Association between ANGPTL-4 and the proinflammatory process in cancer cachexia patients.
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ABSTRACT:
SUBMITTER: Neto NIP
PROVIDER: S-EPMC6849656 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
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]
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Project description:Weight loss and hematogenous metastases are poor prognosis factors in lung cancer patients that can but do not necessarily co-occur. We retrospectively investigated the clinical association between cachexia, tumor characteristics (such as metastatic burden and mutational status), and treatment in lung cancer patients. The medical records of 394 lung cancer patients from two institutions (Columbia University, USA and Tohoku University, Japan) were reviewed. Information collected included the presence of cachexia, histologic subtype, tumor stage, number of metastases, mutation status, treatment, and survival. Descriptive statistics were performed. Only stage IV patients exhibited >5% weight loss (0.8%, 2.2%, 3.6%, and 5.1%, for stages I to IV; P = 0.0001). Patients with metastases developed cachexia more often than patients without metastases independent of treatment (6.0% and 7.1% weight loss in patients with metastases vs. 2.5% and 2.0% in patients without metastases, before [P = 0.0001] and after [P < 0.0001] treatment, respectively). The change in number of metastatic sites over time correlated with increasing weight loss (5.2%, 10.6%, 13.4%, and 13.4%, for an increase of 0, 1, 2, and ?3 metastatic sites, from initial diagnosis to the endpoint; P < 0.0001). Patients with cachexia had worse survival than patients without cachexia (hazard ratio, 2.94; 95% confidence interval, 2.08-4.16; P < 0.0001). Tumors with mutated KRAS were associated with an increased risk of weight loss (11.4% weight loss in patients with mutated KRAS vs. 6.0% in patients with wild-type KRAS; P = 0.0011). Our findings suggest that the capabilities of lung cancer to metastasize and cause cachexia might be linked intrinsically and are independent of treatments administered. KRAS-mutated tumors were more commonly associated with cachexia.
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Project description:BackgroundThe cachexia index is a useful predictor for cancer cachexia and prognostic assessment. However, its use is limited because of high testing costs and complicated testing procedures. Thus, in this study, we aimed to develop a hand grip strength (HGS)-based cancer cachexia index (H-CXI) as a potential predictor of cancer cachexia and prognosis in patients with cancer.MethodsHere, 14 682 patients with cancer were studied, including the discovery (6592), internal validation (2820) and external validation (5270) cohorts. The H-CXI was calculated as [HGS (kg)/height (m)2 × serum albumin (g/L)]/neutrophil-to-lymphocyte ratio. The Kaplan-Meier method was used to create survival curves, and the log-rank test was used to compare time-event relationships between groups. A Cox proportional hazard regression model was used to determine independent risk factors for overall survival (OS). Logistic regression analysis was used to assess the association of the H-CXI with short-term outcomes and cancer cachexia.ResultsThere was a significant non-linear relationship between the H-CXI and OS in all cohorts. Patients with a low H-CXI had significantly lower OS than those with a high H-CXI in the discovery cohort (6-year survival percentage: 55.72% vs. 76.70%, log-rank P < 0.001), internal validation cohort (6-year survival percentage: 55.81% vs. 76.70%, log-rank P < 0.001), external validation cohort (6-year survival percentage: 56.05% vs. 75.48%, log-rank P < 0.001) and total cohort (6-year survival percentage: 55.86% vs. 76.27%, log-rank P < 0.001). Notably, the prognostic stratification effect of the H-CXI in patients with advanced-stage disease was more significant than that in patients with early-stage disease. The multivariate Cox proportional risk regression model confirmed that a low H-CXI negatively affected the prognosis of patients with cancer in the discovery cohort [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.71-0.80, P < 0.001], internal validation cohort (HR 0.79, 95 %CI 0.72-0.86, P < 0.001), external validation cohort (HR 0.84, 95% CI 0.79-0.89, P < 0.001) and total cohort (HR 0.80, 95% CI 0.77-0.83, P < 0.001). Multivariate logistic regression models showed that a low H-CXI was an independent risk factor predicting adverse short-term outcomes and cancer cachexia in patients with cancer.ConclusionsThe simple and practical H-CXI is a promising predictor for cancer cachexia and prognosis in patients with cancer.
| S-EPMC9891920 | biostudies-literature
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.
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Project description:Cachexia is a syndrome characterized by marked involuntary loss of body weight. Recently, adipose tissue (AT) wasting has been shown to occur before the appearance of other classical cachexia markers. We investigated the composition and rearrangement of the extracellular matrix, adipocyte morphology and inflammation in the subcutaneous AT (scAT) pad of gastrointestinal cancer patients.Surgical biopsies for scAT were obtained from gastrointestinal cancer patients, who were signed up into the following groups: cancer cachexia (CC, n = 11), weight-stable cancer (WSC, n = 9) and weight-stable control (non-cancer) (control, n = 7). The stable weight groups were considered as those with no important weight change during the last year and body mass index <25 kg/m(2). Subcutaneous AT fibrosis was quantified and characterized by quantitative PCR, histological analysis and immunohistochemistry.The degree of fibrosis and the distribution and collagen types (I and III) were different in WSC and CC patients. CC patients showed more pronounced fibrosis in comparison with WSC. Infiltrating macrophages surrounding adipocytes and CD3 Ly were found in the fibrotic areas of scAT. Subcutaneous AT fibrotic areas demonstrated increased monocyte chemotactic protein 1 (MCP-1) and Cluster of Differentiation (CD)68 gene expression in cancer patients.Our data indicate architectural modification consisting of fibrosis and inflammatory cell infiltration in scAT as induced by cachexia in gastrointestinal cancer patients. The latter was characterized by the presence of macrophages and lymphocytes, more evident in the fibrotic areas. In addition, increased MCP-1 and CD68 gene expression in scAT from cancer patients may indicate an important role of these markers in the early phases of cancer.
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Project description:Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular junction (NMJ) may play a key role in cachexia, but this has yet to be investigated in human patients. Here, high-resolution morphological analyses were undertaken on NMJs of rectus abdominis obtained from patients undergoing upper GI cancer surgery compared with controls (N = 30; n = 1,165 NMJs). Cancer patients included those with cachexia and weight-stable disease. Despite the low skeletal muscle index and significant muscle fiber atrophy (P < 0.0001) in patients with cachexia, NMJ morphology was fully conserved. No significant differences were observed in any of the pre- and postsynaptic variables measured. We conclude that NMJs remain structurally intact in rectus abdominis in both cancer and cachexia, suggesting that denervation of skeletal muscle is not a major driver of pathogenesis. The absence of NMJ pathology is in stark contrast to what is found in related conditions, such as age-related sarcopenia, and supports the hypothesis that intrinsic changes within skeletal muscle, independent of any changes in motor neurons, represent the primary locus of neuromuscular pathology in cancer cachexia.
| S-EPMC7269586 | biostudies-literature
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.
2020-05-29 | GSE131835 | GEO
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.
2020-10-28 | PXD016474 | Pride
Project description:Host lipid metabolism reprogramming is essential for hepatitis C virus (HCV) infection and progression to severe liver disease. Direct-acting antivirals (DAAs) achieve a sustained virological response (SVR) in most patients, but virus eradication does not always protect against hepatocellular carcinoma (HCC). Angiopoietin-like protein-3 (ANGPTL-3) and angiopoietin-like protein-4 (ANGPTL-4) regulate the clearance of plasma lipids by inhibiting cellular lipase activity and possess emerging roles in tumourigenesis. We used ELISA and RT-qPCR to investigate ANGPTL-3 and ANGPTL-4 expression in HCV patients with characterised fibrosis throughout the natural history of hepatitis C and in long-term HCV infection in vitro, before and after DAA treatment. ANGPTL-3 was decreased in patients with advanced fibrosis compared to other disease stages, while ANGPTL-4 was progressively increased from acute infection to cirrhosis and HCC, peaking at the advanced fibrosis stage. Only ANGPTL-3 mRNA was down-regulated during early infection in vitro, although both ANGPTLs were increased later. DAA treatment did not alter ANGPTL-3 levels in advanced fibrosis/cirrhosis and in HCV infection in vitro, in contrast to ANGPTL-4. The association between ANGPTLs and fibrosis in HCV infection was underlined by an inverse correlation between the levels of ANGPTLs and serum transforming growth factor- β (TGF-β). Collectively, we demonstrate the pivotal role of advanced fibrosis in defining the expression fate of ANGPTLs in HCV infection and after treatment and propose a role for ANGPTL-3 as a contributor to post-treatment deregulation of lipid metabolism that could predispose certain individuals to HCC development.
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