IL-4 mRNA Is Downregulated in the Liver of Pancreatic Cancer Patients Suffering from Cachexia

Prokopchuk, Olga; Steinacker, Jürgen M.; Nitsche, Ulrich; Otto, Stephanie; Bachmann, Jeannine; Schubert, Elaine C.; Frieß, Helmut; Martignoni, Marc E.

doi:10.1080/01635581.2017.1247885

Cited by 20 publications

(17 citation statements)

References 29 publications

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“…Our knowledge about hepatic inflammation in human cancer cachexia is particularly scarce. Previous studies reported liver macrophage infiltration and down‐regulation of IL‐4 gene expression in liver sections of cachectic pancreatic cancer patients 64,65 . A mild cholestasis was documented in a cohort of cachectic and non‐cachectic patients with various cancer types and was characterized by an increase in serum levels of alkaline phosphatase and gamma‐glutamyl transpeptidase 66 .…”

Section: Discussionmentioning

confidence: 94%

Inflammation‐induced cholestasis in cancer cachexia

Thibaut

Sboarina

Roumain

et al. 2020

J cachexia sarcopenia muscle

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Background Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia. Methods We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two interventional studies were performed using a neutralizing interleukin 6 antibody and a bile acid sequestrant, cholestyramine. Our findings were evaluated in a cohort of 94 colorectal cancer patients with or without cachexia (43/51). Results In colon carcinoma 26 cachectic mice, we discovered alterations in five inflammatory pathways as well as in other pathways, including bile acid metabolism, fatty acid metabolism, and xenobiotic metabolism (normalized enrichment scores of −1.97, −2.16, and −1.34, respectively; all Padj < 0.05). The hepatobiliary transport system was deeply impaired in cachectic mice, leading to increased systemic and hepatic bile acid levels (+1512 ± 511.6 pmol/mg, P = 0.01) and increased hepatic inflammatory cytokines and neutrophil recruitment to the liver of cachectic mice (+43.36 ± 16.01 neutrophils per square millimetre, P = 0.001). Adaptive mechanisms were set up to counteract this bile acid accumulation by repressing bile acid synthesis and by enhancing alternative routes of basolateral bile acid efflux. Targeting bile acids using cholestyramine reduced hepatic inflammation, without affecting the hepatobiliary transporters (e.g. tumour necrosis factor α signalling via NFκB and inflammatory response pathways, normalized enrichment scores of −1.44 and −1.36, all Padj < 0.05). Reducing interleukin 6 levels counteracted the change in expression of genes involved in the hepatobiliary transport, bile acid synthesis, and inflammation. Serum bile acid levels were increased in cachectic vs. non‐cachectic cancer patients (e.g. total bile acids, +5.409 ± 1.834 μM, P = 0.026) and were strongly correlated to systemic inflammation (taurochenodeoxycholic acid and C‐reactive protein: ρ = 0.36, Padj = 0.017). Conclusions We show alterations in bile acid metabolism and hepatobiliary secretion in cancer cachexia. In this context, we demonstrate the contribution of systemic inflammation to the impairment of the hepatobiliary transport system and the role played by bile acids in the hepatic inflammation. This work paves the way to a better understanding of the role of the liver in cancer cachexia.

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Section: Discussionmentioning

confidence: 94%

Inflammation‐induced cholestasis in cancer cachexia

Thibaut

Sboarina

Roumain

et al. 2020

J cachexia sarcopenia muscle

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“…IL-4 was lower in the more cachectic G68 group. IL-4 mRNA has previously been shown to be downregulated in the liver of pancreatic cancer patients suffering from cachexia [24]. GRO is known to increase muscle fatty acid oxidation contributing to the breakdown of muscle [25].…”

Section: Discussionmentioning

confidence: 99%

Local and Systemic Cytokine Profiling for Pancreatic Ductal Adenocarcinoma to Study Cancer Cachexia in an Era of Precision Medicine

Gerber

Underwood

Judge

et al. 2018

IJMS

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Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy.

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“…IL4 has also been shown to recruit myoblasts to form mature myotubes, and further studies have demonstrated that this cytokine can exert a pro‐migratory effect in vitro . Interestingly, in pancreatic cancer patients affected by cachexia, IL4 messengers are down‐regulated in liver and muscle …”

Section: Introductionmentioning

confidence: 99%

Interleukin‐4 administration improves muscle function, adult myogenesis, and lifespan of colon carcinoma‐bearing mice

Costamagna¹,

Duelen²,

Penna

et al. 2020

J cachexia sarcopenia muscle

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Background Anorexia, body wasting, inflammation, muscle, and adipose tissue loss are hallmarks of cancer cachexia, a syndrome that affects the majority of cancer patients, impairing their ability to endure chemotherapeutic therapies and reducing their lifespan. In the last 10 years, alterations of protein turnover and impairment of adult myogenesis have been proposed as major contributing factors. Methods Muscle stem cells, including satellite cells, mesoangioblasts, and fibroadipogenic progenitors, were isolated and characterized from C26 colon carcinoma‐bearing (C26) mice. Circulating levels of interleukin‐4/13 (IL4/IL13) were analysed by ELISA, and the effects of IL4 on muscle mass and function, protein synthesis, muscle regeneration, and myogenic progenitor cell number were analysed at both functional (treadmill and grip test) and molecular levels (qRT–PCR, immunofluorescence analysis, surface sensing of translation, and western blot). The Kaplan–Meier test was used to analyse the survival curve of IL4‐treated and IL4‐untreated C26 mice. Results The administration of IL4 to C26 mice rescued muscle mass by increasing protein synthesis. The IL4 treatment improved performances and prolonged survival of C26 mice. IL4 administration re‐established both number and function of satellite cells and fibroadipogenic progenitors without affecting mesoangioblasts in C26 mice, rescuing myogenesis. Upon IL4 treatment, a high number of cytotoxic lymphocytes and type II macrophages were observed with a subsequent increase in necrotic areas of C26 tumours. Conclusions The results here presented shed new light on IL4 signalling during muscle wasting and early stages of muscle regeneration that explain the beneficial effect observed in IL4‐treated C26 mice. These findings might aid to develop therapeutic approaches to improve mobility and quality of life in cachectic patients.

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IL-4 mRNA Is Downregulated in the Liver of Pancreatic Cancer Patients Suffering from Cachexia

Abstract: We speculate that suppression of IL-4 is involved in cancer cachexia, although the exact mechanisms have to be further elucidated.

Cited by 20 publications

References 29 publications

Inflammation‐induced cholestasis in cancer cachexia

Inflammation‐induced cholestasis in cancer cachexia

Local and Systemic Cytokine Profiling for Pancreatic Ductal Adenocarcinoma to Study Cancer Cachexia in an Era of Precision Medicine

Interleukin‐4 administration improves muscle function, adult myogenesis, and lifespan of colon carcinoma‐bearing mice

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