Marked Increased Production of Acute Phase Reactants by Skeletal Muscle during Cancer Cachexia

Massart, Isabelle S; Paulissen, Geneviève; Loumaye, Audrey; Lause, Pascale; Pötgens, Sarah A.; Thibaut, Morgane M.; Balan, Estelle; Deldicque, Louise; Atfi, Azeddine; Louis, Édouard; Gruson, Damien; Bindels, Laure B.; Meuwis, Marie‐Alice; Thissen, Jean‐Paul

doi:10.3390/cancers12113221

Cited by 11 publications

(18 citation statements)

References 59 publications

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“…Although sarcopenia is well-known to be associated with worse treatment response in terms of reduced OS and RFS in GC [ 13 ], its impact on histologic response has not yet been elucidated. It can be argued that muscle mass may be involved in the drug pharmacokinetics and the synthesis of several acute-phase proteins [ 38 ] needed for the treatment response, but these results need to be confirmed due to the small sample size. Moreover, a greater pathological response may correspond to a reduction in dysphagia, and consequently, a better nutritional intake.…”

Section: Discussionmentioning

confidence: 99%

Body Composition Changes in Gastric Cancer Patients during Preoperative FLOT Therapy: Preliminary Results of an Italian Cohort Study

Rinninella

Strippoli

Cintoni³

et al. 2021

Nutrients

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Background: The impact of the new chemotherapy, fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) on body composition in gastric cancer (GC) patients remains unknown. We assessed body composition changes of GC patients receiving the FLOT regimen and their impact on treatment outcomes. Methods: Preoperative pre- and post-FLOT computed tomography (CT) scans of advanced GC patients were studied. Lumbar skeletal muscle index (SMI) and adipose indices were calculated before and after FLOT. Results: A total of 26 patients were identified between April 2019 and January 2020. Nineteen patients were sarcopenic at diagnosis. The mean BMI decreased (from 24.4 ± 3.7 to 22.6 ± 3.1; p < 0.0001) as well as the SMI (from 48.74 ± 9.76 to 46.52 ± 9.98; p = 0.009) and visceral adipose index (VAI) (from 49.04 ± 31.06 to 41.99 ± 23.91; p = 0.004) during preoperative FLOT therapy. BMI, SMI, and VAI variations were not associated with toxicity, Response Evaluation Criteria in Solid Tumors (RECIST), response, delay and completion of perioperative FLOT chemotherapy, and the execution of gastrectomy; a decrease of SMI ≥ 5% was associated with a higher Mandard tumor regression grade (p = 0.01). Conclusions: Almost three-quarters (73.1%) of GC patients were sarcopenic at diagnosis. Preoperative FLOT was associated with a further reduction in SMI, BMI, and VAI. These changes were not associated with short-term outcomes.

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Section: Discussionmentioning

confidence: 99%

Body Composition Changes in Gastric Cancer Patients during Preoperative FLOT Therapy: Preliminary Results of an Italian Cohort Study

Rinninella

Strippoli

Cintoni³

et al. 2021

Nutrients

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“…We previously showed that muscle APR production, which requires mobilization of amino acids coming from muscle proteolysis, was associated with muscle atrophy in cachexia preclinical models, and it was negatively correlated with muscularity in cachectic cancer patients. 29 Therefore, by decreasing APR synthesis, AdipoRon could indirectly protect against protein catabolism. Finally, AdipoRon hindered muscular gene expression of components of the non‐canonical NF‐κB pathway that is involved in atrogene induction during cachexia.…”

Section: Discussionmentioning

confidence: 99%

Administration of adiponectin receptor agonist AdipoRon relieves cancer cachexia by mitigating inflammation in tumour‐bearing mice

Massart,

Kouakou,

Pelet

et al. 2024

J cachexia sarcopenia muscle

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BackgroundCancer cachexia is a life‐threatening, inflammation‐driven wasting syndrome that remains untreatable. Adiponectin, the most abundant adipokine, plays an important role in several metabolic processes as well as in inflammation modulation. Our aim was to test whether administration of AdipoRon (AR), a synthetic agonist of the adiponectin receptors, prevents the development of cancer cachexia and its related muscle atrophy.MethodsThe effect of AR on cancer cachexia was investigated in two distinct murine models of colorectal cancer. First, 7‐week‐old CD2F1 male mice were subcutaneously injected with colon‐26 carcinoma cells (C26) or vehicle (CT). Six days after injection, mice were treated for 5 days with AdipoRon (50 mg/kg/day; C26 + AR) or the corresponding vehicle (CT and C26). Additionally, a genetic model, the ApcMin/+ mouse, that develops spontaneously numerous intestinal polyps, was used. Eight‐week‐old male ApcMin/+ mice were treated with AdipoRon (50 mg/kg/day; Apc + AR) or the corresponding vehicle (Apc) over a period of 12 weeks, with C57BL/6J wild‐type mice used as controls. In both models, several parameters were assessed in vivo: body weight, grip strength and serum parameters, as well as ex vivo: molecular changes in muscle, fat and liver.ResultsThe protective effect of AR on cachexia development was observed in both cachectic C26 and ApcMin/+ mice. In these mice, AR administration led to a significant alleviation of body weight loss and muscle wasting, together with rescued muscle strength (P < 0.05 for all). In both models, AR had a strong anti‐inflammatory effect, reflected by lower systemic interleukin‐6 levels (−55% vs. C26, P < 0.001 and −80% vs. Apc mice, P < 0.05), reduced muscular inflammation as indicated by lower levels of Socs3, phospho‐STAT3 and Serpina3n, an acute phase reactant (P < 0.05 for all). In addition, AR blunted circulating levels of corticosterone (−46% vs. C26 mice, P < 0.001 and −60% vs. Apc mice, P < 0.05), the predominant murine glucocorticoid known to induce muscle atrophy. Accordingly, key glucocorticoid‐responsive factors implicated in atrophy programmes were—or tended to be—significantly blunted in skeletal muscle by AR. Finally, AR protected against lipid metabolism alterations observed in ApcMin/+ mice, as it mitigated the increase in circulating triglyceride levels (−38%, P < 0.05) by attenuating hepatic triglyceride synthesis and fatty acid uptake by the liver.ConclusionsAltogether, these results show that AdipoRon rescued the cachectic phenotype by alleviating body weight loss and muscle atrophy, along with restraining inflammation and hypercorticism in preclinical murine models. Therefore, AdipoRon could represent an innovative therapeutic strategy to counteract cancer cachexia.

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“…The collagen β(1-O)galactosyltransferase type 1 ( COLGALT1 ) has been identified, whose loss of function also causes muscle atrophy [ 46 ]. Many proteins such as RPL7A have increased expression in cancer [ 47 ]. Other critical regulators of muscle atrophy such as protein arginine methyltransferases ( PRMTs ) - PRTM5 is linked by the GCN method [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Detection of Target Genes for Drug Repurposing to Treat Skeletal Muscle Atrophy in Mice Flown in Spaceflight

Manian

Orozco-Sandoval

Díaz-Martínez

et al. 2022

Genes

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Skeletal muscle atrophy is a common condition in aging, diabetes, and in long duration spaceflights due to microgravity. This article investigates multi-modal gene disease and disease drug networks via link prediction algorithms to select drugs for repurposing to treat skeletal muscle atrophy. Key target genes that cause muscle atrophy in the left and right extensor digitorum longus muscle tissue, gastrocnemius, quadriceps, and the left and right soleus muscles are detected using graph theoretic network analysis, by mining the transcriptomic datasets collected from mice flown in spaceflight made available by GeneLab. We identified the top muscle atrophy gene regulators by the Pearson correlation and Bayesian Markov blanket method. The gene disease knowledge graph was constructed using the scalable precision medicine knowledge engine. We computed node embeddings, random walk measures from the networks. Graph convolutional networks, graph neural networks, random forest, and gradient boosting methods were trained using the embeddings, network features for predicting links and ranking top gene-disease associations for skeletal muscle atrophy. Drugs were selected and a disease drug knowledge graph was constructed. Link prediction methods were applied to the disease drug networks to identify top ranked drugs for therapeutic treatment of skeletal muscle atrophy. The graph convolution network performs best in link prediction based on receiver operating characteristic curves and prediction accuracies. The key genes involved in skeletal muscle atrophy are associated with metabolic and neurodegenerative diseases. The drugs selected for repurposing using the graph convolution network method were nutrients, corticosteroids, anti-inflammatory medications, and others related to insulin.

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Marked Increased Production of Acute Phase Reactants by Skeletal Muscle during Cancer Cachexia

Cited by 11 publications

References 59 publications

Body Composition Changes in Gastric Cancer Patients during Preoperative FLOT Therapy: Preliminary Results of an Italian Cohort Study

Body Composition Changes in Gastric Cancer Patients during Preoperative FLOT Therapy: Preliminary Results of an Italian Cohort Study

Administration of adiponectin receptor agonist AdipoRon relieves cancer cachexia by mitigating inflammation in tumour‐bearing mice

Detection of Target Genes for Drug Repurposing to Treat Skeletal Muscle Atrophy in Mice Flown in Spaceflight

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