Advances in cancer cachexia: Intersection between affected organs, mediators, and pharmacological interventions

Abstract

Advanced cancer patients exhibit cachexia, a condition characterized by a significant reduction in the body weight predominantly from loss of skeletal muscle and adipose tissue. Cachexia is one of the major causes of morbidity and mortality in cancer patients. Decreased food intake and multi-organ energy imbalance in cancer patients worsen the cachexia syndrome. Cachectic cancer patients have a low tolerance for chemo- and radiation therapies and also have a reduced quality of life. The presence of tumors and the current treatment options for cancer further exacerbate the cachexia condition, which remains an unmet medical need. The onset of cachexia involves crosstalk between different organs leading to muscle wasting. Recent advancements in understanding the molecular mechanisms of skeletal muscle atrophy/hypertrophy and adipose tissue wasting/browning provide a platform for the development of new targeted therapies. Therefore, a better understanding of this multifactorial disorder will help to improve the quality of life of cachectic patients. In this review, we summarize the metabolic mediators of cachexia, their molecular functions, affected organs especially with respect to muscle atrophy and adipose browning and then discuss advanced therapeutic approaches to cancer cachexia.

Keywords: Adipose tissue browning; Cachexia; Cancer; Cytokines; Mediators; Skeletal muscle wasting.

Fig. 1.

Different stages of cancer cachexia. Based on the severity of disease and degree of loss of body weight, cachexia syndrome is classified as pre-cachexia, cachexia, and refractory cachexia. Pre-cachexia: Pre-cachexia is a condition with less than 5% of weight loss accompanied by anorexia and muscular fatigue. Cachexia: Patients with an involuntary weight loss of > 5% within six months that cannot be entirely reversed by conventional nutritional support and leads to progressive functional impairment. An increase in anorexia, weight loss (due to loss of muscle and fat), inflammation, metabolic dysregulation, and a decrease in muscle strength, mobility, and quality of life are the clinical symptoms of cachexia. Refractory cachexia: Weight loss is variable. Due to the higher level of active catabolism and increased expression of ubiquitin ligases, weight loss management is no longer possible, and patients are unlikely to benefit from any treatment, with very poor chances of survival. A severe reduction in skeletal and respiratory muscle strength leads to impaired mobility and inadequate respiration.

Fig. 2.

Muscle anabolic and catabolic signaling and regulation of muscle wasting in cancer cachexia. Reduced muscle anabolic signaling: IGF-1 acts as an anabolic growth factor that stimulates muscle protein synthesis as well as proliferation and differentiation of muscle stem cells (satellite cells). IGF-1 binds with its receptor IGF1R, resulting in phosphorylation of insulin receptor substrate (IRS) and activation of PI3K/AKT signaling. Activation of PI3K/AKT signaling leads to the activation of downstream targets required for protein synthesis. Cancer cachexia causes impaired IGF-1 signaling, which leads to muscle atrophy. In addition to protein synthesis, AKT signaling also phosphorylates and inactivates the FoxO transcription factor, which is a negative regulator of myogenesis, and finally inhibits the expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF1. Increased muscle catabolism signaling: Tumor and immune cells induce inflammatory cytokines IL-1 and TNF-α, which activate transcription factor NF-κB via IKK. NF-κB signaling causes muscle wasting in cachexia through increased activity of Murf-1 and atrogin-1. Myostatin and activin bind to activin type II receptor (ActRIIB) and ALK4/5 and subsequently phosphorylate Smad2/3. Phosphorylated Smad2/3 makes a complex with Smad4 that translocates to the nucleus and induces muscle wasting. In addition, myostatin/activin signaling inhibits FoxO phosphorylation via reducing AKT activity, which increases the expression of ubiquitin ligases (Murf-1 and atrogin-1) as well as activates autophagy, subsequently increasing muscle protein breakdown. Another cytokine IL-6 binds to its receptors IL-6R and activates JAK/STAT3 signaling, which is implicated in muscle protein wasting.

Fig. 3.

Regulation of adipose wasting in cancer cachexia. During cancer cachexia, the tumor secretes several inflammatory cytokines such as TNF-α, IL-6, IFN-γ, and LIF. After secretion from the tumor, TNF-α inhibits the recycling of GLUT4 from the cytoplasm to the plasma membrane. In addition, it also activates monocyte chemotactic protein (MCP-1), which recruits monocytes followed by activated macrophages in the adipose tissue (AT), leading to inflammation. Inside the AT, macrophages also secrete TNF-α and IL-6, which induce lipolysis by activating hormone-sensitive lipase (HSL). Similarly, IFN-γ prevents uptake of glucose as well as free fatty acids, which results in insulin resistance along with lipid breakdown in the AT. Finally, LIF binds to its receptor LIFR and co-receptor gp130 and activates the JAK/STAT pathway. Activation of the JAK/STAT pathway further upregulates HSL activity. Overall, cytokines released from the tumor during cachexia lead to AT wasting, which may contribute to body weight loss in cachectic patients.

Fig. 4.

Cancer cachexia as a multi-organ metabolic syndrome: Although muscle and adipose tissue wasting are the main characteristics of cancer cachexia, tumor and host-derived factors and systemic inflammation also influence many other organs such as brain, liver, heart, bone, pancreas, cardiac muscle, and gut, which are involved in the cachectic process. Tumor-derived cytokines cause systemic inflammation in the hypothalamus and stimulate neuropeptides involved in the regulation of food intake. Anorexia exacerbates body wasting in cancer cachexia. In addition to tumor-derived mediators, adipokines, muscle-derived cytokines (myokines) and brain-derived anorexia factors also influence the wasting of skeletal muscle and AT as well as increase inflammation in the tumor microenvironment. This inter-tissue communication directly or indirectly influences tissue metabolism and the severity of the cachexia syndrome. Inflammatory cytokines can increase lipolysis in white adipose tissue (WAT), which releases free fatty acids that further fuel the tumor and facilitate muscle wasting. Cachexia can cause adipose tissue browning (WAT switches to brown adipose tissue) and increased thermogenesis. In turn, the myokines activate pathogenic mechanisms in the skeletal muscle and adipose tissue. Muscle wasting releases free amino acids resulting from active protein degradation during cancer cachexia, which drives the acute phase response in the liver. Cancer-associated gut microbiota dysfunction alters mitochondrial energy metabolism in skeletal muscle, contributing to the negative energy balance in cachectic cancer patients. In the case of cancer-mediated bone metastasis, increased activity of the osteoclasts results in the activation of TGF-β from the bone matrix, which can facilitate muscle wasting and reduce muscle strength. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)