased cross-sectional area (Figure 2). Muscle wasting is caused by a change in the balance between protein synthesis and degradation in favor of the latter.

The loss of muscle mass and strength primarily results from excessive proteolysis mediated by the ubiquitin-proteasome system (UPS). Most muscle proteins, including myofibrillar components and cytoskeletal elements, are degraded by the UPS and the reduction in muscle strength is caused by the loss of contractile machinery18. Activation of protein breakdown involves elevated expression of E3 Ubiquitin ligases Atrogin1 and MuRF1. Mice lacking these enzymes are resistant to muscle loss18,19. Therefore, blocking the activation of these E3 ligases could prevent muscle loss. 

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Figure 2: Atrophy of skeletal muscle tissue is  associated with enhanced protein degradation, which shrinks muscle fibres.

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Figure 3: Our working model for  PTHrP action during cancer cachexia.

PTHrP in Cancer Cachexia

Recent studies described important roles for adipose tissue thermogenesis in energy wasting linked to cancer while PTHrP emerged as an inducer of adipose tissue browning and a key factor driving energy wasting10. Our work showed that PTHrP promotes the activity of brown fat and the browning of white fat depots (Figure 3). Neutralization of PTHrP or loss of its receptor in tumor-bearing mice lowers energy expenditure and preserves fat and muscle mass10,20.

Although tumor-derived PTHrP is linked to skeletal muscle wasting, PTHrP alone fails to cause muscle atrophy. PTHrP receptor is not expressed in muscle fibers and PTHrP treatment of cultured myotubes does not cause cellular atrophy10,20. It is likely that this hormone collaborates with other tumor-induced molecules to promote muscle wasting (Figure 3).

EDA2R/NIK Signaling in Muscle Wasting

EDA2R is the transmembrane receptor for the A2 isoform of Ectodysplasin A (EDA), a member of the TNF family. While EDA-A1 and its receptor EDAR regulate ectodermal development21,22, EDA-A2/EDA2R signalling is involved in muscle pathophysiology23. Our gene expression analysis in muscle tissues revealed that EDA2R is upregulated in tumour-bearing mice and cachectic patients with lung, colorectal, pancreatic and gastrointestinal cancers24.

We found that stimulation of primary myotubes with EDA-A2 triggered pronounced cellular atrophy by inducing the expression of muscle atrophy-related genes Atrogin1 and MuRF1. EDA-A2-driven myotube atrophy involved activation of the noncanonical NFĸB pathway and depended on NIK kinase activity24 (Figure 4). While EDA-A2 overexpression induced muscle wasting in mice, the deletion of EDA2R or muscle NIK protected from tumour-driven loss of muscle mass and function24. Tumour-induced Oncostatin M (OSM) activated the EDA2R/NIK pathway, which required muscle OSM receptor activity24. Our results demonstrated that EDA2R/NIK signalling mediates cancer-associated muscle atrophy and the therapeutic targeting of this pathway may be beneficial in preventing muscle loss.

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Figure 4: EDA2R/NIK signaling in skeletal muscle.

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Figure 5: OSM/OSMR signaling in skeletal muscle.

Oncostatin M in Muscle Wasting

Oncostatin M (OSM) is a member of the IL-6 family of cytokines and has crucial functions in cell growth, differentiation, and inflammation25. Elevated OSM levels have been observed in cancer and inflammatory diseases in humans25,26. We found that OSM is a potent inducer of muscle atrophy27. It utilizes the JAK/STAT3 pathway to trigger cellular atrophy in primary myotubes (Figure 5). Identification of OSM targets by RNA sequencing revealed the induction of various muscle atrophy-related genes, including Atrogin1, Ampd3, Mt1, Mt2 and Serpina3n. OSM overexpression in mice caused muscle loss, while muscle-specific deletion of OSM Receptor (OSMR) and the neutralization of OSM preserved muscle mass and function in tumor-bearing mice24,27. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the elements of this pathway may serve as therapeutic targets in blocking muscle wasting.  

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