Cancer cachexia is a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass, which negatively affects quality of life and portends a poor prognosis. Numerous molecular substrates and mechanisms underlie the dysregulation of skeletal muscle synthesis and degradation observed in cancer cachexia, including proinflammatory cytokines (TNFα, IL1, and IL6), and the NF-κB, IGF1/AKT/mTOR, and myostatin/activin–SMAD pathways. Recent preclinical and clinical studies have demonstrated that anti-cachexia drugs (such as MABp1 and soluble receptor antagonist of myostatin/activin) not only prevent muscle wasting but also may prolong overall survival. In this review, we focus on the significance of cachexia signaling in patients with cancer and highlight promising drugs targeting tumor cachexia in clinical development. Clin Cancer Res; 22(16); 3999–4004. ©2016 AACR.

Cancer cachexia is a complex metabolic syndrome characterized by an irreversible loss of skeletal muscle mass, which leads to progressive functional impairment (1). Cachexia is a significant cause of morbidity and mortality, affecting 60% to 80% of patients with cancer, and is particularly common in individuals with pancreatic cancer (2, 3). In addition to functional impairment, cachexia is associated with increased fatigue and emotional distress, all of which considerably compromise quality of life. Moreover, patients with cancer with cachexia are less likely to respond to chemotherapy and radiation and are more likely to endure treatment toxicities (4). Importantly, cachexia may be a direct result of malignancy as well as the chemotherapeutics (e.g., bevacizumab or sorafenib) used to treat it. Sarcopenia, a related but distinct condition, also results in loss of muscle mass but is attributable to aging and inactivity, rather than anorexia, a feature of cachexia marked by decreased energy expenditure and reduced fat accumulation (5). The definition of cachexia has evolved in recent years (1), and much remains to be understood regarding the interplay between cachexia, anorexia, and sarcopenia and how these entities affect cancer development, treatment resistance, and patient outcomes.

Studies evaluating the metabolic alterations inducing cancer cachexia have revealed several tumor-derived cytokines and pathways implicated in skeletal muscle degradation (6) and have led to the development of promising therapies for the prevention of muscle wasting (7). However, advances in this field have been impeded by a lack of consensus regarding the clinical assessment of cancer cachexia as well as the heterogeneity of disease presentation (8). A better understanding of the molecular mechanisms underlying tumor cachexia has the potential to identify novel therapeutic targets and inform the development of successful interventions. In this review, we critically summarize cachexia signaling in patients with cancer and highlight recent preclinical and clinical advances in the management of this paraneoplastic syndrome.

Cachexia pathways in muscle tissue

Cancer cachexia ultimately results from an imbalance in the regulation of muscle protein synthesis and degradation. Such muscle wasting is orchestrated by extracellular ligands which activate several intersecting intracellular signaling pathways (Fig. 1). In particular, proinflammatory cytokines derived from immune or tumor cells, including TNFα, IL1, and IL6, have been shown to trigger muscle wasting through activation of NF-κB and JAK/STAT pathways, respectively. Accumulating evidence also suggests that the IGF1 pathway induces skeletal myogenesis, while myostatin and activin serve as negative regulators of IGF1 signaling to inhibit muscle growth and promote degradation. Other major skeletal muscle proteolytic pathways include the ubiquitin/proteasome system (UPS), as well as the autophagy/lysosomal, calpain, and the caspase pathways (9–11). The UPS has received the most attention, through which the ubiquitin E3 ligases, muscle ring finger protein 1 (MuRF-1), and atrophy gene 1/muscle atrophy F-box (Atrogin-1/MAFbx), act as the two main regulators of muscle protein breakdown.

Figure 1.

Cachexia signaling regulating protein synthesis and degradation in muscle and anti-cachexia drugs in development. IGF1/Akt/mTOR signaling: Binding of IGF1 to IGF1R results in phosphorylation of the insulin receptor substrate (IRS). IRS activates PI3K/Akt signaling, which then stimulates protein synthesis by activating mTOR. mTOR activates the ribosomal S6K and eukaryotic initiation factor 4E-BP-1, leading to protein synthesis. Akt also phosphorylates and inhibits FoxOs, which is a negative regulator of myogenesis. Myostatin/activin signaling: Myostatin/activin binds to type II receptor (ActRIIB) and induces its dimerization with the activin type I receptor. Subsequent phosphorylation of Smad2/3 recruits Smad4. The Smad complex is translocated into the nucleus to induce transcriptional changes, which result in muscle wasting. Simultaneously, myostatin/activin reduces Akt activity and suppresses FoxOs phosphorylation. Dephosphorylated FoxOs are translocated into the nucleus and induce the transcription of target genes, which regulate the ubiquitin/proteasome and autophagy/lysosome systems. IL6 signaling: The binding of IL6 to its receptors induces homodimerization of gp130 and its complex, which activate JAK/STAT3 signaling. Phosphorylated STAT3 forms a dimer and translocates into the nucleus, leading to increased protein degradation. TNFα and IL1 signaling: Binding of TNFα or IL1 to its receptor activates the IKK complex, which phosphorylates IκBa proteins. This signal-induced phosphorylation targets IκBa for polyubiquitination and subsequent degradation by the proteasome, thereby allowing the RelB/p52 complex to translocate to the nucleus to transcribe respective target genes.

Figure 1.

Cachexia signaling regulating protein synthesis and degradation in muscle and anti-cachexia drugs in development. IGF1/Akt/mTOR signaling: Binding of IGF1 to IGF1R results in phosphorylation of the insulin receptor substrate (IRS). IRS activates PI3K/Akt signaling, which then stimulates protein synthesis by activating mTOR. mTOR activates the ribosomal S6K and eukaryotic initiation factor 4E-BP-1, leading to protein synthesis. Akt also phosphorylates and inhibits FoxOs, which is a negative regulator of myogenesis. Myostatin/activin signaling: Myostatin/activin binds to type II receptor (ActRIIB) and induces its dimerization with the activin type I receptor. Subsequent phosphorylation of Smad2/3 recruits Smad4. The Smad complex is translocated into the nucleus to induce transcriptional changes, which result in muscle wasting. Simultaneously, myostatin/activin reduces Akt activity and suppresses FoxOs phosphorylation. Dephosphorylated FoxOs are translocated into the nucleus and induce the transcription of target genes, which regulate the ubiquitin/proteasome and autophagy/lysosome systems. IL6 signaling: The binding of IL6 to its receptors induces homodimerization of gp130 and its complex, which activate JAK/STAT3 signaling. Phosphorylated STAT3 forms a dimer and translocates into the nucleus, leading to increased protein degradation. TNFα and IL1 signaling: Binding of TNFα or IL1 to its receptor activates the IKK complex, which phosphorylates IκBa proteins. This signal-induced phosphorylation targets IκBa for polyubiquitination and subsequent degradation by the proteasome, thereby allowing the RelB/p52 complex to translocate to the nucleus to transcribe respective target genes.

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Cytokines activate protein degradation in cancer cachexia

Multiple cytokines, including TNFα, IL1, and IL6, have been implicated in facilitating a cachectic state (12), and their expression or upregulation is prompted by both tumor- and host-derived factors. High serum levels of these cytokines are present in many patients with cancer with cachexia.

TNFα has long been recognized as a mediator of cancer cachexia. Its administration leads to increased protein degradation in cultured muscle cells (13) and in rat muscle (14). In murine models, TNFα and recombinant IL1 act synergistically to reduce muscle protein content (15). Mechanistically, these cytokines increase NF-κB–mediated transcription and subsequent ubiquitin conjugation activity (16), thereby inducing skeletal muscle protein loss. The NF-κB protein family is composed of five transcription factors [p65 (Rel A), Rel B, c-Rel, p52, and p50], which are expressed in skeletal muscle and mediate a variety of processes depending on the cell type and upstream trigger (17). Activation of NF-κB is achieved by nuclear transport of NF-κB heterodimers, acting in concert with the ubiquitination and degradation of the NF-κB inhibitory protein, IκB. TNFα, and IL1 activate the IKK complex, which then phosphorylates IκBa proteins, marking them for polyubiquitination and proteasomal degradation, thereby releasing NF-κB. Activated NF-κB then activates MuRF1 and Atrogin-1 (18), both of which are ligases that promote protein degradation.

IL6, secreted mainly from tumor and immune cells, induces activation of inflammatory and degradation pathways, resulting in suppression of protein synthesis in muscle cells. IL6 bound to its receptor, IL6R, recruits the associated cell surface glycoprotein and signal transducer, gp130, to induce downstream JAK/STAT signaling. Prolonged activation of the IL6/JAK/STAT axis is an established mechanism of tumorigenesis as well as the muscle wasting observed in cancer cachexia (12). In ApcMin, Lewis lung carcinoma (LLC) and Colon-26 tumor-implanted mice, IL6 and STAT3 activation have been shown to be integral to loss of skeletal muscle. Furthermore, STAT3 was sufficient to induce remarkable muscle fiber atrophy, even in non–tumor-bearing mice (12, 19).

Myostatin and activin signals have a distinct role in the negative regulation of myogenesis

Myostatin and activin are TGFβ superfamily ligands involved in skeletal muscle degradation. Myostatin is predominantly secreted from muscle cells and acts as a key negative regulator of muscle growth; its genetic deficiency results in dramatic muscle hypertrophy (20, 21). Activin A is a homodimer formed from two inhibin betaA chains (22) and is involved in many physiologic functions, including embryogenesis, cell growth, differentiation, and the immune response (23). Myostatin and activin act via heteromeric complexes of two related transmembrane type I and type II serine/threonine kinase receptors to activate downstream signal transduction. Myostatin or activin A binds to its respective type II activin receptor (activin: ACVR2B or ACVR2A; myostatin: ACVR2B) on the muscle cell membrane, leading to its dimerization and subsequent recruitment and activation of type I receptors (activin: ALK4 or 7; myostatin: ALK5 or 7). The activated type I receptor then phosphorylates SMAD2 and SMAD3, which together with the common mediator, SMAD4, translocate to the nucleus. This SMAD complex then regulates transcriptional responses leading to muscle wasting (24).

IGF1/AKT/mTOR pathway has anabolic effects on muscle by inhibiting protein degradation and promoting myogenesis

IGF1 signaling is a major anabolic pathway involved in muscle development and regeneration (25). Several studies have shown that IGF1/Akt signaling suppresses protein breakdown and promotes muscle growth (26, 27). Binding of IGF1 to its receptor triggers the activation of PI3K/Akt signal transduction, inducing protein synthesis by blocking the repression of mTOR. Activated mTOR phosphorylates its two major targets, S6K1 and 4E-BP1, which play a key role in myogenesis. Akt further phosphorylates and inactivates forkhead box O proteins (FoxOs: FoxO1, FoxO3 and FoxO4) by promoting their export from the nucleus to the cytoplasm (28). FoxOs are transcriptional regulators of autophagy, which promote protein ubiquitination and degradation in muscle cells. Myostatin and activin suppress Akt activity, leading to disinhibition of FoxO3 (29, 30) and subsequent upregulation of MuRF-1, Atrogin-1 (or MAFbx), and autophagy genes to induce muscle protein degradation.

Nutritional support alone, or in conjunction with anabolic drugs such as enobosarm (an oral, nonsteroidal, selective androgen receptor modulator) or anamorelin (an orally active ghrelin receptor antagonist), has failed to deliver clinical benefit in patients with cancer with cachexia (31). Directly targeting the cachexia pathway may indeed prove to be a more successful endeavor. To this end, recent preclinical and clinical studies have offered a number of drugs with promising activity against cancer-induced muscle wasting (Table 1).

Table 1.

Summary of clinical trials evaluating treatments for cancer cachexia

InhibitorDrugTypeDiseaseModelOutcomeReference
TNFα Etanercept TNFα ligand bound to Fc-IgG11 Cancer Phase III RCT (placebo) No inhibition of muscle wasting NCT00046904 (34) 
 Etanercept TNFα ligand bound to Fc-IgG11 Cancer Phase II/III RCT (placebo) Ongoing NCT00127387 
 Infliximab TNFα-specific mAb NSCLC Phase II/III RCT (placebo) + docetaxel Trial stopped early because of decreased quality of life in infliximab-treated group NCT00040885 (35) 
 Infliximab TNFα-specific mAb Pancreatic cancer Phase II RCT (placebo) + gemcitabine No statistically significant differences in LBM NCT00060502 (36) 
IL6 Clazakizumab (ALD-518) IL6-specific mAb Cancer Phase I Well tolerated (40) 
 Clazakizumab (ALD-518) IL6-specific mAb NSCLC Phase II RCT (placebo) Less loss of LBM Increased hemoglobin NCT00866970 (41, 42) 
IL1α MABp1 IL1α-specific mAb Cancer Phase I Serum IL6 level decreasedDisease control was observed NCT01021072 (38) 
 MABp1 IL1α-specific mAb Colorectal cancer Phase III RCT (placebo) A trend in decreased risk of deathPhysical functions did not decline NCT01767857 (39) 
 MABp1 IL1α-specific mAb Colorectal cancer Phase III RCT (placebo) Ongoing NCT02138422 
ActRIIB Bimagrumab (BYM338) ActRIIB-specific mAb Cancer Phase II RCT (placebo) Ongoing NCT01433263 
Myostatin LY2495655 Myostatin-specific mAb Cancer Phase I Well toleratedIncreased hand grip strength and improved functional tests NCT01524224 (49) 
 LY2495655 Myostatin-specific mAb Pancreatic cancer Phase II Ongoing NCT01505530 
InhibitorDrugTypeDiseaseModelOutcomeReference
TNFα Etanercept TNFα ligand bound to Fc-IgG11 Cancer Phase III RCT (placebo) No inhibition of muscle wasting NCT00046904 (34) 
 Etanercept TNFα ligand bound to Fc-IgG11 Cancer Phase II/III RCT (placebo) Ongoing NCT00127387 
 Infliximab TNFα-specific mAb NSCLC Phase II/III RCT (placebo) + docetaxel Trial stopped early because of decreased quality of life in infliximab-treated group NCT00040885 (35) 
 Infliximab TNFα-specific mAb Pancreatic cancer Phase II RCT (placebo) + gemcitabine No statistically significant differences in LBM NCT00060502 (36) 
IL6 Clazakizumab (ALD-518) IL6-specific mAb Cancer Phase I Well tolerated (40) 
 Clazakizumab (ALD-518) IL6-specific mAb NSCLC Phase II RCT (placebo) Less loss of LBM Increased hemoglobin NCT00866970 (41, 42) 
IL1α MABp1 IL1α-specific mAb Cancer Phase I Serum IL6 level decreasedDisease control was observed NCT01021072 (38) 
 MABp1 IL1α-specific mAb Colorectal cancer Phase III RCT (placebo) A trend in decreased risk of deathPhysical functions did not decline NCT01767857 (39) 
 MABp1 IL1α-specific mAb Colorectal cancer Phase III RCT (placebo) Ongoing NCT02138422 
ActRIIB Bimagrumab (BYM338) ActRIIB-specific mAb Cancer Phase II RCT (placebo) Ongoing NCT01433263 
Myostatin LY2495655 Myostatin-specific mAb Cancer Phase I Well toleratedIncreased hand grip strength and improved functional tests NCT01524224 (49) 
 LY2495655 Myostatin-specific mAb Pancreatic cancer Phase II Ongoing NCT01505530 

Abbreviations: LBM, lean body mass; RCT, randomized control trial.

TNFα

Administration of TNFα results in increased skeletal muscle proteolysis associated with higher levels of conjugated ubiquitin (32). TNFα is also involved in anorexia associated with tumor growth, as suggested by the use of TNF inhibitors in anorectic tumor-bearing rats. Specifically, the injection of TNF inhibitor in tumor-bearing rats significantly improves food intake and body weight (33). Despite these promising preclinical data, TNFα inhibitors have not demonstrated meaningful clinical benefit. In two phase II studies, which randomized patients with advanced cancer to either etanercept (a recombinant fusion protein of TNFα type II receptor, which blocks TNFα activity) or infliximab (a recombinant anti-TNF-α antibody) versus placebo (34, 35), no significant benefit was shown with respect to reducing muscle wasting, restoring lean body mass, or improving quality of life. Likewise, the addition of infliximab to gemcitabine to treat cachexia in patients with advanced pancreatic cancer did not yield any significant benefit when compared with placebo (36). In fact, a phase II/III randomized, placebo-controlled study combining infliximab with docetaxel in patients with non–small cell lung cancer (NSCLC) was terminated early due to significantly worse quality of life in the experimental group. Recent data suggest that a monoclonal antibody against fibroblast growth factor-inducible 14 (Fn14), which is related to the TNF receptor superfamily and is a receptor for the TWEAK cytokine, may help prevent tumor-induced cachexia and prolong survival in C26 tumor–bearing mice (37). Interestingly, TWEAK blockade using an anti-TWEAK antibody had no effect on Fn14-induced cachexia, suggesting the presence of a second, as yet unidentified ligand for Fn14.

IL1

An IL1a-specific humanized monoclonal antibody, MABp1, has shown promising results in patients with cancer cachexia. A phase I dose-escalation and expansion study was performed to assess the safety and tolerability of MABp1 in patients with refractory cancer (38). MABp1 was well tolerated, with demonstrated efficacy on body composition and quality of life, as well as potential antitumor effects in the response analysis. The most common adverse event in this study was proteinuria (all grade, n = 11; 21%). Subsequently, a phase III randomized study comparing MABp1 monotherapy to megestrol acetate was performed in patients with advanced colorectal cancer with cachexia (39). In this study, MABp1-treated patients had a trend toward improved median overall survival without worsening physical function, compared with patients receiving megestrol acetate. A placebo-controlled, double-blind phase III study in refractory patients with colorectal cancer is ongoing.

IL6

ALD518, a humanized monoclonal antibody that binds with high affinity to human IL6, is being developed for the treatment of anemia, cachexia, and fatigue (12). A phase I study of 9 patients with advanced cancer has reported statistically significant differences in hand grip strength and fatigue after ALD518 administration (40). In a phase II randomized placebo-controlled study in 124 patients with advanced NSCLC, ALD518 resulted in less lean body mass reduction, improved lung symptom scores, and reversed fatigue and anemia (41, 42). ALD518 is well tolerated, with minimal adverse effects and has the potential to improve anemia and fatigue, as well as reduce cancer-related cachexia.

Myostatin/activin pathway

Several studies have suggested that serum levels of activin (43, 44) and myostatin (43) are increased in patients with cancer cachexia. In mouse models, inhibition of myostatin/activin signaling has been shown to increase muscle mass and improve physical performance and muscle function (45, 46). A recombinant decoy ActRIIB antagonist, which inhibits both myostatin and activin-mediated Smad2/3 signal transduction, dramatically prevented muscle wasting and prolonged survival in multiple mouse models without affecting inflammatory cytokine levels (47). A myostatin-specific antibody (PF-354) has also been shown to suppress tumor-induced muscle wasting and loss of muscle function, even in mildly cachexic mice (48). Unfortunately, clinical trials testing the ActRIIB decoy were stopped because of gum and nose bleeding events in healthy adults and boys with Duchenne muscular dystrophy. Another myostatin-specific antibody (LY2495655) and its receptor ActRIIB-specific antibody (bimagrumab or BYM338) showed promising results in clinical trials. A phase I study of LY2495655 in patients with advanced cancer not receiving chemotherapy showed that LY2495655 was well tolerated and provided durable improvement in hand grip strength and functional tests (49). A phase II study of LY2495655 in patients with advanced pancreatic cancer receiving standard chemotherapy is ongoing, with overall survival as the primary endpoint (NCT1505530). Similarly, BYM338 has previously shown an improvement in thigh muscle volume at 8 weeks in patients with inclusion body myositis (50) and is now being tested in a randomized, double-blind, placebo-controlled phase II trial in patients with lung and pancreatic cancer (NCT01433263). Interestingly, this pathway may also play an important role in prevention strategies. For example, in a study of patients with early-stage gastric cancer, myostatin expression was found to be upregulated in muscle tissue before the onset of significant weight loss (51), suggesting that early intervention to prevent cancer cachexia may delay tumor recurrence or progression and improve outcomes.

Little is known regarding how modulation of cachexia signaling influences tumor biology. However, studies suggest that activation of cachexia signaling may contribute to tumor progression. Gallot and colleagues reported on the effect of myostatin signaling on cancer biology using LLC tumor–bearing mice. In this study (52), tumor weight was significantly lower in Mstn−/− mice than in wild-type mice. In addition, gene expression analysis in tumor tissue showed this phenotype to be associated with reduced expression of genes involved in angiogenesis, tumor metabolism, activin signaling, and apoptosis. These results are consistent with studies showing that the soluble type II receptor antagonist of myostatin and activin (sActRIIB) reduced tumor weight and incidence of lung metastases (45, 53). Taken together, myostatin/activin signaling has a critical role not only in muscle cell degradation but also in cancer progression, although it should be noted that these data have not been reproduced in other studies. Interestingly, myostatin/activin signaling has been associated with activation of angiogenesis. For instance, ALK5 overexpression promotes tumor angiogenesis, invasion, and metastatic potential by upregulating matrix metalloproteinase-9 in tumor cells (54). Conversely, an inhibitor of the type I activin like receptor (SB431542) has been shown to decrease VEGF expression and inhibit angiogenesis. These data warrant further investigation and may lead to novel drug combinations with inhibitors of cachexia signaling.

The mechanisms of cancer cachexia are heterogeneous and multifactorial. Targeting the cachexia signaling pathway has shown promising results in preclinical and early clinical trials but primarily to prevent muscle wasting rather than prolong survival. Ongoing phase III clinical trials are testing the clinical efficacy of these novel compounds. Improving the classification, objective assessment, and monitoring of patients with cancer with cachexia remain challenges to the clinical development of agents targeting this pathway. A refined understanding of how cancer cachexia affects oncogenic signaling in different cancer types and host status is critically needed to develop more successful therapeutic interventions. Identifying predictive biomarkers for these compounds, based on the precise mechanism of cachexia affected, will be essential to bringing these compounds into the clinic.

H.-J. Lenz is a consultant/advisory board member for Bayer, Boehringer Ingelheim, Celgene, Merck Serono, and Roche. No potential conflicts of interest were disclosed by the other authors.

Conception and design: Y. Miyamoto, H.-J. Lenz

Development of methodology: H.-J. Lenz

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): H.-J. Lenz

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): W. Zhang, H.-J. Lenz

Writing, review, and/or revision of the manuscript: Y. Miyamoto, D.L. Hanna, W. Zhang, H. Baba, H.-J. Lenz

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): D.L. Hanna, H.-J. Lenz

Study supervision: H.-J. Lenz

H.-J. Lenz was supported by the NIH under award number P30CA014089, Wunder Project, Call to Cure, and Danny Butler Memorial Fund.

1.
Fearon
K
,
Strasser
F
,
Anker
SD
,
Bosaeus
I
,
Bruera
E
,
Fainsinger
RL
, et al
Definition and classification of cancer cachexia: an international consensus
.
Lancet Oncol
2011
;
12
:
489
95
.
2.
Bruera
E
. 
ABC of palliative care. Anorexia, cachexia, and nutrition
.
BMJ
1997
;
315
:
1219
22
.
3.
Wigmore
SJ
,
Plester
CE
,
Richardson
RA
,
Fearon
KC
. 
Changes in nutritional status associated with unresectable pancreatic cancer
.
Br J Cancer
1997
;
75
:
106
9
.
4.
Andreyev
HJ
,
Norman
AR
,
Oates
J
,
Cunningham
D
. 
Why do patients with weight loss have a worse outcome when undergoing chemotherapy for gastrointestinal malignancies?
Eur J Cancer
1998
;
34
:
503
9
.
5.
Biolo
G
,
Cederholm
T
,
Muscaritoli
M
. 
Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: from sarcopenic obesity to cachexia
.
Clin Nutr
2014
;
33
:
737
48
.
6.
Tisdale
MJ
. 
Reversing cachexia
.
Cell
2010
;
142
:
511
2
.
7.
Han
HQ
,
Zhou
X
,
Mitch
WE
,
Goldberg
AL
. 
Myostatin/activin pathway antagonism: molecular basis and therapeutic potential
.
Int J Biochem Cell Biol
2013
;
45
:
2333
47
.
8.
Fearon
KC
,
Glass
DJ
,
Guttridge
DC
. 
Cancer cachexia: mediators, signaling, and metabolic pathways
.
Cell Metab
2012
;
16
:
153
66
.
9.
Glickman
MH
,
Ciechanover
A
. 
The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction
.
Physiol Rev
2002
;
82
:
373
428
.
10.
Zhao
J
,
Brault
JJ
,
Schild
A
,
Cao
P
,
Sandri
M
,
Schiaffino
S
, et al
FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells
.
Cell Metab
2007
;
6
:
472
83
.
11.
Hasselgren
PO
,
Wray
C
,
Mammen
J
. 
Molecular regulation of muscle cachexia: it may be more than the proteasome
.
Biochem Biophys Res Commun
2002
;
290
:
1
10
.
12.
Narsale
AA
,
Carson
JA
. 
Role of interleukin-6 in cachexia: therapeutic implications
.
Curr Opin Support Palliat Care
2014
;
8
:
321
7
.
13.
Li
YP
,
Reid
MB
. 
NF-kappaB mediates the protein loss induced by TNF-alpha in differentiated skeletal muscle myotubes
.
Am J Physiol Regul Integr Comp Physiol
2000
;
279
:
R1165
70
.
14.
Garcia-Martinez
C
,
Lopez-Soriano
FJ
,
Argiles
JM
. 
Acute treatment with tumour necrosis factor-alpha induces changes in protein metabolism in rat skeletal muscle
.
Mol Cell Biochem
1993
;
125
:
11
8
.
15.
Fong
Y
,
Moldawer
LL
,
Marano
M
,
Wei
H
,
Barber
A
,
Manogue
K
, et al
Cachectin/TNF or IL-1 alpha induces cachexia with redistribution of body proteins
.
Am J Physiol
1989
;
256
:
R659
65
.
16.
Li
YP
,
Schwartz
RJ
,
Waddell
ID
,
Holloway
BR
,
Reid
MB
. 
Skeletal muscle myocytes undergo protein loss and reactive oxygen-mediated NF-kappaB activation in response to tumor necrosis factor alpha
.
FASEB J
1998
;
12
:
871
80
.
17.
Hunter
RB
,
Stevenson
E
,
Koncarevic
A
,
Mitchell-Felton
H
,
Essig
DA
,
Kandarian
SC
. 
Activation of an alternative NF-kappaB pathway in skeletal muscle during disuse atrophy
.
FASEB J
2002
;
16
:
529
38
.
18.
Cai
D
,
Frantz
JD
,
Tawa
NE
 Jr
,
Melendez
PA
,
Oh
BC
,
Lidov
HG
, et al
IKKbeta/NF-kappaB activation causes severe muscle wasting in mice
.
Cell
2004
;
119
:
285
98
.
19.
Bonetto
A
,
Aydogdu
T
,
Jin
X
,
Zhang
Z
,
Zhan
R
,
Puzis
L
, et al
JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia
.
Am J Physiol Endocrinol Metab
2012
;
303
:
E410
21
.
20.
McPherron
AC
,
Lawler
AM
,
Lee
SJ
. 
Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member
.
Nature
1997
;
387
:
83
90
.
21.
Schuelke
M
,
Wagner
KR
,
Stolz
LE
,
Hubner
C
,
Riebel
T
,
Komen
W
, et al
Myostatin mutation associated with gross muscle hypertrophy in a child
.
N Engl J Med
2004
;
350
:
2682
8
.
22.
Chen
YG
,
Lui
HM
,
Lin
SL
,
Lee
JM
,
Ying
SY
. 
Regulation of cell proliferation, apoptosis, and carcinogenesis by activin
.
Exp Biol Med (Maywood)
2002
;
227
:
75
87
.
23.
Chen
YG
,
Wang
Q
,
Lin
SL
,
Chang
CD
,
Chuang
J
,
Ying
SY
. 
Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis
.
Exp Biol Med (Maywood)
2006
;
231
:
534
44
.
24.
Sartori
R
,
Milan
G
,
Patron
M
,
Mammucari
C
,
Blaauw
B
,
Abraham
R
, et al
Smad2 and 3 transcription factors control muscle mass in adulthood
.
Am J Physiol Cell Physiol
2009
;
296
:
C1248
57
.
25.
Sacheck
JM
,
Ohtsuka
A
,
McLary
SC
,
Goldberg
AL
. 
IGF-I stimulates muscle growth by suppressing protein breakdown and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1
.
Am J Physiol Endocrinol Metab
2004
;
287
:
E591
601
.
26.
Rommel
C
,
Bodine
SC
,
Clarke
BA
,
Rossman
R
,
Nunez
L
,
Stitt
TN
, et al
Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways
.
Nat Cell Biol
2001
;
3
:
1009
13
.
27.
Izumiya
Y
,
Hopkins
T
,
Morris
C
,
Sato
K
,
Zeng
L
,
Viereck
J
, et al
Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice
.
Cell Metab
2008
;
7
:
159
72
.
28.
Calnan
DR
,
Brunet
A
. 
The FoxO code
.
Oncogene
2008
;
27
:
2276
88
.
29.
Sartori
R
,
Gregorevic
P
,
Sandri
M
. 
TGFbeta and BMP signaling in skeletal muscle: potential significance for muscle-related disease
.
Trends Endocrinol Metab
2014
;
25
:
464
71
.
30.
Trendelenburg
AU
,
Meyer
A
,
Rohner
D
,
Boyle
J
,
Hatakeyama
S
,
Glass
DJ
. 
Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size
.
Am J Physiol Cell Physiol
2009
;
296
:
C1258
70
.
31.
Lok
C
. 
Cachexia: the last illness
.
Nature
2015
;
528
:
182
3
.
32.
Argiles
JM
,
Lopez-Soriano
FJ
. 
Catabolic proinflammatory cytokines
.
Curr Opin Clin Nutr Metab Care
1998
;
1
:
245
51
.
33.
Torelli
GF
,
Meguid
MM
,
Moldawer
LL
,
Edwards
CK
 III
,
Kim
HJ
,
Carter
JL
, et al
Use of recombinant human soluble TNF receptor in anorectic tumor-bearing rats
.
Am J Physiol
1999
;
277
:
R850
5
.
34.
Jatoi
A
,
Dakhil
SR
,
Nguyen
PL
,
Sloan
JA
,
Kugler
JW
,
Rowland
KM
 Jr
, et al
A placebo-controlled double blind trial of etanercept for the cancer anorexia/weight loss syndrome: results from N00C1 from the North Central Cancer Treatment Group
.
Cancer
2007
;
110
:
1396
403
.
35.
Jatoi
A
,
Ritter
HL
,
Dueck
A
,
Nguyen
PL
,
Nikcevich
DA
,
Luyun
RF
, et al
A placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in elderly and/or poor performance non-small cell lung cancer patients (N01C9)
.
Lung Cancer
2010
;
68
:
234
9
.
36.
Wiedenmann
B
,
Malfertheiner
P
,
Friess
H
,
Ritch
P
,
Arseneau
J
,
Mantovani
G
, et al
A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia
.
J Support Oncol
2008
;
6
:
18
25
.
37.
Johnston
AJ
,
Murphy
KT
,
Jenkinson
L
,
Laine
D
,
Emmrich
K
,
Faou
P
, et al
Targeting of Fn14 prevents cancer-induced cachexia and prolongs survival
.
Cell
2015
;
162
:
1365
78
.
38.
Hong
DS
,
Hui
D
,
Bruera
E
,
Janku
F
,
Naing
A
,
Falchook
GS
, et al
MABp1, a first-in-class true human antibody targeting interleukin-1alpha in refractory cancers: an open-label, phase 1 dose-escalation and expansion study
.
Lancet Oncol
2014
;
15
:
656
66
.
39.
Fisher
GA
. 
A phase III study of xilonix in refractory colorectal cancer patients with weight loss
.
J Clin Oncol
33
, 
2015
(
suppl 3; abstr 685
).
40.
Clarke
SJ
,
Smith
JT
,
Gebbie
C
,
Sweeney
C
,
Olszewski
N
. 
A phase I, pharmacokinetic (PK), and preliminary efficacy assessment of ALD518, a humanized anti-IL-6 antibody, in patients with advanced cancer
.
J Clin Oncol
27
:
15s
, 
2009
(
suppl; abstr 3025
).
41.
Rigas
JR
,
Schuster
M
,
Orlov
SV
,
Milovanovic
B
,
Prabhash
K
,
Smith
JT
, et al
Effect of ALD518, a humanized anti-IL-6 antibody, on lean body mass loss and symptoms in patients with advanced non-small cell lung cancer (NSCLC): results of a phase II randomized, double-blind safety and efficacy trial
.
J Clin Oncol
28
:
15s
, 
2010
(
suppl; abstr 7622
).
42.
Schuster
M
,
Rigas
JR
,
Orlov
SV
,
Milovanovic
B
,
Prabhash
K
,
Smith
JT
, et al
ALD518, a humanized anti-IL-6 antibody, treats anemia in patients with advanced non-small cell lung cancer (NSCLC): results of a phase II, randomized, double-blind, placebo-controlled trial
.
J Clin Oncol
28
:
15s
, 
2010
(
suppl; abstr 7631
).
43.
Padrao
AI
,
Oliveira
P
,
Vitorino
R
,
Colaco
B
,
Pires
MJ
,
Marquez
M
, et al
Bladder cancer-induced skeletal muscle wasting: disclosing the role of mitochondria plasticity
.
Int J Biochem Cell Biol
2013
;
45
:
1399
409
.
44.
Loumaye
A
,
de Barsy
M
,
Nachit
M
,
Lause
P
,
Frateur
L
,
van Maanen
A
, et al
Role of activin A and myostatin in human cancer cachexia
.
J Clin Endocrinol Metab
2015
;
100
:
2030
8
.
45.
Busquets
S
,
Toledo
M
,
Orpi
M
,
Massa
D
,
Porta
M
,
Capdevila
E
, et al
Myostatin blockage using actRIIB antagonism in mice bearing the Lewis lung carcinoma results in the improvement of muscle wasting and physical performance
.
J Cachexia Sarcopenia Muscle
2012
;
3
:
37
43
.
46.
Benny Klimek
ME
,
Aydogdu
T
,
Link
MJ
,
Pons
M
,
Koniaris
LG
,
Zimmers
TA
. 
Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia
.
Biochem Biophys Res Commun
2010
;
391
:
1548
54
.
47.
Zhou
X
,
Wang
JL
,
Lu
J
,
Song
Y
,
Kwak
KS
,
Jiao
Q
, et al
Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival
.
Cell
2010
;
142
:
531
43
.
48.
Murphy
KT
,
Chee
A
,
Gleeson
BG
,
Naim
T
,
Swiderski
K
,
Koopman
R
, et al
Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice
.
Am J Physiol Regul Integr Comp Physiol
2011
;
301
:
R716
26
.
49.
Jameson
GS
,
Von Hoff
DD
,
Weiss
GJ
,
Richards
DA
,
Smith
DA
,
Becerra
C
, et al
Safety of the antimyostatin monoclonal antibody LY2495655 in healthy subjects and patients with advanced cancer
.
J Clin Oncol
30
, 
2012
(
suppl; abstr 2516
).
50.
Amato
AA
,
Sivakumar
K
,
Goyal
N
,
David
WS
,
Salajegheh
M
,
Praestgaard
J
, et al
Treatment of sporadic inclusion body myositis with bimagrumab
.
Neurology
2014
;
83
:
2239
46
.
51.
Aversa
Z
,
Bonetto
A
,
Penna
F
,
Costelli
P
,
Di Rienzo
G
,
Lacitignola
A
, et al
Changes in myostatin signaling in non-weight-losing cancer patients
.
Ann Surg Oncol
2012
;
19
:
1350
6
.
52.
Gallot
YS
,
Durieux
AC
,
Castells
J
,
Desgeorges
MM
,
Vernus
B
,
Plantureux
L
, et al
Myostatin gene inactivation prevents skeletal muscle wasting in cancer
.
Cancer Res
2014
;
74
:
7344
56
.
53.
Toledo
M
,
Busquets
S
,
Penna
F
,
Zhou
X
,
Marmonti
E
,
Betancourt
A
, et al
Complete reversal of muscle wasting in experimental cancer cachexia: additive effects of activin type II receptor inhibition and beta-2 agonist
.
Int J Cancer
2016
;
138
:
2021
9
.
54.
Mori
S
,
Matsuzaki
K
,
Yoshida
K
,
Furukawa
F
,
Tahashi
Y
,
Yamagata
H
, et al
TGF-beta and HGF transmit the signals through JNK-dependent Smad2/3 phosphorylation at the linker regions
.
Oncogene
2004
;
23
:
7416
29
.