Cancer cachexia: molecular mechanisms and treatment strategies

Abstract

Muscle wasting is a consequence of physiological changes or a pathology characterized by increased catabolic activity that leads to progressive loss of skeletal muscle mass and strength. Numerous diseases, including cancer, organ failure, infection, and aging-associated diseases, are associated with muscle wasting. Cancer cachexia is a multifactorial syndrome characterized by loss of skeletal muscle mass, with or without the loss of fat mass, resulting in functional impairment and reduced quality of life. It is caused by the upregulation of systemic inflammation and catabolic stimuli, leading to inhibition of protein synthesis and enhancement of muscle catabolism. Here, we summarize the complex molecular networks that regulate muscle mass and function. Moreover, we describe complex multi-organ roles in cancer cachexia. Although cachexia is one of the main causes of cancer-related deaths, there are still no approved drugs for cancer cachexia. Thus, we compiled recent ongoing pre-clinical and clinical trials and further discussed potential therapeutic approaches for cancer cachexia.

Keywords: Cachexia; Cancer; Multi-organ; Muscle wasting; Sarcopenia; Treatment.

Fig. 1

Cancer cachexia as multi-organ syndrome. This scheme shows the interaction of major organs that are associated with and commonly affected by cachexia. Cancer cachexia that happens in the muscle (center) is dependent on the alterations in other organs, such as adipose tissue, brain, gut, cardiac muscle, and immune cells. Cachexia-inducing tumors secrete many factors, such as cytokines, PTHrP, and other mediators, to induce muscle wasting directly, as well as affecting other organs such as brain, cardiac muscle, gut, and adipocyte tissue, which aggravates cachexia syndrome. WAT, white adipocyte tissue; PTHrP, parathyroid hormone-related protein; TNF-α, tumor necrosis factor-α; IL-1, interleukin-1; IL-6, interleukin 6; IL-8, interleukin-8; IL-10, interleukin 10; and NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells

Fig. 2

Muscle anabolic and catabolic signalings involved in muscle growth and wasting. Growth factors and nutrients activate PI3K-AKT-mTOR pathway, resulting in an increase in muscle protein synthesis. Furthermore, MAPK and SMAD 1/5/8 activation also induces protein transcription, leading to muscle growth. Conversely, in cachexia conditions, inflammatory cytokines from tumors and immune cells induce activation of transcription factor NF-kB, leading to UPS and ALS activation, which leads to muscle wasting. Furthermore, activin and myostatin bind to the ActRIIB, which phosphorylates SMAD2/3, activating UPS. Glucocorticoid and AngII also activate UPS and ALS pathway, respectively, and lead to muscle wasting. GH, growth hormone; IGF1R, IGF1 receptor; IR, Insulin receptor; BMP, bone morphogenetic protein; BMPRII, BMP receptor II; AR, androgen receptor; ActRIIb, activin type II receptor; AngII, Angiotensin II; AT1R, type 1 angiotensin II receptors; IL-6R, Interleukin 6 receptor; IL1bR, IL1b receptor; TNFaR, TNF receptor; PIF, proteolysis-inducing factor; PIFR, proteolysis-inducing factor receptor; GR, glucocorticoid receptor; ROS, Reactive oxygen species; UPS, ubiquitin (Ub)-proteasome system; and ALS, autophagy-lysosome system. The dashed lines indicate inhibited pathways

Fig. 3

Anabolic pathway leading to muscle growth. Insulin or IGF1 binds to the IGF1R and activates IRS-1 which leads to PI3K-AKT-mTOR pathway activation. AKT activates IKK inhibitor and further inhibits the NF-kB pathway, which is implicated in muscle atrophy induction. Furthermore, AKT also negatively regulates the FoxO protein that is responsible for protein degradation. Besides AKT, the mTOR pathway is also activated by nutrients, leading to phosphorylation of S6K that induces protein synthesis and muscle growth. IGF1, Insulin-like growth factor 1; IGF1R, IGF1 receptor; IRS-1, Insulin receptor substrate 1; and OXPHOS, Oxidative phosphorylation. The dashed lines indicate inhibited pathways

Fig. 4

Catabolic pathways lead to muscle atrophy. During catabolic states, multiple intracellular signaling pathways are activated and stimulate muscle wasting via protein degradation, Ca2 + -dependent proteolysis system, and autophagy. These catabolic effects in muscle are mediated by specific transcription factors, such as FOXO proteins, NF-κB, and SMAD2 or SMAD3. The activation of these transcription factors results from extracellular stimuli or from stimulation of JAK-STAT signaling and a decrease in the PI3K-AKT-mTOR pathway. Together, these pathways accelerate protein degradation, proteolysis, and autophagy, leading to muscle atrophy. RAGE, receptor for advanced glycation end-product; HMGB1, high mobility group box 1; ActRIIb, activin type II receptor; IGF1, insulin-like growth factor 1; IGF1R, IGF1 receptor; PIF, proteolysis-inducing factor; PIFR, proteolysis-inducing factor receptor; FOXO, forkhead box protein O; and NF-kB, nuclear factor-κB

Fig. 5

Treatment strategies for cancer cachexia-associated muscle atrophy. Several inhibitors are tested to inhibit muscle atrophy caused by protein degradation, ROS, UPS, inflammation, myostatin, and GDF15. On the other hand, exercise, nutrition, and appetite stimulants are used to induce food intake and IGF1, which leads to the inhibition of muscle wasting. TNF-a, tumor necrosis factor-α; IL-6, interleukin 6; ROS, reactive oxygen species; G-Rd, ginsenoside Rd; and IGF1, insulin-like growth fact. The dashed lines indicate inhibited pathways