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Association between ANGPTL-4 and the proinflammatory process in cancer cachexia patients.

ABSTRACT: Background:Contradictory results are reported for the role of angiopoietin-like 4 (ANGPTL-4) in the development of cancer-cachexia and inflammation, given its importance in angiogenesis and inflammatory signaling. Our aim was to analyze the levels of ANGPTL-4 in colorectal cancer patients with a stable weight and those with cachexia in order to establish a relationship between ANGPTL-4 and the inflammatory process. Results:Plasma and tumor levels of ANGPTL-4 were higher in CC in comparison to other groups. A positive association was verified between plasmatic ANGPTL-4 and NF?B levels in tumor from CC. In WSC, we identified an association between the plasmatic ANGPTL-4, IL-15, and IL-10 in tumor and IL-15 in MES. Increased levels of NF?B and TNF-R1 in MES were detected in CC in comparison to WSC. Specifically in CC-group, a positive correlation was found between ANGPTL-4 levels and those of IL-1?, TNF-?, and NF?B in tumor, along with an association between ANGPTL-4 levels with IL-1? and MCP-1 levels in tumor; and ANGPTL-4 and IL-1? levels in MES. Methods:We studied 102 patients, who were divided into three groups: control patients (C, n=37), cancer patients with a stable weight (WSC, n=23), and cancer-cachexia patients (CC, n=42). Samples of plasma, tumor, mesenteric (MES) and subcutaneous adipose tissue were removed for the determination of ANGPTL-4 levels and other proinflammatory factors. Conclusions:ANGPTL-4 levels were higher in plasma and tumor of CC-group, and positively associated with pro-inflammatory and pro-tumorigenic factors. Our results suggest an opposite effect of ANGPTL-4 depending on the concentration and presence of cachexia.

SUBMITTER: Neto NIP

PROVIDER: S-EPMC6849656 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Association between ANGPTL-4 and the proinflammatory process in cancer cachexia patients.

Neto Nelson Inácio Pinto NIP Boldarine Valter Tadeu VT Hachul Ana Claudia Losinskas ACL Oyama Lila Missae LM Lima Joanna Darck Carola Correia JDCC Fernandez Estefania Simoes ES Otoch José Pinhata JP de Alcântara Paulo Sérgio Martins PSM Tokeshi Flavio F Seelaender Marilia Cerqueira Leite MCL Oller do Nascimento Claudia Maria da Penha CMDP

Oncotarget 20191105 60

<h4>Background</h4>Contradictory results are reported for the role of angiopoietin-like 4 (ANGPTL-4) in the development of cancer-cachexia and inflammation, given its importance in angiogenesis and inflammatory signaling. Our aim was to analyze the levels of ANGPTL-4 in colorectal cancer patients with a stable weight and those with cachexia in order to establish a relationship between ANGPTL-4 and the inflammatory process.<h4>Results</h4>Plasma and tumor levels of ANGPTL-4 were higher in CC in c ...[more]

PMID: 31741709

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Project description:BACKGROUND:Ovarian cancer is the fifth leading cause of cancer-related deaths amongst women in the United States. Cachexia is the primary cause of death in approximately 30% of cancer patients, and is often evidenced in ovarian cancer patients. We tested the steroidal lactone Withaferin A to examine if it could ameliorate ovarian cancer-induced cachexia. METHODS:Six-week-old severely immunodeficient female mice were xenografted with the ovarian cancer cell line A2780 followed by treatment with Withaferin A or vehicle. Changes in functional grip strength were assessed on a weekly basis. Postmortem, H&E staining was performed on skeletal muscle sections and immunofluorescent immunohistochemistry was performed on skeletal muscle and tumor sections. The levels of NF-?B-related proinflammatory cytokines were assessed in the xenografted tumors and in resident host skeletal muscle. RESULTS:Xenografting of the A2780 cell line resulted in a significant rate of mortality, which was attenuated by a therapeutic dosage of Withaferin A. Mice that received vehicle treatment following xenografting exhibited functional muscle decline over the course of the study. The therapeutic dosage Withaferin A treatment attenuated this reduction in grip strength, whereas the supratherapeutic dosage of Withaferin A was found to be toxic/lethal and demonstrated a further decline in functional muscle strength and an increased rate of mortality on par with vehicle treatment. At a histological level, the vehicle treated tumor-bearing mice exhibited a profound reduction in myofibrillar cross-sectional area compared to the vehicle treated tumor-free control group. The atrophic changes induced by the xenografted tumor were significantly ameliorated by treatment with Withaferin A. The combination of functional muscle weakening and induction of myofibrillar atrophy corroborate a cachectic phenotype, which was functionally rescued by Withaferin A. Further, treatment completely abolished the slow-to-fast myofiber type conversion observed in the settings of cancer-induced cachexia. In both host resident skeletal muscle and the xenografted tumors, we report an increase in NF-?B-related proinflammatory cytokines that was reversed by Withaferin A treatment. Finally, we demonstrated that Withaferin A significantly downregulates cytosolic and nuclear levels of phospho-p65, the active canonical NF-?B transcription factor, in xenografted tumors. CONCLUSIONS:Cumulatively, our results demonstrate a previously overlooked role of Withaferin A in a xenograft model of ovarian cancer. We propose mechanisms by which Withaferin A reduces NF-?B-dependent pro-inflammatory cytokine production leading to an attenuation of the cachectic phenotype in an i.p. xenograft model of ovarian cancer.

Project description:BackgroundAlthough systemic inflammation is an important feature of the cancer cachexia, studies on the association between systemic inflammation and prognostic of cancer cachexia are limited. The objective of this study is to evaluate whether the neutrophil-to-lymphocyte ratio (NLR) is associated with outcome and quality of life for patients with cancer cachexia and investigated any interaction between NLR and the clinical parameters.MethodsThis is a multicentre cohort study of 2612 cancer patients suffering from cachexia diagnosed between June 2012 and December 2019. The main parameters measured were overall survival (OS) time and all-cause mortality. The association between NLR and all-cause mortality was evaluated using hazard ratios (HRs) and the restricted cubic spline model with a two-sided P-value. Optimal stratification was used to solve threshold points. We also evaluated the cross-classification of NLR for each variable of survival.ResultsOf the 2612 participants diagnosed with cancer cachexia, 1533 (58.7%) were male, and the mean (SD) age was 58.7 (11.7) years. Over a median follow-up of 4.5 years, we observed 1189 deaths. The overall mortality rate for patients with cancer cachexia during the first 12 months was 30.2% (95%CI: 28.4%-32.0%), resulting in a rate of 226.07 events per 1000 patient-years. An increase in NLR had an inverted L-shaped dose-response association with all-cause mortality. The optimal cut-off point for NLR as a predictor of mortality in cancer patients with cachexia was 3.5. An NLR of 3.5 or greater could independently predict OS (HR, 1.51, 95%CI: 1.33-1.71). These associations were consistent across subtypes of cancer. Several potential effect modifiers were identified including gender, BMI, tumour type, KPS score and albumin in content. Increasing NLRs were independently associated with a worsening in the majority of EORTC QLQ-C30 domains. Elevated baseline NLR was associated with low response and poor survival in patients treated with immunotherapy.ConclusionsThe baseline NLR status was found to be a significant negative prognostic biomarker for patients with cachexia; this effect was independent of other known prognostic factors.

Project description:Cancer cachexia (CC) is a poorly understood cause of morbidity and mortality, which has no efficacious treatment or generally-accepted management strategy. The consensus definition for CC identified skeletal muscle loss as a key marker in the diagnosis and classification of cachexia. The importance of fat wasting however, is less understood. During cachexia, different adipose depots demonstrate differential wasting rates. Studies from animal models have suggested adipose tissue may be a key driver of muscle wasting through fat-muscle crosstalk but human studies in this area are lacking. We performed global gene expression profiling of intra-abdominal (IAAT) and subcutaneous (SAT) adipose from weight stable and cachectic cancer patients and healthy controls. Cachexia was defined as >2% weight loss plus low CT-muscularity. Biopsies of SAT and IAAT were taken from patients undergoing resection for oesophago-gastric cancer, and healthy controls (donor nephrectomy) (n=16 and 8 respectively). RNA was isolated and reverse transcribed. cDNA was hybridised to the Affymetrix Clariom S Microarray and data was analysed using R/Bioconductor. Differential expression of genes was assessed using empirical Bayes and moderated-t-statistic approaches. Category enrichment analysis was used with a tissue-specific background to examine the biological context of differentially expressed genes. Selected differentially regulated genes were validated by qPCR. ELISA for Intelectin-1 was performed on IAAT samples for the corresponding patients. The current cohort plus 12 additional patients from each group also had plasma Intelectin-1 ELISA carried out. In IAAT versus SAT comparisons there were 2101, 1722 and 1659 significantly regulated genes in the cachectic, weight stable and control groups respectively. There were 2200 significantly regulated genes from IAAT in cachectic patients compared to controls and 1253 significantly regulated genes from IAAT in weight stable cancer patients compared to controls. The gene showing the largest difference in expression was Intelectin-1 (Omentin-1) (FDR corrected p=0.0001); a novel adipocytokine associated with weight loss in other groups. Genes involving inflammation were enriched in cancer and control IAAT versus SAT though different groups of genes contributed. Energy metabolism and fat browning genesets were downregulated in cancer IAAT as were key fat browning genes (e.g. UCP1). SAT and IAAT have unique gene expression signatures. IAAT is metabolically active in cancer, and maybe a target for therapeutic manipulation. IAAT may play a fundamental role in cachexia, but the downregulation of energy metabolism genes implies a limited role for fat browning in human cachectic patients, in contrast to pre-clinical models.

Project description:Background Loss of skeletal muscle mass in advanced cancer is recognized as an independent predictor of mortality. Mechanisms involved in this wasting process and parameters for early diagnosis are still lacking. As skeletal muscle is considered as a secretory organ, the aim of this present experimental work was to characterize the changes in muscle proteome and secretome associated with cancer-induced cachexia to better understand cellular mechanisms involved in this wasting process and to identify secreted proteins which might reflect the ongoing muscle atrophy process. Methods We investigated first the changes in the muscle proteome associated with cancer-induced cachexia by using differential label-free proteomic analysis on muscle of the C26 mouse model. The differentially abundant proteins were submitted to sequential bioinformatic secretomic analysis in order to identify potentially secreted proteins. Selected reaction monitoring and Western blotting were used to verify the presence of candidate proteins at the circulating level. Their muscle source was demonstrated by assessing their gene expression in skeletal muscle and in cultured myotubes. Finally, we also investigated their regulation in muscle cells. Alterations in several molecular pathways potentially involved in muscle atrophy were highlighted using Gene ontology enrichment analyses. Results Our results revealed a dramatic increased production (2-to 25-fold) by the muscle of several acute phase reactants (APR: Haptoglobin, Serpina3n, Complement C3, Serum amyloid A1) which are also released in the circulation during C26 cancer cachexia. Their production was confirmed in other preclinical models of cancer cachexia as well as in cancer patients. The muscular origin of these APR was demonstrated by their increased expression in skeletal muscle and myotubes. Glucocorticoids and pro-inflammatory cytokines contribute directly to their increased expression in muscle cells in vitro, while the role of IL-6 in the muscular induction of these APR was demonstrated in vivo. Conclusions Cancer is associated with marked changes in muscle secretome during muscle wasting. Our study demonstrates a marked increased production of APR by skeletal muscle in pre-clinical models of cancer cachexia and in cancer patients. Further studies are required to unravel the potential role of these proteins in muscle atrophy and their interest as biomarkers of cancer cachexia.

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Association between ANGPTL-4 and the proinflammatory process in cancer cachexia patients.

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Association between ANGPTL-4 and the proinflammatory process in cancer cachexia patients.

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