Cancer-Mediated Muscle Cachexia: Etiology and Clinical Management

Abstract

Muscle cachexia has a major detrimental impact on cancer patients, being responsible for 30% of all cancer deaths. It is characterized by a debilitating loss in muscle mass and function, which ultimately deteriorates patients’ quality of life and dampens therapeutic treatment efficacy. Muscle cachexia stems from widespread alterations in whole-body metabolism as well as immunity and neuroendocrine functions, and these global defects often culminate in aberrant signaling within skeletal muscle, causing muscle protein breakdown and attendant muscle atrophy. This review summarizes recent landmark discoveries that significantly enhance our understanding of the molecular etiology of cancer-driven muscle cachexia, and further discuss emerging therapeutic approaches seeking to simultaneously target those newly-discovered mechanisms to efficiently curb this lethal syndrome.

Introduction

Muscle cachexia is the hidden killer of cancer, with roughly one out of three patients succumbing to the end-organ results of muscle weakness before their primary disease has run its course [1]. With recent advances in the treatment for cancers once thought terminal, attention has turned to mitigating the downstream effects of cancer to improve survival rates and quality of life across all cancers [2]. A major downstream consequence of several cancer types is muscle cachexia, which is currently defined as “a multifactorial syndrome driving skeletal muscle wasting, with or without loss of fat mass, that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment” [3]. The presence of the tumor triggers massive reprograming in whole body metabolism along with persistent inflammatory responses, which together differentiate cancer-associated muscle cachexia from other forms of muscle wasting conditions, such as sarcopenia, loss of muscle mass due to aging and inactivity, and muscle cachexia associated with chronic diseases, such as chronic obstructive pulmonary disease, chronic kidney failure, heart failure, and AIDS [4].

Muscle cachexia typically involves a combination of anorexia and abnormal metabolism, which together culminate in a hypercatabolic state in which the rate of muscle proteolysis outweighs that of protein synthesis. This in turn results in progressive loss of muscle mass and strength, leading to decreased physical function and consequently detrimental psychosocial outcomes [3]. If disease progression is severe enough, patients may experience difficulty eating, moving, breathing, and eventually undergo cardiac and respiratory failure resulting in death [5]. Besides worsening the pathogenic process of cancer, muscle cachexia also interferes with the therapeutic treatments. In fact, skeletal muscle atrophy decreases patient tolerance of several common cancer therapies [6], while several common chemotherapeutic agents are themselves known to worsen symptoms of muscle cachexia in a vicious cycle [7–9]. There currently exist no official guidelines for the management of cancer-derived muscle cachexia, but the current mainstay of treatment is supplemental nutrition [10, 11]. Patient responses to this approach have been mixed, with some studies reporting clear benefits while others reporting no significant amelioration in body weight or quality of life [11]. Clearly, the current standard of care for cancer-associated muscle cachexia could be improved by developing targeted therapies that simultaneously address the global metabolic dysregulation along with the altered skeletal muscle signaling pathways that orchestrate the muscle wasting process.

The overall impact of cancer-driven muscle cachexia is enormous, occurring almost in every type of cancer and affecting an estimated 50% of all cancer patients [12]. More precisely, the prevalence of muscle cachexia ranges from about 70% in pancreatic cancer to 30% or less in other types, such us breast and prostate cancers [5] (Table 1). While newly diagnosed patients may or may not exhibit signs of muscle cachexia, rates of muscle cachexia are very high near the end of life across all primary cancer types [13]. Difficulty in determining diagnostic criteria and lack of initial screening among presenting cancer patients has led to a dearth of reliable data that can be utilized to stratify cachectic cancer patients. Muscle cachexia is not irreversible, as removal of primary tumors has been shown to result in the reversal of the cachectic phenotype [14]. Besides being dependent on the tumor types and advanced stages of cancer, muscle cachexia increases in prevalence and severity with male sex, advanced age, cardiac comorbidities, and chemotherapeutic treatment from certain classes of cancer drugs [5]. Additional studies also indicate that genetic risk factors may also play a role [15]. Regardless of the factors initiating or aggravating muscle cachexia, the most recent available literature clearly show that muscle cachexia cannot be adequately treated by current approaches, therefore emphasizing an unmet need to better understand its mechanistic paradigms with the hope to find better therapies. This review attempts this momentous task by first describing the intracellular and circulating mediators of muscle cachexia, including circulating factors, dysregulation of metabolic pathways, the effects and interplay of various tissues, such as the liver, gut, fat, and brain, and the role of tumors and chemotherapy. Next, the actual effects of muscle cachexia on signaling pathways in skeletal muscle is discussed, including muscle homeostasis, apoptosis, and proteolysis. Finally, current therapeutic approaches to muscle cachexia is summarized and future potential therapies is presented (Box1).

Table 1:

Prevalence of cachexia in various cancers.

Cancer type	Estimated cachexia prevalence in at risk patients (%)	Patients at Risk to develop Cachexia (%)	Cachexia prevalence (%) Pressoir	Cachexia prevalence (%) Hebuterne
Liver	50.1	90	ND	ND
Pancreatic	45.6	90	ND	66.7
Lung	37.2	80	40.2	45.3
Head and Neck	42.3	70	45.6	48.2
Gastric	33.3	70	49.5	60.2
Colorectal	31.8	50	31.2	39.3
Endometrial	32.2	40	32	44.8
Kidney and renal pelvis	31.6	40	ND	ND
Non-Hodgkin lymphoma	28.4	30	34.2	34
Urinary bladder	25.2	30	ND	ND
Thyroid	39.9	30	ND	ND
Breast	23.5	30	18.3	20.5
Melanoma	22.1	20	ND	ND
Prostate	15.3	20	ND	13.9

Text Box1.

Outline of Topics

• Cellular and Humor Mediators of Cancer-Induced Cachexia

  • Circulating Factors
  • Liver, Energy Wasting, and Acute-Phase Protein Response
  • White Adipose Tissue Browning
  • Central Signaling
  • Tumor and Metastasis
  • Chemotherapy
  • Gut
• Skeletal Muscle Dysregulation

  • Changes in Muscle Homeostasis
  • Energy Wasting and Pro-Apoptotic Pathways
  • Protein Wasting Pathways
• Therapeutic Strategies

  • Cytokine Inhibitors
  • Myostatin/Activin-A and Twist11 inhibitors
  • Appetite Modulators
  • NSAIDS, Beta-Blockers, and Other Approaches

• Concluding Remarks and Future Directions

Cellular and Humoral Mediators of Muscle Cachexia

At its core, cancer-associated muscle cachexia is simply a metabolic dysregulation wherein the body consumes itself to compensate for the increased metabolic needs and the lack of proper nutrient intake secondary to the development of a tumor. This process is actually an intricate weave of tumor-mediated changes in local or global metabolism, the body’s pro-inflammatory immune response to tumor development, and the crosstalk between various tissues, including muscle, liver, adipose, brain, gut, and tumor, all mediated by a host of circulating factors. Development of effective therapies requires a basic understanding of each of these components.

Circulating Factors

Cancer-derived muscle cachexia is unique among other forms of cachexia in that the presence of a tumor causes a systemic inflammatory state characterized by a storm of circulating factors (Figure 1). Of most interest among these molecules are the cocktail of pro-inflammatory cytokines released by tumors and by immune cells responding to tumors, which include IL-6, IL-1, tumor necrosis factor alpha (TNF-α), interferon gamma (INF-γ), leukemia inhibitory factor (LIF), TNF-related weak inducer of apoptosis (TWEAK), and several members of the transforming growth factor beta (TGF-β) superfamily, particularly myostatin, activin-A, and growth/differentiation factors 11 and 15 (GDF11/GDF15) [5]. These signaling peptides mediate muscle cachexia in a paracrine manner by acting on cell surface receptors in muscle cells, where they activate signaling pathways that result in increased transcription of target genes typically associated with ubiquitination or autophagy (Figure 1).

Figure 1:

Schematic diagram showing major signaling pathways involved in cancer-associated cachexia. Cancer cell-derived circulating factors including IL-6, TNF-α, and myostatin/activin-A bind with their respective cell surface receptors to activate NFκB, STAT3 and SMAD2/3, respectively, which in turn induce the expression of Atrogin-1 and MuRF-1, resulting in muscle protein degradation and muscle atrophy.

In a healthy state, TNF-α plays a key role orchestrating apoptosis in the acute-phase reaction and maintenance of body homeostasis, but in cancer it takes on a significant role in tumor growth and metastasis as well as muscle cachexia [16]. TNF-α alone can inhibit differentiation of skeletal myocytes [17, 18], while together with INF-γ and other cytokines it acts to decrease muscle protein content and increases myofibrillar degradation in differentiated myocytes [19]. TWEAK, another member of the TNF-α superfamily, also mediates skeletal muscle wasting by binding to the TNF receptor superfamily member 12A (TNFRSF12A), the overexpression of which is known to correlate with muscle cachexia [20]. Both TNF-α and TWEAK activate nuclear factor kappa B (NF-κB) signaling in skeletal muscle, leading to increased proteolysis via ubiquitination [21, 22].

Interleukins (ILs) have been heavily studied in both their pathophysiologic role in muscle cachexia and as therapeutic targets. IL-6 in particular has long been known as a primary mediator of muscle cachexia, suppressing protein synthesis in skeletal muscle and promoting increased energy expenditure and decreased fat mass [1, 23]. It is also known to affect ketogenesis in the liver by inhibiting peroxisome proliferator-activated receptor-alpha (PPAR-α; reviewed below) [24]. Another member of the IL-6 family, LIF, also induces skeletal muscle wasting and increases lipolysis via receptors on both adipocytes and the hypothalamus [25, 26]. IL-1α induces muscle cachexia and anorexia via increased proteolysis in skeletal muscle, while IL-1β affects the hypothalamic-pituitary-adrenal axis to cause a pro-cachectic shift in muscle gene expression, thereby increasing skeletal muscle proteolysis [27, 28]. IL-8 plays a major role in tumor metastasis, which is thought to be related to the development of muscle cachexia during cancer progression [29] (reviewed below). Other interleukins such as IL-10, IL-11, and IL-12 have been implicated in muscle cachexia development, but it is not yet proven whether they exert similar primary effects [1, 24].

Members of the TGF-β superfamily are also primary targets in the study of muscle cachexia and development of therapeutic agents. Myostatin, a protein that normally functions as an autocrine negative regulator of muscle growth, is known to cause significant loss of fat and muscle when overexpressed in wild-type mice [30]. Increased myostatin levels alter gene expression in skeletal muscle to promote protein degradation and inhibit protein synthesis and myoblast proliferation [31]. Several clinical trials show improved symptoms in cachectic patients when treated with antibodies against myostatin or soluble myostatin receptors (NCT01433263, NCT00755638). Activin-A, another TGF-β superfamily member, is thought to mimic the effects of myostatin on skeletal muscle due to their binding to the same receptors, activin type II receptor A or B (ActRIIA/ActRIIB) [32]. Tumor cells secrete high levels of systemic activin-A, which in turn causes increased muscle atrophy by promoting protein degradation and inhibiting protein synthesis, as does local myostatin [33, 34]. Finally, GDF11 and GDF15 are known to mediate anorexia and subsequently muscle cachexia by acting on the central nervous system to induce weight loss and decreased appetite [35–37].

There also exist several other circulating factors that, while not strictly peptide pro-inflammatory cytokines, still act as mediators of cancer-derived muscle cachexia. For instance, heat shock proteins 70 and 90 (Hsp70/90) are released in extracellular vesicles from tumor cells and travel to muscle cells via the circulatory system, where they induce skeletal muscle catabolism and myotube atrophy through activation of Toll-like receptor 4 (TLR4) and the downstream p38/MAPK pathway [38]. Similarly, a recent study showed that the zinc transporter ZIP4 increases release of extracellular vesicles from pancreatic tumor cells via the RAB27B GTPase, which in turn induces myofibrillar loss and myotube thinning in skeletal muscle [39]. Several microRNAs, including miR-21, miR-203, miR-206, miR-29, and miR-155, have also been implicated in the pathophysiology of muscle cachexia [1]. Most of these are transported from tumors to skeletal muscle in extracellular vesicles, where they potentiate the catabolic and proteolytic effects [1]. miR-21 and miR-29 in particular potentiate skeletal muscle wasting by stimulation of Toll-like receptor 7 (TLR7), which in turn causes activation of apoptosis in myoblasts [40, 41]. TLRs themselves are highly expressed in cachectic muscle, possibly in response to factors secreted by tumor cells [42]. Tumor-derived prostaglandins, especially prostaglandin E₂, also mediate increased skeletal muscle catabolism and tumor-induced hypercalcemia [43]. Finally, some circulating factors cause cachectic symptoms by acting on adipocytes instead of skeletal muscle. For instance, parathyroid hormone-related protein (PTHrP) causes white adipose tissue (WAT) browning by binding to the PTH/PTHrP receptor (PTHR) on white adipocytes, which is thought to contribute indirectly to skeletal muscle wasting [44, 45]. The presence of circulating tumor-derived PTHrP is associated with increased muscle wasting in patients with metastatic cancer [44], but the link between WAT browning and muscle cachexia has yet to be fully explored. Together, these circulating factors mediate the complex signaling processes in skeletal muscle, adipose tissue, and other organs that cause the symptoms of cancer-derived muscle cachexia.

Liver, Energy Wasting, and Acute-Phase Protein Response

Muscle cachexia can be thought of, at root, as an energy wasting disorder where the amount of energy consumed (catabolism) is increased, while the amount of energy intake from the diet is simultaneously decreased. The balance of energy consumed versus energy taken in is shifted in a manner dependent on the type and stage of tumor, which could conceivably explain the difference in muscle cachexia prevalence rates across different tumor types [31]. Merely replacing the loss of energy intake with the parenteral nutrition is often ineffective at reversing the symptoms of cancer-derived muscle cachexia, therefore leading to the general notion that the increased catabolic component of the energy wasting syndrome is primarily responsible for onset of symptoms [46].

Cancer often causes changes in the resting energy expenditure (REE) of the body. The REE is responsible for about 70% of the total energy expenditure in sedentary individuals, and it can be elevated (as in pancreatic and lung cancers) or unchanged (as in gastric and colorectal cancer) [12]. These changes in REE may be a result of futile cycling and increased thermogenesis in the liver, brown adipose tissue (BAT), and skeletal muscle. Tumors generate energy primarily through anaerobic respiration, causing increased glucose uptake and lactate release in a process known as the Warburg effect [47]. This excess lactate is shunted to the liver, where it is converted back into glucose via gluconeogenesis and released into the circulation to be used by extrahepatic tissues in a process similar to the Cori cycle that creates the same effect for skeletal muscle. This tumor-derived futile cycling of glucose and lactate combined with the increased metabolic needs of the tumor itself significantly increase the REE of cancer patients and is thought to contribute to muscle cachexia [48]. Additionally, cancer patients tend to develop insulin resistance and other metabolic hormonal abnormalities, such as increased plasma levels of glucagon and glucocorticoids, further contributing to decreased energy supply to peripheral tissues [49].

The release of free amino acids during skeletal muscle breakdown can also contribute to the overall energy-wasting syndrome. These molecules can either be inefficiently converted to energy through oxidative phosphorylation in peripheral tissues or converted to glucose via gluconeogenesis in the liver for later transport to peripheral tissues [50, 51]. This process only continues to feed the cancer cells, as their preferred diet is high levels of glucose and free amino acids like glutamate [49]. Finally, muscle cachexia is associated with reduced ketogenesis in the liver, causing increased release of glucocorticoids, which are known to promote muscle atrophy [52, 53]. Since ketogenesis is usually upregulated during starvation, it is thought that suppression of ketogenesis is due to the release of IL-6 by the tumor and subsequent inhibition of PPAR-α, the master regulator of ketogenesis in the liver [52, 54].

The presence of an acute phase response (APR) also elevates REE, further contributing to muscle cachexia [55]. The APR is a hepatic response to inflammation where IL-6 and other pro-inflammatory cytokines stimulate synthesis of C-reactive protein (CRP), complement B and C3, and other proteins needed for immediate defense while inhibiting synthesis of proteins non-essential for defense such as transferrin and albumin [56]. CRP levels constitute the standard measurement of APR, and both weight loss and median survival time in cancer have been shown to positively correlate with increased serum CRP levels [57]. It is thought that the APR induces excessive catabolism in skeletal muscle to break down proteins into amino acids to be transported to the liver and synthesized into acute-phase proteins [58]. Thus, as cancer cells begin to invade and steal the body’s metabolic sources of energy, attempts by the body to maintain homeostasis result in further breakdown of skeletal muscle and adipose tissue that eventually leading to greater organ dysfunction.

White Adipose Tissue Browning

The metabolic dysregulation of muscle cachexia is also associated with loss of white adipose tissue (WAT), the primary site of triacylglycerol storage in mammals (Figure 2). This is due to increased lipid mobilization via activation of hormone-sensitive lipase (HSL), reduced uptake of triacylglycerols into adipose tissue due to deactivation of lipoprotein lipase (LPL), and decreased de novo synthesis of lipids in adipose tissue during tumor-bearing states [59]. These effects are mediated by IL-6, zinc-α2-glycoprotein (ZAG), insulin resistance, increased glucocorticoid levels, and other cytokinetic and hormonal changes [60–62]. Additionally, a process called WAT browning converts WAT into beige adipose tissue, a newly discovered type of adipose tissue similar to BAT because of its expression of uncoupling protein 1 (UCP1) [63]. This protein allows protons to flow back across the inner mitochondrial membrane, uncoupling the electron transport chain from ATP synthesis and releasing the potential energy of the proton gradient in the form of heat instead of chemical energy [63]. WAT browning is therefore supposed to contribute to weight loss by further wasting energy, and it has been linked to progression of cancer-derived muscle cachexia in several mouse models [64]. However, this process has yet to be fully validated in human patients [65]. Finally, it is hypothesized that crosstalk between adipose tissue and skeletal muscle contributes to cancer-derived muscle cachexia, but this question has yet to be experimentally explored [66].

Figure 2:

Schematic diagram showing major physio-pathological processes involved in cancer-associated cachexia. Cancer cell-derived circulating factors act on brain, muscle and adipose tissues to trigger changes that together culminate in extreme weight loss.

Central Signaling

While most studies have focused on the dysregulated energy output pathways involved in muscle cachexia, altered central signaling can have profound effects on metabolism and appetite, and therefore affects the balance between energy intake and output (Figure 2). The inflammatory response to tumor burden activates anorexigenic (satiety) pathways and inhibits orexigenic (hunger) pathways in the hypothalamus, thereby lowering neuropeptide Y (NPY) levels and decreasing food intake [67]. Alterations in smell and taste, side effects of anticancer therapy, decreased motor activity, and psychological effects of disease and treatment can also significantly contribute to anorexia in cancer patients [68–70]. GDF15 is known to cause anorexia and subsequent weight loss by binding to its receptor GDNF family receptor α-like (GFRAL) in the brain [37]. Increased GDF15 levels are associated with poor prognosis and weight loss in cancer patients [71]. The hypothalamus also affects metabolic processes in response to IL-1β signaling, which activates the hypothalamic-pituitary-adrenal axis and releases glucocorticoids, which stimulate pro-catabolic and anti-anabolic processes in skeletal muscle [72]. It is also thought that activation of the central melanocortin system may induce muscle wasting, though this has yet to be fully explored [73].

Tumor and Metastasis

The process of tumor maturation and metastasis involve several circulating factors and signaling pathways already known to promote muscle cachexia. For instance, cancer cells secrete the pro-cachectic cytokines IL-6 and IL-8 during the epithelial-to-mesenchymal transition (EMT), a process crucial for developing metastatic capability [74]. Inhibition of Twist1, a protein intimately involved in EMT in pancreatic cancer cells, protected against development of cachectic symptoms in a mouse model [75]. Similarly, pre-metastatic niche (PMN) conditioning prepares distant tissues for colonization by cancer cells in a process involving the release of TNF-α, IL-6, and TGF-β, all pro-inflammatory cytokines implicated in muscle cachexia development [76, 77]. PMN conditioning also induces a systemic inflammatory response similar to the pro-cachectic APR [29]. Finally, signals from metastatic niches often cause increased levels of several pro-cachectic proteins, including PTHrP, TGF-β, GDF-15, and activin-A [78–80]. Although experimental evidence linking muscle cachexia directly to metastatic progression remains minimal, this data suggests a connection between cancer-derived muscle cachexia and metastasis.

Chemotherapy

The presence of muscle cachexia is well known to decrease survival and quality of life of cancer patients [81]. This is mainly due to its reduction of therapeutic efficacy of common chemotherapeutic agents, as well as decreased patient tolerance to side effects [81]. However, it has become clear that chemotherapy itself can be a cause of muscle cachexia, thereby contributing to a destructive positive feedback loop. Most chemotherapeutic agents cause severe anorexia, nausea, and vomiting, which clearly contribute to a cachectic state by reducing nutrient intake and causing negative energy balance [82]. Additionally, recent studies in murine models of cancer have shown that several chemotherapeutic drugs, including 5-fluorouracil, anti-tubulin taxanes, cisplatin, irinotecan, and leucovorin can cause metabolic dysregulation that further contributes to the cachectic state [7, 83, 84]. Another study showed that bleomycin directly causes increased levels of IL-6 and IL-33 in healthy mice, leading to increased atrogin-1 expression and attendant muscle protein degradation, suggesting that chemotherapy might directly cause muscle cachexia via the metabolic and immunologic signaling pathways described earlier [85]. Thus, the catabolic effects of anticancer agents work in tandem with their anorexic effects to promote muscle cachexia and decrease patient survival.

Gut

As the primary site of nutrient intake, the gut plays a previously underrated role in the energy imbalance of cancer-associated muscle cachexia. With more efforts to study the impact of the gut microbiome on human health, a gut microbiota-muscle axis has been postulated that may contribute to cancer-associated muscle cachexia [86]. This may occur through the release of metabolites by gut microbiota that activate TLRs or other receptors in skeletal muscle, or through microbiota-related gut inflammation and dysfunction of the gut barrier leading to decreased nutrient intake and inflammation leading to muscle atrophy [86, 87]. Gut microbiota also affect transcription of several intestinal regulators of energy metabolism, including AMP-activated protein kinase (AMPK) and fasting-induced adipocyte factor (FIAF) [88]. Finally, the gastrointestinal tract is responsible for producing the peptide hormone ghrelin, which increases appetite via hypothalamic orexigenic pathways and inhibits apoptosis and protein degradation in skeletal muscle [89, 90]. Ghrelin also activates WAT and downregulates BAT as well as induces release of pro-anabolic growth hormone and insulin-like growth factor 1 (IGF-1) [91–93]. Cancer patients often experience ghrelin resistance, wherein the hypothalamus exhibits a decreased response to ghrelin [94]. This physiological lack of ghrelin function is thought to contribute to muscle cachexia and has been the target of several successful clinical trials, though concerns remain for the potential of increased tumor growth with these drugs via growth hormone and IGF-1 release [95, 96].

Skeletal Muscle Dysregulation

Muscle Homeostasis

While the metabolic and signaling pathways altered in cancer-associated muscle cachexia are complex, they exert their effects in skeletal muscle by affecting a few specific signaling pathways. This occurs as the previously described circulating factors bind to their cognate receptors on skeletal muscle cells and activate a small number of internal signaling pathways. Thus, the changes in muscle homeostasis- insulin resistance, increased proteolysis, decreased protein synthesis, increased Cori cycling, increased apoptosis, increased inflammatory state, and mitochondrial dysfunction, to name a few- are mediated by a host of circulating factors that converge onto a few internal pathways leading to the final effect of skeletal muscle breakdown.

Energy Wasting and Pro-Apoptotic Pathways

Skeletal muscle contraction requires copious amounts of energy. Skeletal muscle mitochondrial dysfunction is common in cancer-associated muscle cachexia, leading to decreased ATP synthesis and an inability to replace expended energy [97]. This is thought to be a result of the increased expression and activity of uncoupling proteins 2 and 3 (UCP2 and UCP3) known to occur in skeletal muscle of humans and mice with cancer-associated muscle cachexia [98, 99]. UCPs are deemed to cause mitochondrial uncoupling, an energy-wasting process in which the proton gradient across the inner mitochondrial membrane is dissipated in the form of heat energy instead of being used to power ATP synthase for ATP production [100]. TNF-α is a primary inducer of UCP-2 and UCP-3 activity [100, 101]. TNF-α also activates the p38/MAPK pathway, which stabilizes and activates peroxisome proliferator-activated receptor coactivator 1α (PGC1α), a protein normally involved in mitochondrial biogenesis [102]. Overexpression of PGC1α leads to increased mitochondrial respiration and increased expression of genes linked to mitochondrial uncoupling [102]. Increased PGC1α expression also causes muscle atrophy and cancer-associated muscle cachexia in rodent models [103, 104]. Thus, it was postulated that PGC1α may contribute to energy wasting via TNF-α-p38/MAPK signaling. However, another study showed that PGC1α can rescue cachectic tumor-bearing mice from muscle wasting by blocking the activation of FoxO3 and the ubiquitin-proteasome pathway, indicating that further study is needed to determine the precise role of this protein in cancer-associated muscle cachexia [105].

Skeletal muscle cells in muscle cachexia experience calcium deregulation and apoptosis by several mechanisms. PCG1α overexpression in models of cancer-associated muscle cachexia is also known to stimulate expression of mitofusin 2 (Mfn2), a protein that physically ties the sarcoplasmic reticulum to mitochondria in skeletal muscle for control of Ca²⁺ signaling [106]. Increased Mfn2 expression predisposes skeletal muscle cells to Ca²⁺-overloading, leading to Ca²⁺-mediated apoptosis [107]. Thus, PGC1α promotes both energy wasting and apoptosis of skeletal muscle. Increased expression of sarco/endoplasmic reticulum Ca²⁺-ATPase 1 and 2 (SERCA1 and SERCA2) are also seen in cancer-associated muscle cachexia [108]. Skeletal muscle tightly controls Ca²⁺ flow, with increased cytosolic Ca²⁺ causing muscle contraction and increased production of ATP by mitochondria in a process called excitation-contraction coupling [109]. The SERCA Ca²⁺ pumps normally function in transporting Ca²⁺ from the cytosol into the sarcoplasmic reticulum for storage. They consume significant amounts of ATP under normal conditions, and their increased activity in muscle cachexia causes both energy inefficiency through excessive ATP consumption and Ca²⁺-overload as increased cytosolic ADP mediates leakage of Ca²⁺ from sarcoplasmic reticulum to cytosol [108]. Hence, in muscle cachexia increased SERCA activity contributes further to energetic inefficiency and apoptosis in skeletal muscle.

Protein Wasting Pathways

The prominent hallmark of cancer-associated muscle cachexia is skeletal muscle wasting and atrophy due to increased proteolysis (Figure 2). This takes place through activation of several intrinsic pathways of protein breakdown by a variety of circulating factors. Some protein degradation occurs via autophagy and calpain-dependent myofilament cleavage that release myofilaments from intact myofibrils for further degradation by ubiquitin-mediated proteolysis [110, 111]. Studies have shown increased expression of key autophagic genes in cancer patients, including Beclin-1, p62, and the lipidated form of microtubule-associated protein 1A/1B light chain 3B protein (LC3B-II) [112, 113]. Autophagy in cachectic mice is also stimulated by TNF-α and activation of the NF-kB pathway, which has already been implicated in cancer-associated muscle cachexia [114]. However, the actual effect of changes in these mechanisms, while significant, has yet to be fully studied in humans [5].

The best-studied effector of increased proteolysis in cancer-associated muscle cachexia is the ubiquitin-proteasome pathway. This pathway, normally used for degradation of short-lived cytosolic proteins, involves attachment of a short ubiquitin residue to proteins as a marker of degradation, whereupon they are transported to a proteasome for proteolysis [115]. Several muscle-specific E3 ubiquitin ligases are responsible for the ubiquitination reaction; these include muscle RING finger-containing protein 1 (MuRF1) and Atrogin-1 (also known as MAFbx) [116]. These proteins bind to myosin heavy chain (MHC) and other components of the thick strand of the sarcomere to effect myofibrillar proteolysis, and they are also thought to inhibit protein synthesis [116]. As the mediators that mark proteins for degradation, these ligases represent the final major point of regulation in the ubiquitination pathway and are thus controlled at the transcriptional level by a number of different intracellular signaling pathways related to muscle cachexia.

Several pathways in muscle cells involve upregulating inducers of MuRF1 and Atrogin-1. TNF-α, TWEAK, and IL-1 activate the nuclear factor kappa B (NF-kB) pathway, resulting in translocation of activated NF-kB to the nucleus to enhance MuRF1 and Atrogin-1 transcription [116]. NF-kB signaling also causes overexpression of the protein-paired box 7 (PAX7), a transcription factor that inhibits myocyte regeneration and contributes to muscle atrophy by repressing MyoD and myogenin transcriptional activity [117]. TNF-α and IL-1 also increase transcription of MuRF1 and Atrogin-1 via activation of the p38/MAPK pathway, further contributing to proteolysis [116]. In similar fashion, inflammatory signals such as lipopolysaccharide (LPS) from gut microbiota activates the TLR/myeloid differentiation factor 88 (TLR/MyD88) signaling complex on skeletal myocytes, causing muscle atrophy [1]. It was previously thought that this TLR/MyD88 activation led to activation of NF-kB signaling resulting in proteolysis, but new evidence suggests that X-box binding protein 1 (XBP1) signaling may instead be involved [42, 86].

NF-kB signaling is not the only pathway affected by pro-cachectic circulating factors. IL-6 acts by binding to its receptor on skeletal muscle cells and activating the Janus kinase/signal transducer and activation of transcription (JAK/STAT) pathway, leading to activation of STAT3 and its translocation into the nucleus where it increases expression of MuRF1, Atrogin-1, and autophagy-associated genes [118]. TNF-α and IFN-γ also activate STAT3 via the JAK/STAT pathway in a synergistic manner independent from IL-6 signaling [119]. STAT3 further amplifies its signal by activating another regulatory protein of interest, myostatin, through increased expression of CCAAT/enhancer-binding protein delta (C/EBPδ) [118]. Myostatin and activin-A both bind to the ActRIIB receptor in skeletal muscle cells, which recruits the type-I receptor ALK4 and thereby activates the small mother against decapentaplegic 2 and 3 proteins (SMAD2 and SMAD3) [120]. Activated SMAD2 and SMAD3 recruit SMAD4 into a protein complex, and the assembled SMAD2/3/4 complex then translocates to the nucleus to increase transcription of MuRF1, Atrogin-1 and genes that promote protein degradation while inhibiting transcription of genes that promote protein synthesis and proliferation [121].

Recent evidence suggests that the transcription factor Twist1 also plays a significant role in activin-A-mediated upregulation of MuRF1 and Atrogin-1 expression. Twist1 has already been implicated in several roles related to carcinogenesis such as overriding cell senescence and apoptotic mechanisms and inducing the epithelial-to-mesenchymal transition [122, 123]. Interestingly, our recent study revealed that tumor-derived activin-A acts on muscle satellite cells to increase transcription of Twist1, which in turn increases expression and secretion of myostatin to induce its own expression in nearby muscle fibemyostatin to induce its own expression in nearby muscle fibers. Thisrs. This feed-forward loop culminates in increased transcription of MuRF1 and Atrogin-1 and attendant muscle protein breakdown and muscle atrophy [75]. Of particular significance, conditional deletion of the Twist1 gene in satellite cells of tumor-bearing mice significantly decreased cancer-induced muscle wasting and greatly improved overall survival [75]. Thus, Twist1 represents one of several significant mechanisms by which myostatin and activin-A can affect expression of MuRF1 and Atrogin-1.

Myostatin and activin-A also increase MuRF1 and Atrogin-1 expression by binding to ActRIIB and thereby inhibiting the activity of AKT, resulting in dephosphorylation of forkhead box O1, O3, and O4 (FoxO1, FoxO3, and FoxO4) [120]. The dephosphorylated forms of the FoxO proteins can then enter the nucleus and upregulate transcription of proteolytic genes, including MuRF1 and atrogin-1 [124]. This inhibition of AKT and subsequent activation of FoxO proteins is also stimulated by proinflammatory cytokines, although the exact mechanisms remain uncertain [1]. The insulin resistance seen in cancer-associated muscle cachexia also increases proteolysis through this mechanism, as IGF-1 normally functions by activating insulin receptor substrate 1 (IRS1)-PI3K-AKT signaling [125]. Insulin resistance decreases AKT signaling in muscle cells, allowing FoxO-mediated upregulation of proteolysis and downregulating mammalian target of rapamycin (mTOR)-mediated protein synthesis via an AKT-dependent mechanism [126]. Finally, glucocorticoids induce proteolysis and repress protein synthesis by AKT-mediated activation of FoxO proteins and inhibition of mTOR, respectively [72]. The intricate crosstalk between these intracellular signaling pathways combined with the multi-pathway effects of several circulating factors indicate the cooperation of these pathways in promoting and amplifying the proteolytic pro-cachectic signal mediated by MuRF1 and Atrogin-1.

Current Therapeutic Strategies

The advent of definitive diagnostic criteria was a much-needed step in the recognition of the clinical significance of cancer-associated muscle cachexia, but effective treatments for the condition remain sadly lacking. The current standard of care focuses on supplemental nutrition and megestrol acetate, a synthetic progesterone derivative that improves appetite and caloric intake [127]. Although many approaches to therapy have been taken in the last decade, no other pharmacological interventions are yet in use for muscle cachexia due to lack of improvement in muscle mass or strength, intolerable side effects, or both. The therapeutic efficacy of megestrol acetate itself has been questioned, with some researchers arguing that weight gained from megestrol acetate therapy may be due to increased body fat and fluid retention instead of increased body mass [128, 129]. Thus, there is no clear gold standard of care with which to compare new pharmacological interventions for efficacy and tolerability. Nevertheless, the past decade has seen an unprecedented number of attempts to target different individual pathways associated with muscle cachexia, each with a varying degree of success. Some of the more important approaches taken in recent years are summarized in Table 2. Other reviews of the current clinical landscape for cancer-associated muscle cachexia can be found elsewhere [1, 130, 131].

Table 2:

Key clinical trials for cancer cachexia.

Phase	Design	Status	Cancer	Patient	Therapy	Result	Identifier
Phase III	Randomized	Completed	Mixed	63	Etanercept	•No improvement in weight, appetite, or median survival  •Higher rates of neurotoxicity and lower rates of anemia and thrombo cytopenia  •Analyzed using Fisher exact test	NCT00046904
Phase III	Randomized	Completed	NSCLC	67	Infliximab + docetaxel	•No improvement in weight or appetite; generally well tolerated  •Increased fatigue and decreased quality of life  •Analyzed using chi-squared and Wilcoxon rank sum tests	NCT00040885
Phase II	Randomized	Completed	Mixed	31	Thalidomide	•Significant decrease in fat mass but no improvement in lean muscle mass; generally well tolerated  •No significant improve ment in cytokine levels or symptoms compared to control  •Analyzed using Wilcoxon signedrank test, chi-squared test, Mann-Whitney U test	Yennurajalingamet al. (2012)
Phase II	Randomized	Completed	Mixed	70	Pentoxifylline	•Significant improvement in quality of life score at 4 weeks which disappe ared at 8 weeks; generally well tolerated  •No significant difference in weight and arm circumference compared to control  •Analyzed usingindepen dent sample t-test and ANOVA	Mehrzad et al. (2016)
Phase II	Randomized	Completed	NSCLC	124	ALD518	•Significantly reduced loss of lean body mass over 12 weeks; significant improvement in symptom and fatigue scores over 12 weeks; generally well tolerated  •Analyzed using paired t-test	Bayliss et al. (2011)
Phase II	Randomized	Completed	Mixed	21	OHR118	•Weight stabilization or gain in 7 out of 11 patients; improvement in symptoms, appetite, depression, and timed sit-to-stand; generally well tolerated  •Analyzed using paired t-test	NCT01206335
Phase II	Randomized	Completed	Cholangiocarcinoma	50	Selumetinib	•Improved skeletal muscle without increased survival  •Analyzed using t-test and log-rank test	Prado et al. (2012)
Phase II	Randomized	Terminated	Mixed	8	Ruxolitinib	•None; terminated due to insufficient recruitment	NCT02072057
Phase III	Randomized	Completed	Colorectal	333	MABp1	•Significant increase in clinical response as measured by improved lean muscle mass and clinical symptoms (pain, fatigue, and anorexia; generally well tolerated  •Analyzed using log-rank test and univariate Cox model	Hickish et al. (2017)
Phase III	Randomized	Terminated	Colorectal	643	MABp1	•None; crossed prospective futility boundary of the primary endpoint (increased overall survival)	NCT01767857
Phase II	Randomized intention-totreat	Terminated	Pancreatic	125	LY2495655	•No significant improve ment in overall survival; slightly improved response in patients with <5% weight loss at enrollment  •Increased rates of diarrhea, fatigue, and anorexia in treatment group  •Analyzed using Kaplan-Meier and Cox proportional hazard models	Golan et al. (2018)
Phase I	Randomized	Completed	Prostate	77	AMG 745	•Significantly increased lean body mass and decreased fat mass Increased rates of diarrhea, fatigue, contusion, and injection site reactions in treatment group  •Analyzed using ANOVA	Padhi, et al. (2014)
Phase I	Randomized	Completed	Healthy	48	ACE031	•Significant increase in mean total body lean mass and thigh muscle volume at 29 day; Improved adipose and bone biomarkers; generally well tolerated  •Injection site erythema at highest dose  •Analyzed using t-test and ANCOVA	Attie et al. (2013)
Phase II	Randomized	Completed	NSCLC and PDAC	57	Bimagrumab	•Significant increase in lean muscle mass and thigh muscle volume; significant decrease in total body weight  •Increased side effects such as cancer progression, anemia, and dehydration in treatment group	NCT01433263
Phase II	Randomized	Completed	Mixed	51	RC-1291	•None; no results posted	NCT00378131
Phase I	Randomized	Completed	Healthy	29	RC-1291	•Significant weight gain; Generally well tolerated  •Analyzed using ANOVA increased body weight and lean body mas; generally well tolerated  •No improvement in handgrip strength	Garcia and Polvino (2007)
Phase III	Randomized	Completed	NSCLC	484	Anamorelin HCl	•Improved appetite, increased body weight and lean body mass; generally well tolerated  •No improvement in handgrip strength	NCT01387269
Phase III	Randomized	Completed	NSCLC	228	Anamorelin HCl	•Improved appetite, increased body weight and lean body mass; generally well tolerated  •No improvement in handgrip strength	NCT00622193
Phase II	Randomized	Completed	Not specified	44	Megestrol acetate + eicosapentaenoic acid + celecoxib + nutritional supplements	•Significant increase in body weight, lean body mass, and appetite; increased quality of life; generally well tolerated	Madeddu et al. (2009)
Phase II	Randomized	Completed	Mixed	46	Delta-9tetrahydro-cannabinol	•Significant improvement in chemosensory perception, taste, appetite, quality of life, sleep, and total caloric intake; generally well tolerated  •Analyzed using chi-squared test, Fisher’s exact test, and ANOVA	Brisbois et al. (2011)
N/A	Single group assignment	Completed	Mixed	24	Cannabis	•Improved weight, appetite, mood, pain, and fatigue  •High rates of side effects including fatigue, dizziness, disorientation, anxiety, hallucinations, and altered mental status	NCT02359123
Phase II	Randomized	Completed	NSCLC	47	Nabilone	•Significantly increased caloric intake and quality of life at 8 weeks; generally well tolerated  •Analyzed using chi-squared and t-test	Turcott et al. (2018)
Phase II	Randomized	Completed	Head/neck or gastrointestinal	11	Celecoxib	•Significantly increased body mass index and weigh; Increased quality of life; Generally well tolerated  •Analyzed using ANOVA and Wilcoxon sum rank test	Lai et al. (2008)
Phase II	Nonrandomized	Completed	Mixed	24	Celecoxib	•Significant increase in lean body mass; improvement in grip strength and quality of life; generally well tolerated  •Analyzed using ANOVA and Wilcoxon sum rank test	Mantovani et al. (2010)
Phase III	Randomized	Completed	Mixed	60	L-carnitine + celecoxib +/- megestrol acetate	•Both arms showed similarly improved lean body mass and physical performance; very well tolerated  •Analyzed using t-test and chi-squared test	Madeddu et al. (2012)
Phase II	Randomized	Completed	NSCLC	37	VT-122 (propranolol + etodolac)	•Small increase in lean body mass; no improvement in handgrip strength  •Rare serious adverse events such as anemia and thrombocyto penia	NCT00527319
Phase II	Randomized	Completed	NSCLC or colorectal	87	Espindolol	•Significant weight gain and increased lean body mass; hand grip strength, stair climbing power, and 6-minute walk test increased Increased dyspnea in treatment group  •Analyzed using ANOVA, t-test, Fisher’s exact test, and chi-squared test	Stewart Coats et al. (2016)
Phase III	Randomized	Completed	NSCLC	321	GTx-024	•No significant improvement in lean muscle mass or stair climb power  •No significant increase in adverse effects compared to control group	NCT01355484
Phase II	Randomized	Completed	Not specified	159	GTx-024	•No significant improvement in lean muscle mass or stair climb power  •No significant increase in adverse effects compared to control group	NCT00467844
Phase II	Randomized intention-totreat	Completed	Mixed	108	Erythropoeitin +/- indomethacin	•Trend towards improvement in general health; significantly improved total body fat and lean body mass; generally well tolerated  •Analyzed using ANOVA and log-rank tests	Lindholm et al. (2004)
Phase II	Randomized intention-totreat	Completed	Mixed	159	Enobosarm	•Significant increase in lean body mass; generally well tolerated  •-Analyzed using Wilcoxon signed rank test, Wilcoxon rank sum test, paired t-test, and Cox proportional hazard model	Dobs et al. (2013)
Phase I/II	Non-random	Completed	Mixed	13	Formoterol + megestrol acetate	•Significantly increased mean quadriceps volume and appetite; trend towards increased quadriceps and handgrip strength  •Tremor, peripheral edema, tachycardia, and dyspepsia noted in some patients  •Analyzed using t-test	Greig et al. (2014)

Cytokine Inhibitors

As key modulators of cachectic activity in various tissues, the cytokines TNF-α, IL-6, IL-1, and TGF-β have been considered to be important targets for pharmacologic therapy. However, phase III clinical trials of the TNF-α receptor-blocker etanercept and the anti-TNF-α monoclonal antibody infliximab were unsuccessful in improving muscle wasting or appetite, and infliximab therapy was associated with increased fatigue and inferior quality of life [132, 133] (NCT00046904, NCT00040885). Similarly, phase II trials involving inhibitors of TNF-α expression thalidomide and pentoxifylline showed little to no improvement in lean muscle mass [134, 135]. Anti-IL-6 therapies have shown slightly more promise, as the humanized anti-IL-6 monoclonal antibody Clazakizumab was shown to prevent loss of lean muscle mass in phase II clinical trials [136]. The peptide-nucleic acid immunomodulator OHR/AVR118 targets both TNF-α and IL-6, and a phase II study in cachectic cancer patients showed significant improvement in anorexia, strength, and prevention of weight loss with no serious side effects [137] NCT01206335. Inhibitors of JAK/STAT3 signaling Selumetinib and Ruxolitinib have also been shown to promote significant weight gain in cancer patients, but further phase II clinical trials of these drugs have been hampered by low recruitment and their effects have yet to be proven on a large scale in muscle cachexia [138] (NCT02072057). The anti-IL-1α humanized monoclonal antibody Xilonix was shown to be effective in improving lean body mass and symptoms of muscle cachexia in a phase III trial of advanced colorectal cancer patients, but a second phase III trial was terminated for crossing the prospective futility boundary of the primary endpoint, increased overall survival [139] (NCT01767857). Preclinical experiments investigating TGF-β blockade and IL-15 administration as potential therapies for cancer-associated muscle cachexia have also shown promising results [140, 141].

Myostatin/Activin-A and Twist1 Inhibitors

The rise of myostatin and activin-A as autocrine, paracrine, and endocrine mediators of skeletal muscle growth has led to several clinical trials that block them or their downstream mediators. LY2495655, a humanized monoclonal antibody to myostatin, has shown promise in several phase I and II clinical trials by significantly increasing thigh muscle volume in cachectic cancer patients with no major side effects [142]. The phase II trial showed that LY2495655 was more effective in pre-cachectic patients (<5% weight loss) than in cachectic patients (5% weight loss or more), suggesting that this drug may be more useful in preventing cachectic weight loss than in restoring lean muscle mass [142]. AMG745, an anti-myostatin peptibody, also showed improved lean body mass in a phase I study of prostate cancer patients receiving androgen deprivation therapy; however, a phase II study of this drug was withdrawn by Amgen [143]. Administration of ACE031, a soluble ActRIIB receptor, showed a significant increase in total lean body mass and thigh muscle volume and was generally well tolerated in a phase I study of healthy post-menopausal women; however, this drug has yet to be tested in trials of cancer-associated muscle cachexia [144]. The ActRII receptor antibody bimagrumab was also shown to strongly increase skeletal muscle mass in mice and protect muscles from glucocorticoid-induced atrophy [145]. A randomized controlled phase II trial of bimagrumab in cachectic non-small-cell lung cancer and pancreatic cancer patients resulted in significantly increased lean muscle mass but paradoxical loss in total body weight (NCT01433263).

Finally, our preclinical study using the Twist1 competitive inhibitor JQ1 demonstrated that pharmacological inhibition of Twist1 significantly protected mice against cancer-associated muscle cachexia and greatly increased overall survival in a mouse model of pancreatic ductal adenocarcinoma [75]. Because inhibition of Twist1 improved both cachectic symptoms and overall survival, Twist1 represents an exciting new potential target for pharmacological inhibition of the myostatin-activin-A axis.

Appetite Modulators

Many studies have also been conducted on the use of various appetite-modulating drugs in cancer-associated muscle cachexia. Ghrelin has been a target of several recent clinical trials due to its far-reaching effects on appetite and metabolism. Anamorelin HCl, a ghrelin analogue with extended half-life, has been extensively tested in a series of phase I, II, and III clinical trials, where it was shown to be largely well-tolerated and effective in producing significant improvement in weight gain, lean muscle mass, and anorexic/cachectic symptoms in cachectic cancer patients [146–149] (NCT01395914, NCT01387282, NCT01387269 NCT00378131, NCT00622193). However, it failed to provide significant improvement in handgrip strength during phase III trials [148, 149] (NCT00622193). Another appetite-modulating approach is medroxyprogesterone acetate, a progesterone derivative similar to megestrol acetate that has been shown to improve anorexia, body weight, and quality of life in phase II clinical trials [128]. Endocannabinoids such as delta-9-tetrahydrocannabinol (THC) and nabilone have also been tested as appetite stimulants in phase II clinical trials, and results have generally shown increased appetite and quality of life with no major side effects [150–152] (NCT02359123).

NSAIDs, Beta-Blockers, and Other Approaches

Other attempts at treating cancer-associated muscle cachexia include celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, which has been shown in phase II clinical trials to improve quality of life, handgrip strength, lean body mass, and BMI in cachectic cancer patients with no major side effects [153, 154]. The combination of celecoxib with L-carnitine has also proven effective in phase III clinical trials in improving lean body mass and physical performance with no toxic side effects [155]. The drug VT-122, a combination of the nonselective beta-blocker propranolol with the COX-2 inhibitor etodolac, improved lean body mass but not handgrip strength in a phase II trial of cachectic lung cancer patients (NCT00527319). Another nonselective beta-blocker, espindolol, was shown to reverse weight loss, increase handgrip strength, improve fat-free mass, and maintain fat mass in a phase II trial of cachectic cancer patients [156]. Erythropoietin has been shown to provide some nutritional and functional benefit as well, and a mouse model shows improvement in muscle wasting using this drug in combination with exercise therapy [157, 158]. The non-steroidal selective androgen receptor modulator (SARM) Enobosarm (also known as GTx-024) produced significant improvement in lean body mass, quality of life, and physical function in a phase IIb trial, but two phase III clinical trials showed no improvement in lean muscle mass [159] (NCT00467844, NCT01355484). A phase I/II trial of formoterol, a beta-2 agonist, and megestrol acetate in cachectic cancer patients showed increased appetite and mean quadriceps volume in the seven patients who completed the trial [160]. Nutritional approaches such as nutrition counseling and administration of dietary supplements such as eicosapentaenoic acid, an omega3-polyunsaturated fatty acid, have produced mixed results [131]. Finally, physical exercise has been shown to increase muscle mass and strength while lowering serum levels of inflammatory pro-cachectic circulating factors and improving response to anticancer therapy; however, more randomized controlled trials are needed to prove its efficacy in cancer patients with advanced disease [161, 162].

Concluding Remarks and Future Directions

Muscle cachexia severely affects all types of cancer patients and is a major cause of mortality, yet it lacks effective therapies despite years of research and a variety of therapeutic approaches. As new research continues to elaborate upon the multisystem complexity of cancer-associated muscle cachexia, it is clear that new approaches to therapy that address this complexity are warranted. Several key points stand out when considering the current state of affairs in the clinical management of cancer-associated muscle cachexia. First, researchers continually face issues with small sample sizes, heterogeneity of clinical sampling, and patient dropout rates in clinical trials. Only a few trials have been able to recruit enough patients over a wide enough distribution to truly evaluate a drug’s therapeutic potential, and development of several promising therapies have been stalled or delayed due to lack of patient recruitment or high dropout rates. This ties in closely with another problem: the lack of clinically relevant staging criteria and biomarkers. Discovery and characterization of biomarkers that correlate with disease severity and the development of scoring systems that accurately stage disease would help to clarify the efficacy of new therapies in subpopulations of cachectic cancer patients and better define the recruitment criteria for clinical trials in a more standardized fashion. In addition, a translational gap remains between preclinical studies of muscle cachexia and safe, effective treatments in humans. This may be due in part to the multisystem complexity of the disease and the added variables of comorbidities, advanced age, and psychosocial effects of cancer that are difficult to reproduce in animal models. It has also been argued that the few cell lines commonly used to study cancer-associated muscle cachexia may have evolved into subclones that no longer produce consistent results between laboratories, and thus researchers ought to make more use of newer genetically engineered models that are more aligned with the clinical subsets of muscle cachexia in different cancers [5].

Most importantly, consensus is growing that targeting one molecule or pathway is not enough to treat the multifactorial, multisystem process that is cancer-associated muscle cachexia. Almost every therapeutic approach to date has attempted to modify a single symptom or signaling pathway known to contribute to cancer-associated muscle cachexia with only minimal success. A commonly suggested solution to this problem is the development of multimodal treatment programs that combine pharmacologic, nutritional, and exercise interventions to combat muscle cachexia on several fronts simultaneously [131]. This approach may be rendered even more effective by developing pharmacological agents that can simultaneously target multiple signaling pathways involved in muscle cachexia, thereby maximizing effect while minimizing the number of drugs to be administered. Many of the drugs currently being used in clinical trials are monoclonal antibodies, due to their incredible design plasticity and their safety and efficacy in patient use. Recent studies have announced the development of bispecific antibodies that can bind to two separate targets, such as CD3 on T cells and CD20 on cancer cells [163]. These new drugs represent an exciting new approach to cancer therapy and have launched a new wave of clinical trials [164]. This technology could easily be adapted to create monoclonal antibodies that target multiple pathways associated with muscle cachexia by binding both the IL-6 receptor and the ActRIIB receptor, for instance. The signaling pathways that promote cancer-associated muscle cachexia are known to be highly intertwined, which might account for some of the difficulty in effecting major improvements in lean muscle mass and strength by designing therapies that target single pathways. If the future of muscle cachexia treatment is exploring multimodal therapy, then it is only logical to make the pharmacologic arm of that treatment plan more effective by targeting multiple pathways with a single drug.

Outstanding Questions.

What are the molecular and physiopathological mechanisms underlying the difference between different types of cancer in their ability to induce muscle cachexia?

What are the genetic and epigenetic events in tumors that trigger secretion of inflammatory cytokines leading to muscle cachexia?

Is browning of fat required for muscle loss and vise-versa?

How muscle cachexia contributes to chemotherapy resistance?

Why nutrition supplement is ineffective at reversing muscle cachexia in cancer patients?

Could multi-specific immunotherapeutic tools targeting different signaling pathways simultaneously be used to curb muscle cachexia in cancer patients?

Highlights.

Cancer-associated muscle cachexia is a severe muscle-wasting syndrome that occurs in the majority of cancer patients and strongly predicts negative outcomes.

The deterioration in muscle function and homeostasis are mediated by a host of tumor-derived circulating factors that converge onto common signaling pathways leading to the final effect of muscle breakdown.

The flurry of experiments conducted in the last decades has largely failed to achieve therapeutic breakthroughs for muscle cachexia. To attain the goal of an effective new treatment, it is becoming now imperative to fully understand not only the factors at play in the development of muscle cachexia and the complex relationships between them, but also why past and current therapeutic endeavors failed to curb this deadly syndrome.

Glossary

Ketogenesis

a series of biochemical reactions that produce ketone bodies (e.g., acetoacetate, acetone, β-hydroxy-butyrate) through breakdown of amino acids and fatty acids. The main function of ketogenesis is to supply energy to skeletal muscle during fasting or caloric restriction. Excessive ketogenesis can culminate in muscle atrophy and eventually death

Warburg effect

a process of anaerobic glycolysis used by cancer cells to generate new metabolites that support the high demand in energy required for sustained cell proliferation. Normal cells generate energy through aerobic glycolysis and oxidative phosphorylation

Cori cycle

a feed-forward metabolic loop in which muscle cells produce lactate through anaerobic glycolysis and release it into the circulatory system, where it is transported to the liver to be converted into glucose, which is then released and transported back into muscle, where it is metabolized back to lactate

Acute phase response

an inflammatory-mediated process in the liver that affects the circulating levels of acute-phase phase proteins, which support the innate immune system to protect against infection and other inflammatory conditions