Cachexia Research Articles

The roles of P-selectin in cancer cachexia.

P-selectin, a cell adhesion molecule of the selectin family, is expressed on the surface of activated endothelial cells (ECs) and platelets. Binding of P-selectin to P-selectin glycoprotein ligand-1 (PSGL-1) supports the leukocytes capture and rolling on stimulated ECs and increases the aggregation of leukocytes and activated platelets. Cancer cachexia is asystemic inflammation disorder characterized by metabolic disturbances, reduced body weight, loss ofappetite, fat depletion, and progressive muscle atrophy. Cachexia status is associated with increased pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), which activates ECs to release P-selectin. Single-nucleotide polymorphisms (SNPs) loci of P-selectin encoding gene SELP are associated with higher level of plasma P-selectin and increase the susceptibility to cachexia in cancer patients. Elevated P-selectin expression has been observed in the hypothalamus, liver, and gastrocnemius muscle in animal models with cancer cachexia. Increased P-selectin may cause excessive inflammatory processes, muscle atrophy, and blood hypercoagulation, thus facilitating the development of cancer cachexia. In this review, physiological functions of P-selectin and its potential roles in cancer cachexia have been summarized. We also discuss the therapeutic potential of P-selectin inhibitors for the treatment of cancer cachexia.

Cancer Cachexia: A Glimpse Into a Neglected Aspect of Palliative Care in Sri Lanka.

Cancer Cachexia: A Glimpse Into a Neglected Aspect of Palliative Care in Sri Lanka.

Development and Characterization of a Cancer Cachexia Rat Model Transplanted with Cells of the Rat Lung Adenocarcinoma Cell Line Sato Lung Cancer (SLC).

Cancer cachexia is a complex malnutrition syndrome that causes progressive dysfunction. This syndrome is accompanied by protein and energy losses caused by reduced nutrient intake and the development of metabolic disorders. As many as 80% of patients with advanced cancer develop cancer cachexia; however, an effective targeted treatment remains to be developed. In this study, we developed a novel rat model that mimics the human pathology during cancer cachexia to elucidate the mechanism underlying the onset and progression of this syndrome. We subcutaneously transplanted rats with SLC cells, a rat lung adenocarcinoma cell line, and evaluated the rats' pathophysiological characteristics. To ensure that our observations were not attributable to simple starvation, we evaluated the characteristics under tube feeding. We observed that SLC-transplanted rats exhibited severe anorexia, weight loss, muscle atrophy, and weakness. Furthermore, they showed obvious signs of cachexia, such as anemia, inflammation, and low serum albumin. The rats also exhibited weight and muscle losses despite sufficient nutrition delivered by tube feeding. Our novel cancer cachexia rat model is a promising tool to elucidate the pathogenesis of cancer cachexia and to conduct further research on the development of treatments and supportive care for patients with this disease.

Carnosol analogue WK-63 alleviated cancer cachexia by inhibiting NF-κB and activating AKT pathways in muscle while inhibiting NF-κB and AMPK pathways in adipocyte

Cancer cachexia is a systemic metabolic disorder syndrome characterized by severe wasting of muscle and adipose tissues while is lack of effective therapeutic approaches. Carnosol (CS) was found in our previous study to exhibit ameliorating effects on cancer cachexia. In the present study, we designed and synthesized 49 CS analogues by structural modification of CS. Results of activity screening revealed that, among the analogues, WK-63 exhibited better effects than CS in ameliorating atrophy of C2C12 myotubes induced by conditioned medium of C26 tumor cells. WK-63 could also dose-dependently alleviate adipocyte lipolysis of mature 3 T3-L1 cells induced by C26 tumor cell conditioned medium. WK-63 alleviated myotube atrophy by inhibiting Nuclear Factor kappa-B (NF-κB) and activating the Protein Kinase B (AKT) signaling pathway, and also alleviated fat loss by inhibiting NF-κB and Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways. Results of pharmacokinetic (PK) assay showed that, compared with other analogues, WK-63 exhibited longer half-life (T1/2) and mean residence time (MRTs), as well as a larger concentration curve area (AUC0-t). These findings suggested that WK-63 might exert optimal effects in vivo. In the C26 tumor-bearing mice model, administration of WK-63 ameliorated the body weight loss and also improved the weight loss of epididymal adipose tissue. WK-63 is expected to be a novel therapeutic option for the treatment of cancer cachexia.

Perception of subjective lived experiences of individuals with anorexia-cachexia in patients with advanced lung cancer

ObjectiveCancer cachexia (CC) is a frequent and debilitating syndrome in patients with cancer. It has serious implications for patients, extending beyond physical problems into psychological, and social domains. The objective of our study was to qualitatively understand the experiences related to CC in patients with advanced lung cancer. MethodsPatients with advanced lung cancer with anorexia (≤ 37 points on Functional Assessment of Anorexia/Cachexia Treatment-ACS) and weight loss were eligible. Patients participated in semi-structured interviews prior to study treatment (n = 19). Qualitative analysis was conducted using interpretative phenomenological approach. ResultsTwo super-ordinate themes emerged (anorexia and weight loss). Patients reported experiencing distress related to anorexia, weight loss, lack of social eating, worsening function, body image, and eating habits. The encouragement to eat by the family was often distressing to the patient. The treatment recommendations by their oncologist for anorexia and weight loss was felt inadequate. Patients felt that the treatment for CC should improve appetite and weight gain as well as their mood and be independent. ConclusionsThe findings of the study suggests that anorexia and weight loss results in high levels of distress due to their effects on physical and psychosocial domains. Further studies are needed to better understand the experience of anorexia and weight loss to develop strategies to effectively treat CC. Trial registrationNCT03637816.

Insulin in combination with pioglitazone prevents advanced cachexia in 256-Walker tumor-bearing rats: effect is greater than treatment alone and is associated with improved insulin sensitivity.

Insulin (INS) resistance and hypoinsulinemia commonly observed in cancer-carrying, can contribute to cachexia. However, the effects of INS and INS sensitizers, such as pioglitazone (PIO), particularly when used in combination therapy, on cancer cachexia have not been evaluated sufficiently. We investigated the effects of INS and PIO, at various doses, either isolated or combined, on cachexia in Walker-256 tumor-bearing rats (TB rats). INS or INS + PIO were administered in TB rats, for 6 or 12days, starting from the day of tumor cells inoculation. INS at 18 or 27 U/kg (12-days treatment), but not 9 U/kg, reduced fat loss and slightly prevented weight loss. However, INS 18 U/kg + PIO 5, 10, 20, or 40mg/kg (6 or 12-day treatment) reduced fat loss and markedly prevented weight loss but did not affect muscle wasting. While TB rats lost weight (37.9% in 12days), TB rats treated with INS 18 U/kg + PIO 5mg/kg showed pronounced weight gain (73.7%), which was greater than the sum (synergism) of the weight gains promoted by isolated treatments with INS 18 U/kg (14.7%) or PIO 5mg/kg (13.1%). The beneficial effect of the INS 18 U/kg + PIO 5mg/kg on weight loss was associated with improved INS sensitivity, as indicated by the higher blood glucose clearance constant (kITT), decreased levels of free fatty acids and triacylglycerols (INS resistance-inducing factors) in the blood, and increased expression of p-Akt (INS signaling pathway protein) in adipose tissue. The combined treatment with INS 18 U/kg + PIO 5mg/kg was more effective in preventing advanced cachexia in TB rats than each treatment alone, emerging as the best approach, considering the lower dosage and higher efficacy. This combination completely preserved adipose mass and markedly reduced weight loss through a synergistic mechanism linked to improved insulin sensitivity. These findings provide new insights into the importance of drug combinations in effectively combating fat loss in advanced cachexia.

Decreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia

Cancer cachexia is a complex metabolic disorder accounting for ~20% of cancer-related deaths, yet its metabolic landscape remains unexplored. Here, we report a decrease in B vitamin-related liver enzymes as a hallmark of systemic metabolic changes occurring in cancer cachexia. Metabolomics of multiple mouse models highlights cachexia-associated reductions of niacin, vitamin B6, and a glycine-related subset of one-carbon (C1) metabolites in the liver. Integration of proteomics and metabolomics reveals that liver enzymes related to niacin, vitamin B6, and glycine-related C1 enzymes dependent on B vitamins decrease linearly with their associated metabolites, likely reflecting stoichiometric cofactor-enzyme interactions. The decrease of B vitamin-related enzymes is also found to depend on protein abundance and cofactor subtype. These metabolic/proteomic changes and decreased protein malonylation, another cachexia feature identified by protein post-translational modification analysis, are reflected in blood samples from mouse models and gastric cancer patients with cachexia, underscoring the clinical relevance of our findings.

THU515 Vitamin D Binding Protein Induces Skeletal Muscle Atrophy And Contributes To Cancer-associated Muscle Wasting

Abstract Disclosure: T. Raiteri: None. S. Reano: None. A. Scircoli: None. I. Zaggia: None. F. Prodam: None. N. Filigheddu: None. Vitamin D binding protein (VDBP), encoded by the Gc gene, is a multifunctional serum glycoprotein synthesized by hepatocytes, whose primary function is the transport of vitamin D metabolites in the bloodstream. In addition, VDBP enhances the chemotactic activity of neutrophil chemoattractants and takes part in the actin-scavenger system by acting as a monomeric G-actin-binding protein. Several studies have reported a correlation between increased levels of VDBP and various pathologies often associated with muscle wasting, including different types of tumors. Given these findings, we hypothesized that VDBP may play a role in muscle atrophy and cancer-associated muscle wasting and investigated its direct effects on skeletal muscle homeostasis in vitro and in vivo. We showed that, in C2C12 myotubes, VDBP uptake through megalin-mediated endocytosis induced mitochondrial dysfunction and exacerbation of mitophagy that resulted in atrophy. Furthermore, VDBP treatment impaired myoblast differentiation and the formation and stability of acetylcholine receptor (AChR) clusters, an in vitro model of neuromuscular junctions (NMJ). The main molecular mechanism behind the atrophic effect of VDBP is the perturbation of intracellular actin dynamics due to VDBP's ability to bind G-actin. To assess if VDBP has a causative role in muscle homeostasis also in vivo, we experimentally induced the expression of VDBP in Gc knock-out mice (VDBP KO) by adeno-associated virus (AAV)-mediated gene delivery, and we observed that a relatively small amount of circulating VDBP was sufficient to affect muscle performances and reduce muscle mass. Moreover, coherently with the in vitro data, VDBP induced morphological abnormalities in the NMJ. Coherently with the upregulation of VDBP observed in cancer patients, we detected an increase of VDBP in two commonly used models of cancer cachexia, C26 colon carcinoma and Lewis Lung Carcinoma (LLC) tumor-bearing mice. To test the hypothesis that VDBP could play a role in cancer-associated muscle wasting, we induced cancer cachexia in VDBP KO mice by inoculating LLC cells. Tumor-bearing VDBP KO mice preserved their body weight and performances, and the muscle loss and NMJ dismantling were minimal compared to cachectic WT mice. Although the primary function of VDBP is the transport of vitamin D metabolites, we demonstrated that VDBP acts as a hormone per se, having a direct pro-atrophic activity on skeletal muscle. Altogether, our data suggest that VDBP is a new player in the onset of cancer-associated muscle wasting, thus representing a potential therapeutic target to treat cancer cachexia. Presentation: Thursday, June 15, 2023

Efficacy and safety of herbal medicines intervention for cachexia associated with cancer: A systematic review and meta-analysis.

As a worldwide public health issue, cancer-induced cachexia can result in decreasing physical function and survival rate. However, the therapeutic effects of conventional approaches, including pharmacotherapy, exercise and nutritional intervention, are far from satisfactory. Herbal medicines (HMs), especially Traditional Chinese Medicine (TCM), are reported to effectively treat cachexia for centuries. The inclusion criteria of all participants in this study pointed to the diagnosis of cachexia, the trial group used herbal medicine (HM) in complementary and alternative medicine, etc. Twelve databases, including EMbase, PubMed, Web of science, Cochrane CENTRAL, CINAHL, CINAHLPlus, PsycINFO, AMED, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Chongqing VIP (CQVIP) were retrieved from inception to March 28, 2022. We conducted the meta-analysis utilizing RevMan 5.3. A trial sequential analysis (TSA) was conducted to assess the adequacy of the sample size for the outcomes. We have registered the protocol and the registration number was CRD42022336446. A total of 66 studies were included, containing 3654 patients diagnosed with cancer cachexia, of which 1833 patients were assigned to the trial group and 1821 patients were treated in the control group. Outcomes cover the primary indicator KPS (RR = 1.84, 95%CI = [1.61, 2.09], p < 0.00001), and other outcomes including adverse events rate (RR = 0.37, 95%CI = [0.23, 0.58], p < 0.0001), albumin (MD = 2.14, 95%CI = [1.56, 2.71], p < 0.00001), haemoglobin (MD = 4.88, 95%CI = [3.26, 6.50], p < 0.00001), TCM syndrome effect (MD = 1.47, 95%CI = [1.31, 1.65], p < 0.00001), effect of weight (RR = 1.62, 95%CI = [1.34, 1.95], p < 0.00001), effect of appetite (RR = 1.23, 95%CI = [1.13, 1.34], p < 0.00001), FAACT (RR = 7.81, 95%CI = [6.12, 9.50], p < 0.00001), PG-SGA (MD = -2.16, 95%CI = [-2.65, -1.67], p < 0.00001) and QOL (MD = 5.76, 95%CI = [4.04, 7.48], p < 0.00001), suggesting that HMs or HMs combined with conventional treatment have an ameliorating effect on cachexia in each respect. Subgroup analysis showed that the five HMs with the best effect on improving KPS and their optimal doses were Coicis Semen (Yiyiren) in 10 g group, Citri Reticulatae Pericarpium (Chenpi) in 15 g group, Dioscoreae Rhizoma (Shanyao) in 10 g group, Ophiopogonis Radix (Maidong) in 10 g group and Ginseng Radix Et Rhizoma (Renshen) in 20 g group. In addition, there were HM combinations of levels 2-6. Egger's test showed publication bias for five outcomes. HMs have a significant effect on improving cancer cachexia on FAACT, TCM syndrome, KPS, QOL, appetite, nutritional status (evaluated by PG-SGA scale), weight, levels of albumin and haemoglobin. And the Adverse events rate is less than that of Western Medicine. The herbs with the best curative effect and their optimal dose were Dioscoreae R. (10 g), Citri R.P. (15 g), Coicis S. (10 g), Ophiopogonis R. (10 g) and Ginseng R.E.R. (20 g). Due to the quality of included studies is not high, further high-quality studies are needed to firmly establish the clinical efficacy of HM.

SAT670 Is Myostatin A Biomarker Of Skeletal Muscle Mass?

Abstract Disclosure: L. Orioli: None. S. Samaras: None. P. Lause: None. M. de Barsy: None. J.M. Thissen: None. A. Loumaye: None. Rationale: Our study aims to determine whether myostatin is a biomarker of muscle mass in cancer cachexia and obesity. Methods: The ACTICA study included cancer patients with and without cachexia. The MYDIASECRET study included obese patients evaluated before and 3 months after bariatric surgery. Body composition was assessed using bioelectrical impedance analysis (BIA101 device, Akern). Skeletal muscle mass (SMM) and appendicular SMM (ASMM) were calculated from Janssen’s and Sergi’s equations, respectively. Results were expressed as indexes (kg/m²). Myostatin plasma concentrations were determined using ELISA. Spearman’s coefficient was used to correlate muscle mass indexes and myostatin. Results: The ACTICA study included 143 patients of whom 70 with cachexia. SMM index (SMMI) and ASMM index (ASMMI) were lower in patients with cachexia compared to those without cachexia (SMMI: 8.0 kg/m² [6.7-9.5] vs 9.0 kg/m² [7.8-10.1], p=0.004; ASMMI: 6.2 kg/m² [5.5-7.1] vs 7.2 kg/m² [6.4-7.8], p&amp;lt;0.001). Myostatin was also lower in patients with cachexia (1434 pg/mL [999-2118] vs 2149 pg/mL [1551-2984], p&amp;lt;0.001). Myostatin was positively correlated with SMMI and ASMMI (SMMI: R=0.500, p&amp;lt;0.001; ASMMI: R=0.479, p&amp;lt;0.001). The MYDIASECRET study included 62 patients. SMMI and ASMMI were decreased after surgery (SMMI: -0.8 kg/m², p&amp;lt;0.001; ASMMI: -1.1 kg/m², p&amp;lt;0.001). Myostatin was also decreased after surgery (1773 pg/mL [1440-2309] vs 2582 pg/mL [1708-3522], p&amp;lt;0.001). Myostatin was positively correlated with SMMI before (R=0.388, p=0.002) and after surgery (R=0.435, p&amp;lt;0.001). Change in myostatin after surgery was also positively correlated with change in SSMI (R=0.287, p=0.023). Conclusion: Myostatin is positively correlated with muscle mass indexes in different conditions, suggesting its potential role as a biomarker of muscle mass. Presentation: Saturday, June 17, 2023

Peripheral insulin resistance is early, progressive, and correlated with cachexia in Walker-256 tumor-bearing rats.

Insulin (INS) resistance is often found in cancer-bearing, but its correlation with cachexia development is not completely established. This study investigated the temporal sequence of the development of INS resistance and cachexia to establish the relationship between these factors in Walker-256 tumor-bearing rats (TBrats). INS hepatic sensitivity and INS resistance-inducing factors, such as free fatty acids (FFA) and tumor necrosis factor-α (TNF-α), were also evaluated. Studies were carried out on Days 2, 5, 8, and/or 12 after inoculation of tumor cells in rats. The peripheral INS sensitivity was assessed by theINS tolerance testand the INS hepatic sensitivity in in situ liver perfusion. TBrats with 5, 8, and 12 days of tumor, but not 2 days, showed decreased peripheral INS sensitivity (INS resistance), retroperitoneal fat, and body weight, compared to healthy rats, which were more pronounced on Day 12. Gastrocnemius muscle wasting was observed only on Day 12 of tumor. The peripheral INS resistance was significantly correlated (r = -.81) with weight loss. Liver INS sensitivity of TBrats with 2 and 5 days of tumor was unchanged, compared to healthy rats. TBrats with 12 days of tumor showed increased plasma FFA and increased TNF-α in retroperitoneal fat and liver, but not in the gastrocnemius, compared to healthy rats. In conclusion, peripheral INS resistance is early, starts along with fat and weight loss and before muscle wasting, progressive, and correlated with cachexia, suggesting that it may play an important role in the pathogenesis of the cachectic process in TBrats. Therefore, early correction of INS resistance may be a therapeutic approach to prevent and treat cancer cachexia.

The Cancer Cachexia Index Can Be Used to Prognostically Predict Patients with Gastric Cancer Undergoing Gastrectomy

Introduction: Cancer cachexia occurs in cancer patients more frequently as the cancer progresses, with a negative impact on treatment outcomes. In this study, we sought to clarify the clinical impact of a cancer cachexia index (CXI) in patients with gastric cancer (GC) undergoing gastrectomy. Methods: Between January 2013 and December 2018, we reviewed data from 556 patients treated for GC at our hospital. CXI was calculated using skeletal muscle index (SMI), serum albumin, and neutrophil-lymphocyte ratios (NLR). Patients were divided into high (n = 414) or low CXI (n = 142) groups. We investigated the clinical impact of CXI in patients with GC undergoing gastrectomy. Results: Multivariate analyses of 5-year overall survival (OS) and cancer-specific survival (CSS) rates indicated that a low CXI was independently associated with unfavorable outcomes for patients with GC. In multivariate analyses, SMI was independent predictor of OS but not CSS. NLR was not an independent predictor of either OS or CSS. Complication incidences (≥ Clavien Dindo 3) were non-significantly higher in the low (vs. high) CXI group. Conclusion: CXI was a more valuable prognostic biomarker when compared with SMI or NLR in GC patients undergoing gastrectomy. We suggest that patients with low CXI values should be given more comprehensive treatment, including exercise and nutritional therapy to improve clinical outcomes.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors. Considering that the continuous endothelium in WAT is the first line of contact with circulating factors, we postulated whether the endothelium itself may orchestrate tissue remodeling. Here, we show using human and mouse cancer models that during precachexia, tumors overactivate Notch1 signaling in distant WAT endothelium. Sustained endothelial Notch1 signaling induces a WAT wasting phenotype in male mice through excessive retinoic acid production. Pharmacological blockade of retinoic acid signaling was sufficient to inhibit WAT wasting in a mouse cancer cachexia model. This demonstrates that cancer manipulates the endothelium at distant sites to mediate WAT wasting by altering angiocrine signals.

Oncometabolite D-2-hydroxyglutarate—dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia

Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.

Exosomal EIF5A derived from Lewis lung carcinoma induced adipocyte wasting in cancer cachexia

Cancer cachexia is a systemic inflammation-driven syndrome, characterized by muscle atrophy and adipose tissue wasting, with progressive weight loss leading to serious impairment of physiological function. Extracellular vesicles (EVs) derived from cancer cells play a significant role in adipocyte lipolysis, yet the mechanism remain uneclucidated. In this study, EVs derived from Lewis lung carcinoma (LLC) cells were extracted and characterized. 3T3-L1 and HIB1B adipocytes were cultured with conditioned medium or EVs from LLC, and LLC cells were used to establish a cancer cachexia mouse model. EVs derived from LLC cells were taken up by 3T3-L1 and HIB1B adipocytes, and derived exosomal EIF5A protein-induced lipolysis of adipocytes. High level of EIF5A was expressed in EVs from LLC cells, exosomal EIF5A is linked to lipid metabolism. Elevated expression of EIF5A is associated with shorter overall survival in lung cancer patients. Western blots, glycerol release and Oil red O staining assays were used to evaluate lipolysis of adipocytes. The reduction of lipolysis in 3T3-L1 and HIB1B adipocytes is achieved through silencing EIF5A or treating with pharmacologic inhibitor GC7 in vitro, and suppressing the expression of EIF5A in LLC cells by infected with shRNA or GC7 treatment partly alleviated white and brown adipose tissue lipolysis in vivo. Mechanistically, EIF5A directly binds with G protein-coupled bile acid receptor 1 (GPBAR1) mRNA to promote its translation and then activates cAMP response element binding protein (CREB) signaling pathway to induce lipolysis. This study demonstrates that exosomal EIF5A from LLC cells, with hypusinated EIF5A, has a lipolytic effect on adipocyte and adipose tissues in cancer cachexia model. Exosomal EIF5A could be involved in lipolysis and these findings indicate that a novel regulator and potential target for cachexia treatment.

Cancer Cachexia: Underlying Mechanisms and Potential Therapeutic Interventions.

Cancer cachexia, a multifactorial metabolic syndrome developed during malignant tumor growth, is characterized by an accelerated loss of body weight accompanied by the depletion of skeletal muscle mass. This debilitating condition is associated with muscle degradation, impaired immune function, reduced functional capacity, compromised quality of life, and diminished survival in cancer patients. Despite the lack of the known capability of fully reversing or ameliorating this condition, ongoing research is shedding light on promising preclinical approaches that target the disrupted mechanisms in the pathophysiology of cancer cachexia. This comprehensive review delves into critical aspects of cancer cachexia, including its underlying pathophysiological mechanisms, preclinical models for studying the progression of cancer cachexia, methods for clinical assessment, relevant biomarkers, and potential therapeutic strategies. These discussions collectively aim to contribute to the evolving foundation for effective, multifaceted counteractive strategies against this challenging condition.

Modelling three-dimensional cancer-associated cachexia and therapy: The molecular basis and therapeutic potential of interleukin-6 transignalling blockade.

Causes and mechanisms underlying cancer cachexia are not fully understood, and currently, no therapeutic approaches are available to completely reverse the cachectic phenotype. Interleukin-6 (IL-6) has been extensively described as a key factor in skeletal muscle physiopathology, exerting opposite roles through different signalling pathways. We employed a three-dimensional ex vivo muscle engineered tissue (X-MET) to model cancer-associated cachexia and to study the effectiveness of selective inhibition of IL-6 transignalling in counteracting the cachectic phenotype. Conditioned medium (CM) derived from C26 adenocarcinoma cells was used as a source of soluble factors contributing to the establishment of cancer cachexia in the X-MET model. A dose of 1.2ng/mL of glycoprotein-130 fused chimaera (gp130Fc) was added to cachectic culture medium to neutralize IL-6 transignalling. C26-conditioned medium induced a cachectic-like phenotype in the X-MET, leading to a decline of muscle mass (-60%; P<0.001), a reduction in myosin expression (-92.4%; P<0.005) and a reduction of the contraction frequency spectrum (-94%). C26-conditioned medium contains elevated amounts of IL-6 (8.61±4.09pg/mL) and IL6R (56.85±10.96pg/mL). These released factors activated the signal transducer and activator of transcription 3 (STAT3) signalling in the C26_CM X-MET system (phosphorylated STAT3/TOTAL +54.6%; P<0.005), which in turn promote an enhancement of Il-6 (+69.2%; P<0.05) and Il6r (+43%; P<0.05) gene expression, suggesting the induction of a feed-forward loop. The selective neutralization of IL-6 transignalling, by gp130Fc, in C26_CM X-MET prevented the hyperactivation of STAT3 (-55.8%; P<0.005), countered the reduction of cross-sectional area (+28.2%; P<0.05) and reduced the expression of proteolytic factors including muscle ring finger-1 (-88%; P<0.005) and ATROGIN1 (-92%; P<0.05), thus preserving the robustness and increasing the contractile force (+20%) of the three-dimensional muscle system. Interestingly, the selective inhibition of IL-6 transignalling modulated gene regulatory networks involved in myogenesis and apoptosis, normalizing the expression of pro-apoptotic miRNAs, including miR-31 (-53.2%; P<0.05) and miR-34c (-65%; P<0.005), and resulting in the reduction of apoptotic pathways highlighted by the sensible reduction of cleaved caspase 3 (-92.5%; P<0.005) in gp130Fc-treated C26_CM X-MET. IL-6 transignalling appeared as a promising target to counter cancer cachexia-related alterations. The X-MET model has proven to be a reliable drug-screening tool to identify novel therapeutic approaches and to test them in preclinical studies, significantly reducing the use of animal models.

Modified Controlling Nutritional Status (mCONUT) serves as a promising prognostic factor in patients with cancer cachexia

BackgroundMalnutrition and systemic inflammation are considered 2 hallmarks of cancer cachexia. Our study aimed to construct a modified Controlling Nutritional Status by introducing C-reactive protein as an inflammatory parameter and investigate its prognostic value in patients with cancer cachexia. MethodsThis multicenter cohort study included 5221 patients with cancer, among whom 1719 were diagnosed with cachexia. Concordance index and receiver operating characteristic curves were used to compare prognostic values between the 2 systems. The primary outcome was overall survival, and comprehensive survival analyses were performed. The secondary outcomes were short-term survival, malnutrition, and quality of life. ResultsDuring the median follow-up of 17.47 mo, 813 deaths were recorded. The modified Controlling Nutritional Status was more accurate than Controlling Nutritional Status in predicting survival in patients with cancer cachexia. Patients in the high Controlling Nutritional Status/modified Controlling Nutritional Status group had a significantly shorter overall survival. Multivariate Cox analysis confirmed high Controlling Nutritional Status (hazard ratio = 1.34, 95% CI, 1.13–1.58; P < 0.001) and modified Controlling Nutritional Status (hazard ratio = 1.46; 95% CI, 1.26–1.69; P < 0.001) were independent risk factors for survival, adjusting for confounders. In subgroup analyses, a high modified Controlling Nutritional Status score had a significantly negative effect on survival in cachexia patients with upper gastrointestinal and colorectal cancer, especially for advanced-stage (stages III and IV) patients. The risk of short-term mortality and experiencing malnutrition rose to 1.48 and 1.13 times, respectively, in the high modified Controlling Nutritional Status group, as well as that for poorer life quality. ConclusionThe modified Controlling Nutritional Status group comprehensively reflects nutritional, immune, and inflammatory status and serves as a powerful prognostic scoring system in patients with cancer cachexia.

Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia.

Previous studies have shown that inhibition of TNF family member FN14 (gene: TNFRSF12A) in colon tumors decreases inflammatory cytokine expression and mitigates cancer-induced cachexia. However, the molecular mechanisms underlying the regulation of FN14 expression remain unclear. Tumor microenvironments are often devoid of nutrients and oxygen, yet how the cachexic response relates to the tumor microenvironment and, importantly, nutrient stress is unknown. Here, we looked at the connections between metabolic stress and FN14 expression. We found that TNFRSF12A expression was transcriptionally induced during glutamine deprivation in cancer cell lines. We also show that the downstream glutaminolysis metabolite, alpha-ketoglutarate (aKG), is sufficient to rescue glutamine-deprivation-promoted TNFRSF12A induction. As aKG is a co-factor for histone de-methylase, we looked at histone methylation and found that histone H3K4me3 at the Tnfrsf12a promoter is increased under glutamine-deprived conditions and rescued via DM-aKG supplementation. Finally, expression of Tnfrsf12a and cachexia-induced weight loss can be inhibited in vivo by DM-aKG in a mouse cancer cachexia model. These findings highlight a connection between metabolic stress and cancer cachexia development.

A nomogram based on clinical characteristics and nutritional indicators for relative and absolute weight loss during radiotherapy in initially inoperable patients with locally advanced esophageal squamous cell carcinoma

ObjectiveRadiation for locally advanced esophageal squamous cell carcinoma often is accompanied by radiation esophagitis, which interferes with oral intake. We aimed to develop a nomogram model to identify initially inoperable patients with relative and absolute weight loss who need prophylactic nutritional supplementation. MethodsA total of 365 initially inoperable patients with locally advanced esophageal squamous cell carcinoma receiving radiotherapy between January 2018 and December 2022 were included in the study, which was divided into discovery and validation cohorts. Receiver operating characteristic and Kaplan-Meier curve analyses were performed to compare the areas under the curve and survival benefits. ResultsA total of 42.2% (154 of 365) of the patients had been diagnosed with cancer cachexia. The malnourished group had a higher interruption rate of radiotherapy and number of complication diseases (P < 0.05). Meanwhile, patients with malnutrition had lower lymphocytes and prognostic nutritional index (P < 0.05). The combined index showed a higher area under the curve value (0.67; P < 0.001) than number of complication diseases (area under the curve = 0.52) and prognostic nutritional index (area under the curve = 0.49) for relative weight loss (≥ 5%). Similarly, the combined index had a higher area under the curve value (0.79; P < 0.001) than number of complication diseases (area under the curve = 0.56), treatment regimens (area under the curve = 0.56), subcutaneous fat thickness (area under the curve = 0.60), pretreatment body weight (area under the curve = 0.61), neutrophils (area under the curve = 0.56), and prognostic nutritional index (area under the curve = 0.50) for absolute weight loss (≥ 5 kg). Absolute and relative weight loss remained independent prognostic factors, with short overall survival rates compared with the normal group (P < 0.05). Patients with high nomogram scores supported by nutritional intervention had less weight loss, better nutrition scores, and increased plasma CD8+ T cells, and interferon gamma. ConclusionsWe developed a nomogram model that was intended to estimate relative and absolute weight loss in initially inoperable patients with locally advanced esophageal squamous cell carcinoma during radiotherapy, which might help facilitate an objective decision on prophylactic nutritional supplementation.