Inflammatory Response in Cancer Cachexia

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1		Aldona Kasprzak	+ 4271 word(s)	4271	2021-04-12 05:20:18	\|
2	format correct	Conner Chen	-1 word(s)	4270	2021-04-20 10:40:57	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms22041565

Cancer cachexia (CC) is a multifactorial clinical complication in numerous human malignancies. Its incidence in Europe is highest in patients with lung (83/36% inpatients/outpatients, respectively) and gastrointestinal cancers (62/42%). There are currently no therapeutic agents used for treatment of this paraneoplastic syndrome, caused by impaired/reduced nutritional intake, or metabolic disorders with increased catabolism and chronic inflammation. In the mechanisms of CC pathogenesis, in addition to inflammation, the role of insulin resistance, damage to mitochondrial function, oxidative stress, as well as the activation of lipolysis and proteolysis through the ubiquitin-proteasome system and macro-autophagy are emphasized. The main target in CC is skeletal and cardiac muscle, as well as the adipose tissue (AT). The most important role in CRC-associated cachexia is played by pro-inflammatory cytokines, including the tumor necrosis factor α (TNFα), originally known as cachectin, Interleukin (IL)-1, IL-6, and certain chemokines (e.g., IL-8). Heterogeneous CRC cells themselves also produce numerous cytokines (including chemokines), as well as novel factors called “cachexokines”. The tumor microenvironment (TME) contributes to systemic inflammation and increased oxidative stress and fibrosis.

tumor microenvironment systemic inflammatory response cancer cachexia colorectal cancer procachectic mediators

1. Criteria of Cancer Cachexia

A great deal of effort has been devoted to defining and describing CC criteria ^[1]. Based on SCRINIO Working Group classification, different stages can be indicated, with different severity of CC, from asymptomatic precachexia (class 1) to symptomatic cachexia (class 4) ^[2]. According to a group of experts participating in a formal international consensus process (2011), CC can be described as a multifactorial syndrome of continuous skeletal-muscle loss, with or without the loss of adipose-tissue mass, functional disorders and a varying extent of appetite impairment that cannot be fully reversed by usual means of nutritional support. It has been confirmed that cachexia develops gradually, through different stages, from precachexia through cachexia to refractory cachexia, with the diagnostic criteria and domains of clinical management of these stages determined ^[3]. In the recent years, updated criteria were indicated for advanced cancer patients, based on a cachexia staging score (CSS) that consists of five components (weight loss, muscle function, appetite, performance status, and abnormal biochemistry), in order to clarify the above-mentioned three-level staging system (precachexia, cachexia, and refractory cachexia) ^[4]. Other authors also note that cachexia was connected to higher susceptibility to toxicities associated with treatment, decrease in life quality, and increase in cancer-related mortality, as well as a decrease in cancer-chemotherapy efficacy ^[5]^[1]. Other clinical characteristics of cachexia include disrupted metabolism, inflammation, and anorexia, resulting in a persistent fatigue ^[6], as well as systemic reprogramming of the host metabolism ^[7]. Furthermore, hypermetabolic patients exhibit more severe and more frequent inflammatory response (higher C-reactive protein (CRP) concentrations), as compared with normometabolic/hypometabolic patients. CRP concentrations, energy intakes, and hypermetabolism, as independent variables, were associated with risk of weight loss >5% ^[8].

In clinical practice, further studies are needed to unify the criteria for the nutritional status of cachexia. The cancer cachexia study group (CCSG) scoring system (0–3) was indicated as the best OS prognostic evaluator in CRC patients from Norway and Canada. In this system, CC is defined by either a weight loss ≥ 5% during the last 6 months, a weight loss 2–5% in combination with a BMI < 20, or a weight loss of 2–5% with the presence of sarcopenia. Cachexia (in 22–55% patients) and malnutrition (in 34% patients) were indicated as independent significant predictors of survival, after adjusting for nationality, age, and gender ^[9]. In turn, malnutrition status was observed in 30–60% of Portuguese patients with CRC ^[10]. Moreover, the study of basal nutritional status in patients with CRC qualified for chemotherapy in Poland, based on the SCRINIO Working Group classification, showed that the majority of them (75%) exhibit precachexia status ^[11].

2. Cancer Cachexia and Systemic Inflammatory Response (SIR)

CC is a secondary disease developing in cancer patients, causing progressive disfunction due to systemic inflammatory response (SIR) ^[1] or is simply called an “inflammatory condition” ^[12]. Host–tumor interaction associated SIR was indicated as the seventh hallmark of cancer ^[13]. SIR is characterized by an increase in concentration of inflammatory factors, such as CRP, TNF-α, IL-1, IL-6, INF-γ, and PIF (previously known as “cancer cachectic factor” or cachexia-associated protein) ^[12]^[14]^[15]^[16]. Hence, while TNF-α is considered a classical wasting-associated “cachectin” ^[17], the list of procachectic mediators is continuously expanded. This section of the paper concisely characterizes the factors that have a proven role in cachexia induction.

2.1. Tumor Necrosis Factor α (TNF-α) and Proteolysis-Inducing Factor (PIF)

The early review papers already indicate the ability of macrophage produced TNF-α to induce cachexia ^[17].

As per the results of the pioneering studies on the causes of muscle wasting in CC, TNF-α and IFN-γ strongly suppress the expression of myosin via RNA-dependent mechanism in myotubes and mouse muscle tissue. In the mouse model of the colon-C26 tumor, it was confirmed that the reduction of this protein was associated with the ubiquitin-dependent proteasome (UPS) pathway ^[18]. TNF-α-mediated inhibition of protein synthesis occurs through the reduction in the active eukaryotic initiation-factor 4E (eIF4E) complex. TNF-α plays a direct role in cachexia, causing catabolic effects not only in muscles but also in AT through the inhibition of lipoprotein lipase, resulting in a loss of AT. Furthermore, this cytokine increases gluconeogenesis and glycogen synthesis ^[19]^[15]. In contrast to TNF-α, sulphated glycoprotein PIF only exerts its effects on the muscle tissue, with inhibition of protein synthesis occurring due to increased phosphorylation of the eIF2 on the alpha-subunit. Serum concentrations of TNF-α do not correlate with weight loss, whereas PIF is detectable in the urine, making it a useful marker of weight loss in cachectic patients ^[15]. Binding of PIF to its receptor in skeletal muscles causes an increase in Ca⁺²_i, initiating a signaling cascade that leads to a decrease in protein synthesis and increase in protein degradation ^[20]. Thus, CC is accompanied by an increase in pro-inflammatory factors, including TNF-α and PIF. The main effects of both of these proteins in the context of CC are muscle atrophy caused by decreased protein synthesis and an increase in protein degradation ^[15]. Additional effects of TNF-α include decreased food intake and increased energy expenditure (reviewed in: ^[21]^[12]). Furthermore, other actions of these factors are presented in the chapter considering the involvement of TME cells in CC.

2.2. Interleukin 1 α and β (IL-1α, IL-1β)

IL-1α is also considered a key mediator in CC, with the mechanisms of its action discussed in recent reviews in the context of possible therapy ^[22]. While the main source of IL-1β are the innate immune cells, IL-1α synthesis is localized in various cell types under physiological and pathological conditions (e.g., innate and adaptive immune cells, epithelial cells, ECs, adipocytes, chondrocytes, and fibroblasts) ^[23]. Furthermore, it needs to be noted that the pleiotropic IL-1 consists of two antagonistic IL-1α and IL-1β cytokines that bind to the same receptor (IL-1R1) and induce the same biological functions. However, both of these proteins show biologically different roles in carcinogenesis. IL-1α’s action is mainly immunostimulatory, while IL-1β exhibits a pro-inflammatory role, especially in the early phases of tumor development ^[23]^[24]. In TME, IL-1 is produced by the tumor, as well as stromal and infiltrating cells supporting cancer progression ^[24]. Considering the subcellular localization, IL-1α can be mostly found inside the cells, both in cytosol and the nucleus, as well as on the cell membrane, rarely being expressed outside the cell. The IL-1α (proIL-1α) precursor form is active and mainly located in cytosol or on cell membranes ^[25]. In turn, IL-1β is only active as a mature secreted molecule, mainly produced by activated myeloid cells. In the early stages of carcinogenesis, both forms of IL-1 serve a different role. The membrane-bound IL-1α exhibits a mainly immunostimulatory activity, while IL-1β in the TME exhibits a pro-inflammatory role in tumorigenesis and tumor-invasion-promoting activity, as well as immunosuppressive activity ^[24]. The activity of IL-1R1, present in numerous TME cells, suggests the participation of IL-1 signaling in various stages of tumor development. The mechanisms of IL-1/IL-1R action in TME cells were thoroughly presented in a recent excellent review ^[23]. The role of IL-1 in tumor progression and its potential in antitumor immunotherapies have been also reviewed by others ^[25].

While there are some studies on the processes involving the action of both IL-1 agonistic molecules in tissue wasting, the direct mechanisms in human CC tissue wasting are not recognized ^[26]^[16]^[27]. Using the mature C2C12 myotubes model, it was proven that both IL-1 isoforms (α and β) act through an oxidant and serine-threonine protein kinase Akt/Forkhead-O (FOXO)-independent mechanism to activate p38 MAPK, stimulate nuclear factor kappa B (NF-κB) signaling, increase the expression of muscle-specific ubiquitin ligases, atrogin 1/muscle atrophy F-box (MAFbx) and muscle RING-finger 1 (MuRF1), and reduce myofibrillar protein in differentiated myotubes. The authors suggest that direct exposure of muscle cells to IL-1 promotes the expression of E3 ligases and stimulates the catabolism of myotubes, without the participation of reactive oxygen species (ROS) or Akt/FOXO signaling ^[27].

In a rodent model of cancer cachexia, a heterogenous expression of Interferon γ (IFN-γ) was also detected in white adipose tissue (WAT). Differential expression of the pleiotropic cytokine, as well as the pathways it activates, could possibly be detected before the onset of refractory cachexia ^[28].

2.3. Interleukin 6 (IL-6)

Elevated serum levels of inflammatory markers such as IL-6 and CRP suggest inflammation as a common feature of cachexia and various inflammatory diseases (reviewed in: ^[29]).

Increased levels of cytokines, such as IL-6 in CC, may result in increased proteolysis and skeletal-muscle atrophy with preferential loss of myofibrillar protein, decreased food intake, and an increase in energy expenditure ^[12]^[30]. Furthermore, animal models were often used for the studies of the molecular mechanisms of CC, especially mice bearing the C26 carcinoma (also referred to as colon-26 (C26) adenocarcinoma) a model with high levels of IL-6 family ligands (reviewed in: ^[31]).

Pleiotropic effects of IL-6 action, including those that promote muscle atrophy, increased muscle wasting and the mechanisms of muscle wasting, are mainly described in animal models ^[32]^[30]^[33]. In mice affected by severe cachexia (Apc^Min/+ mice), IL-6 overexpression altered the expression of proteins regulating mitochondrial biogenesis and fusion in cultured myoblasts (C2C12 cells). The affected specimen could be rescued by the administration of an IL-6 receptor antibody, as well as exercise ^[34]. Further studies proved that IL-6 overexpression in cachectic mice increases the levels of fasting insulin and triglycerides, with the possibility of their normalization through exercise, due to increased oxidative capacity, induction of Akt signaling, and down-regulation of AMP-activated protein-kinase (AMPK) signaling in muscles ^[35]^[36].

Another mouse-model study showed a phenotype switch from WAT to brown fat (WAT browning) during early CC stages, even before muscle atrophy. This occurs due to an increase in the expression of uncoupling protein 1 (UPC1) in WAT. This protein affects the mitochondrial respiration, uncoupling it toward thermogenesis instead of ATP synthesis, which results in an increase in lipid mobilization and energy spending in cachectic mice. In turn, the increase in UPC1 production in WAT is caused by the effects of IL-6, as well as the presence of chronic inflammation ^[37]. Similarly, Han et al. reported a correlation between chronic inflammation (especially that mediated by IL-6) and CC promotion. IL-6 concentration was correlated with serum-free fatty acids (FFA), both in early- and late-stage CC, while serum TNF-α was positively linked to FFA in early-stage but not late-stage CC. Furthermore, WAT lipolysis was increased in early- and late-stage CC, while WAT browning increased only in late-stage CC ^[38]. The WAT browning, as an effect of systemic inflammation, has a particular role in high energy expenditure associated with CC ^[37]^[38]. Recent studies showed augmented expression of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-8 in CC patients as compared to the control group. Furthermore, IL-8 content was also higher in weight-stable cancer (WSC) patients compared to control. The plasma fatty-acid profile was also positively correlated with some of the pro-inflammatory cytokines expression in the CC patients (IL-8, IFN-γ, CCL2, and IL-1Ra) ^[39].

A comparison of serum concentrations of four pro-inflammatory factors (e.g., IL-6, IL-1β, Chemokine (C-X-C Motif) Ligand 8(CXCL8)/IL-8, and TNF-α) in advanced-stage cancer patients showed that IL-1β levels correlated more strongly with clinical characteristics than those of IL-6 ^[40]. There are also some clinical reports of resectable pancreatic cancer patients, which noted low levels of the described pro-inflammatory cytokines (IL-6, IL-1β, IFN-γ, and TNF-α), with their concentrations not correlated with CC, even if more sensitive methods were used for the analyses. Among the 25 tested circulating factors, only the monocyte chemoattractant protein 1 (MCP-1) showed an increase in treatment-naïve cachectic patients, as compared to those unaffected by the condition. Hence, it was suggested as a potential CC biomarker ^[41]. Recent studies by Cao et al. describe reporter cell lines that could detect factors associated with CC, such as myostatin, activin A, and TNF-α. This cell model could be a valuable tool of early-cachectic-state detection and differentiation of cancer-induced cachexia in humans and mice ^[42].

The works summarized above concern the correlations between cachexia determinants and SIR in cancers in general. It needs to be noted that a systemic increase in CRP and cytokines, e.g., IL-6, IL-1, and TNF-α is also observed with age (the so-called “inflamm-aging”), due to persistent sarcopenia. Furthermore, cohort studies mainly indicate TNF-α and IL-6 levels as cachexia markers (reviewed in: ^[43]).

3. Systemic Inflammatory Response in Colorectal Cancer-Associated Cachexia

A direct correlation between cancer cachexia and SIR was also confirmed in patients with CRC ^[13]^[44]^[45]. Most of the available literature concerns the role of the inflammatory process in muscle-tissue changes during CC. In turn, recent studies show a correlation between muscle catabolism and systemic inflammation in CRC. The presence of myopenia (reduced muscle mass) in preoperative CRC patients was significantly correlated with a number of SIR markers, such as elevated CRP concentration, systemic immune-inflammation index (SII), neutrophil-platelet score, and a decreased lymphocyte:monocyte ratio (LMR), prognostic nutritional index, and serum albumin level. Among those, only the increase in CRP level was indicated as an independent risk factor for the presence of preoperative myopenia ^[13]. Other reports indicate a correlation between elevated SIR, as measured by the high modified Glasgow prognostic score (mGPS), CRP, and neutrophil:lymphocyte ratio (NLR) with a low skeletal-muscle index in patients with primary operable CRC ^[46]. In turn, Malietzis et al. reported that host SIR in resectable CRC patients is associated with not only myopenia but also myosteatosis (increased infiltration by inter- and intra-muscular adipose tissue). High neutrophil:lymphocyte ratios (NLR) and low albumin levels were independent predictors of myopenia, with the former being correlated with myosteatosis ^[47]. Furthermore, Sirniö et al. noted correlations between serum levels of several amino acids (AAs) (low with glutamine and histidine and high with phenylalanine), SIR markers, and muscle catabolism in patients with CRC. Hence, the authors proposed several SIR indicators, e.g., mGPS, high blood NLR, and high serum levels of CRP, IL-6, and IL-8. Of the 13 cytokines tested, IL-6 most strongly associated with increased phenylalanine and lower histidine levels. The authors suggest that SIR is associated with glutamine consumption and muscle wasting in CRC ^[44]. In turn, the studies of Ohmori et al. suggest that only TNF-α, the levels of which were negatively correlated with skeletal-muscle index (SMI) and SDS-soluble myosin light chain 1 (SDS-MYL1), is a good serum muscle-atrophy marker in CRC-associated cachexia ^[45]. Other authors confirmed that higher TNF-α concentrations are usually associated with patients with more advanced CRC stages (stage III/IV vs. stage I/II tumors). In turn, patients with the greatest nutritional deficit exhibited higher levels of adipocytokines. However, these TNF-α variations were only significant in CRC vs. control when the nutritional status was evaluated by phase-angle tertiles ^[48].

There was also an attempt to evaluate the role of gut barrier disruption, possibly resulting in persistent activation of the host immune response, as a cause of local and systemic inflammatory changes in CRC-associated cachexia. Comparative studies concerned cachectic and weight-stable CRC patients, analyzing the circulating profile and tissue expression of various cytokines (including chemokines), growth and differentiation factors, as well as morphological intestinal changes in CRC-associated cachexia. Mucosal biopsies were derived from the rectosigmoid region, 20 cm from the tumor margin. An increase in serum concentrations of IL-6 and IL-8 was observed, together with elevated tissue expression of IL-7, IL-13, and transforming growth factor β3 (TGF-β3), as well as rich lymphocyte and macrophage infiltration in the colon of CC patients, compared to those of normal body weight. These changes suggest the presence of repair mechanisms in the damaged large intestine, with expanded recruitment of immune cells and higher tissue production of IL-13 and TGF-β3 ^[6].

Animal models also allowed for the clarification of some of the mechanisms of heart-muscle damage in CRC-associated cachexia involving inflammation. Studies on CD2F1 mice inoculated with C26 cells presented an increase in the production of IL-6, IL-6R, and F4/80 (a marker for macrophages infiltration) in the heart of tumor-bearing vs. non-tumor-bearing mice. Furthermore, increased fibrosis, disrupted myocardial structure, and altered composition of contractile proteins, e.g., troponin I (decreased), myosin heavy-chains isoforms α (decreased), and β (increased), was detected in the cardiac muscle of tumor-bearing mice, resulting in muscle-function impairment ^[49].

Inflammatory changes also play a role in metabolic disturbances observed in patients with CRC-associated cachexia. Mice bearing C26 carcinoma represented a well-established murine model of CC resulting in a high systemic level of IL-6 ^[50]. It was proven that these mice exhibit reduced adipose mass, increased AT lipolysis, and a five-fold increase in FFA plasma levels. These alterations were linked to the activation of IL-6 signaling in WAT through a three-fold increase in phosphorylated STAT3 and high suppressor of cytokine signaling 3 (SOCS3) gene expression levels ^[51]. It was also recently reported that the leukemia inhibitory factor (LIF) secreted by the tumor induces changes in the expression of AT, as well as serum levels of IL-6 and leptin, acting in a JAK-dependent manner. This, in turn, results in cachexia-associated adipose wasting as well as anorexia. The authors noted that the use of JAK inhibitors in both in vitro and in vivo models of CC inhibits this process ^[52].

Lipolysis is also a typical manifestation of CC. Some of the mechanisms of this process were elucidated, mainly in in vitro models, through the evaluation of the activity of enzymes involved in lipid degradation in cancer cachexia. One example of such is spermidine/Spermine N-1 acetyl transferase (SSAT), an important enzyme in polyamine metabolism, which plays other potential roles, e.g., decreasing lipid accumulation. Its activity is stimulated by a multitude of factors, including those associated with cachexia, such as several cytokines, hormones, and natural substances (reviewed in: ^[53]). Constant SSAT activation leads to an increased demand for acetyl-CoA (a cofactor of SSAT), thereby restricting conversion of acetyl-CoA by acetyl-CoA carboxylase (ACC) to malonyl-CoA ^[54]. Malonyl-CoA inhibits the rate-limiting step in the β-oxidation of fatty acids and is a substrate in fatty-acid synthesis. A study of the activity of enzymes responsible for increased lipolysis in a mouse model of cancer cachexia (C26) using a cachexigenic clone 20 (c20), and noncachexigenic clone 5 (c5), showed a significant increase in SSAT as well as a decrease in acetyl-CoA carboxylase (ACC) and malonyl-CoA in cachectic mice ^[55]. The studies of Chiba et al. confirmed these observations, demonstrating a correlation between malonyl-CoA in the liver and symptoms of CC (c5). In turn, in mice bearing the c5 tumor, the levels of SSAT mRNA did not correlate with the severity of CC manifestations. Hence, malonyl-CoA in the liver, correlating with the weight of fat stores in mice, seems to be a good marker of CC. A decrease in malonyl-CoA resulted in lowered fatty-acid synthesis and accelerated lipolysis via activation of carnitine palmitoyltransferase 1 (CPT-1) and ketogenesis. According to the authors, a decrease in the level of malonyl-CoA activity, playing a major role in CC induction, can be also caused by factors other than SSAT. From the panel of investigated pro-inflammatory (e.g., IL-1β, IL-6, and TNF-α) and anti-inflammatory/immunomodulatory cytokines (e.g., IL-10), only IL-10 had a negative correlation with body weight and the weights of skeletal muscle and storage fat ^[54].

In another study, Apc^Min/+ mice (carrying a dominant mutation in the APC gene) are a model of colon cachexia directly related to an intestinal tumor burden and subsequent chronic inflammation (with elevated IL-6 levels). These mice were classified as noncachectic (8 weeks of age), precachectic (14 weeks of age), and severely cachectic (20 weeks of age). These studies confirmed the disturbances in hepatic triglyceride metabolism in catechetic mice. Furthermore, a novel role of hepatic glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) was confirmed in hypertriglyceridemia with marked liver steatosis in Apc^Min/+ mice. It was also reported that GPIHBP1 is involved in the NF-κB signaling pathway in the liver of cachectic mice. The authors found a decrease in the hepatic uptake of fatty acids and lipolysis, with no differences in fatty-acid β-oxidation ^[56].

Clinical studies of CC showed that the increase in serum FFAs (an indicator of enhanced lipolysis) was positively correlated with serum pro-inflammatory cytokine levels (e.g., IL-6 and TNF-α) ^[38]. In turn, disorders of lipid metabolism in cachexia (including mechanisms of lipolysis) were described in recent review papers. The involvement of both inflammatory factors, defects in energy utilization, and molecular mechanisms underlying the WAT dysfunction and browning in CC are all highlighted in the mentioned works ^[26]^[57].

The role of direct adipose-cell involvement in the mechanisms of lipolysis in cachexia is described later in the paper. In turn, a brief summary of selected mediator action during systemic inflammatory response associated with CC is presented in Table 1.

Table 1. Summary of some mechanisms and effects of selected procachectic mediators involved in the cancer cachexia.

Procachectic Mediator	Model of the Study	Target Tissue	Mechanism of Action	Ref.
TNF-α	Murine C2C12 and primary myoblasts; mouse colon-26 cells (C26); various in vitro and in vivo mouse models of CC; patients with CC	Muscle	(i) catabolic effects; (ii) TNF-α + IFN-γ led to ↓expression of myosin via RNA-dependent mechanism in myotubes and muscle tissue; (iii) UPS pathway contribution	^[18]
		Adipose; muscle	(i) catabolic effects; (ii) loss of AT and proteolysis, while causing ↓protein, lipid, and glycogen synthesis; (iii) ↓lipoprotein lipase; ↑gluconeogenesis; (iv) ↓protein synthesis via ↓in the active eIF4F complex; (v) serum levels do not correlate with weight loss	^[19]^[15]
	CRC patients with different stages of CC; BALB/c male mice; C26/clone 20 cells	Adipose	was positively linked to FFA in early- but not late-stage CC	^[38]
	cancer patients with CC; WSC; C		↑level in CC patients vs. C	^[39]
	CRC tissue samples	Muscle	(i) negative correlation with SMI and SDS-MYL1; (ii) positive correlation with HMGB1	^[45] *
	primary operable CRC and control		(i) ↑level was correlated with CRC staging; (ii) patients with the greatest nutritional deficit exhibited ↑levels of adipocytokines	^[48] *
PIF	various mouse models of CC; cancer patients with CC	Muscle	(i) catabolic effect on skeletal muscle; (ii) ↓protein synthesis via ↑phosphorylation of the eIF2 on the alpha-subunit; (iii) its presence is indicative of weight loss; (iv) its presence in the urine of CC patients is indicative of weight loss	^[15]
PIF	C2C12 mouse myoblasts; MAC16 tumors	Muscle	↑Ca⁺²_i, initiating a signaling cascade that leads to a ↓protein synthesis and ↑ in protein degradation	^[20]
IL-1 (α and β)	C2C12 myoblasts, mature C2C12 myotubes model	Muscle	(i) an oxidant and Akt/FOXO-independent mechanism to activate p38 MAPK, ↑NF-κB signaling; (ii) ↑expression of Atrogin 1/MAFbx and MuRF1, and ↓myofibrillar protein in differentiated myotubes; (iii) the direct mechanisms in human CC tissue wasting are not recognized	^[27]
IFN-γ	Various in vitro and in vivo mouse models of CC	Adipose; muscle	(i) with TNF-α led to ↓expression of myosin via RNA-dependent mechanism in myotubes and muscle tissue; (ii) UPS pathway contribution; (iii) changes in expression and signaling may be perceived at stages preceding refractory cachexia	^[18]^[28]
IFN-γ	cancer patients with CC; WSC; C		positive correlation with plasma FA profile	^[39]
IL-6	Apc^Min/+ mice; C2C12 cells	Muscle	(i) ↑muscle wasting; (ii) altered the expression of proteins regulating mitochondrial biogenesis and fusion; (iii) ↓in mitochondrial content during the progression of cachexia; (iv) directly ↑FIS1 expression in muscle cells; (v) ↑indices of ROS in myotubes	^[34]
	mature C2C12 myotubes model; in vitro and in vivo mouse model of CC	Muscle	STAT3 activation is a common feature of muscle wasting, muscle fiber atrophy and exacerbated wasting in CC	^[30]
	Mouse model of CC; C26 cells; human cancerous-tissue samples	Adipose	↑expression of UPC1 in WAT, which affects the mitochondrial respiration, uncoupling it toward thermogenesis instead of ATP synthesis, which results in ↑lipid mobilization and energy spending in CC	^[37]
	CRC patients with different stages of CC; BALB/c male mice; C26/clone 20 cells	Adipose	(i) regulating WAT lipolysis in early-stage cachexia and browning in late-stage cachexia; (ii) correlation with serum FFA	^[38]
	cancer patients with CC; WSC; C		↑level in CC patients vs. control	^[39]
	C26 model of CC	Adipose	(i) ↓AT mass, ↑AT lipolysis, and a 5-fold ↑ in FFA plasma levels; (ii) activation of IL-6 signaling in WAT through a 3-fold ↑ in pSTAT3 and high SOCS3 gene expression levels	^[51] *
	CD2F1 mice inoculated with C26 cells and vehicle	Muscle	(i) ↑IL-6, IL-6R, and F4/80 in the heart of tumor-bearing vs. control; (ii) ↑fibrosis, disrupted myocardial structure, and altered composition of contractile proteins	^[49] *
IL-8	cancer patients with CC; WSC; C		(i) ↑level in CC patients vs. control and in WSC vs. control; (ii) positive correlation with plasma FA profile	^[39]

Legend: ↑, ↓—increase (up-regulation)/decrease expression/level; *—concerns CRC patients/tissues; Akt—serine-threonine protein kinase; AMPK—AMP-activated protein kinase; AT—adipose tissue; C—control; CC—cancer cachexia; (F)FA—(free) fatty acid; FIS1—fission protein 1; FOXO—Forkhead-O; HMGB 1—high mobility group box 1; eIF4E—eukaryotic initiation factor-4E; IL-1, -6, -8—interleukin 1, 6, 8; IFN-γ—interferon gamma; MAPK—AMP-activated protein kinase; MAFbx—muscle atrophy F-box; MAPK—mitogen-activated protein kinase; MuRF1—muscle RING-finger 1; NF-κB—nuclear factor kappa B; PIF—proteolysis-inducing factor; pSTAT3—phosphorylated signal transducer and activator of transcription protein; ROS—reactive oxygen species; SDS-MYL1—SDS-soluble myosin light chain 1; SMI—skeletal-muscle index; SOCS3—suppressor of cytokine signaling 3; TG—triglycerides; TNF-α—tumor necrosis factor α; UPC1—uncoupling protein 1; UPS—ubiquitin-proteasome system; WAT—white adipose tissue; WSC—weight stable cancer.

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