Relationship of serum levels of interleukin-6, soluble interleukin-6 receptor and tumour necrosis factor receptors to the acute-phase protein response in advanced pancreatic cancer

BARBER, Matthew D.; Fearon, K. C. H.; Ross, James A.

doi:10.1042/cs19980185

Cited by 47 publications

(42 citation statements)

References 15 publications

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“…Our study did not demonstrate any differences in serum cytokine concentrations between cancer patients and controls. Although some studies have shown an association between serum cytokines and APPs (Martignoni et al, 2005) several have failed to demonstrate such a link and determination of serum cytokines remains an unreliable measure of tissue cytokine activity (Falconer et al, 1994;Barber et al, 1999). Moreover, these findings suggest that circulating cytokines may not be the key mediators of the APPR.…”

Section: Discussionmentioning

confidence: 99%

Elevated tumour interleukin-1β is associated with systemic inflammation: a marker of reduced survival in gastro-oesophageal cancer

et al. 2006

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Systemic inflammation is associated with adverse prognosis cancer but its aetiology remains unclear. We investigated the expression of proinflammatory cytokines within normal mucosa from healthy controls and tumour tissue in cancer patients and related these levels with markers of systemic inflammation and with the presence of a tumour inflammatory infiltrate. Tissue was collected from 56 patients with gastro-oesophageal cancer and from 12 healthy controls. Tissue cytokine mRNA concentrations were measured by real-time PCR and tissue protein concentrations by cytometric bead array. The degree of chronic inflammatory cell infiltrate was recorded. Serum cytokine and acute phase protein concentrations (including C-reactive protein (CRP)) were measured by enzymelinked immunosorbent assay. Proinflammatory cytokines were significantly overexpressed (interleukin (IL)-1b, IL-6, IL-8 and tumour necrosis factor-a) both at mRNA and protein levels in the cancer specimens compared with mucosa from controls. Interleukin-1b was expressed in greatest (10 -100-fold) concentration and protein levels correlated significantly with systemic inflammation (CRP) (P ¼ 0.05, r ¼ 0.31). A chronic inflammatory infiltrate was observed in 75% of the cancer specimens and was associated with systemic inflammation (CRP: P ¼ 0.01). However, the presence of chronic inflammation per se was not associated with altered cytokine expression within the tumour. Both a chronic inflammatory infiltrate and systemic inflammation (CRP) were associated with reduced survival (P ¼ 0.05 and P ¼ 0.03, respectively). Tumour chronic inflammatory infiltrate and tumour tissue IL-1b overexpression are potential independent factors influencing systemic inflammation in oesophagogastric cancer patients.

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Section: Discussionmentioning

confidence: 99%

Elevated tumour interleukin-1β is associated with systemic inflammation: a marker of reduced survival in gastro-oesophageal cancer

et al. 2006

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“…The proinflammatory cytokines such as IL-6 may lead to an APR and trigger tissue catabolism. A significant positive association has been found between the level of the APR and serum levels of IL-6 and soluble TNF-␣ receptors 55 and 75 (12). Evidence for a role of IL-6 in the development of cancer cachexia has come mainly from studies using the murine colon-26 adenocarcinoma, where increasing levels of IL-6 correlated with the development of cachexia, and treatment with a neutralizing antibody to IL-6, but not TNF-␣ or interferon (IFN)␥, attenuated the development of weight loss and other key parameters of cachexia (249).…”

Section: Interleukins 1 and 6 And Interferon-␥mentioning

confidence: 95%

Mechanisms of Cancer Cachexia

Tisdale

2009

Physiological Reviews

1,009

1,061

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Up to 50% of cancer patients suffer from a progressive atrophy of adipose tissue and skeletal muscle, called cachexia, resulting in weight loss, a reduced quality of life, and a shortened survival time. Anorexia often accompanies cachexia, but appears not to be responsible for the tissue loss, particularly lean body mass. An increased resting energy expenditure is seen, possibly arising from an increased thermogenesis in skeletal muscle due to an increased expression of uncoupling protein, and increased operation of the Cori cycle. Loss of adipose tissue is due to an increased lipolysis by tumor or host products. Loss of skeletal muscle in cachexia results from a depression in protein synthesis combined with an increase in protein degradation. The increase in protein degradation may include both increased activity of the ubiquitin-proteasome pathway and lysosomes. The decrease in protein synthesis is due to a reduced level of the initiation factor 4F, decreased elongation, and decreased binding of methionyl-tRNA to the 40S ribosomal subunit through increased phosphorylation of eIF2 on the α-subunit by activation of the dsRNA-dependent protein kinase, which also increases expression of the ubiquitin-proteasome pathway through activation of NFκB. Tumor factors such as proteolysis-inducing factor and host factors such as tumor necrosis factor-α, angiotensin II, and glucocorticoids can all induce muscle atrophy. Knowledge of the mechanisms of tissue destruction in cachexia should improve methods of treatment.

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“…Interleukin-6 has been implicated as a mediator of growth control in several human neoplasms including multiple myeloma (Hussein et al, 2002), prostatic cancer (Giri et al, 2001) and colonic cancer (Schneider et al, 2000) and elevation of serum IL-6 level have been reported in some cancers such as renal cell carcinoma (Blay et al, 1992), ovarian cancer (Plante et al, 1994), cholangiocarcinoma (Goydos et al, 1998) and pancreatic cancer (Barber et al, 1999). The binding of IL-6 to its receptor induces homodimerisation of gp130, which leads to cross-phosphorylation and activation of the associated JAK2.…”

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confidence: 99%

Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms

et al. 2003

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The suppressor of cytokine signalling-1 (SOCS-1) gene is frequently silenced in human hepatocellular carcinoma by aberrant methylation. The aim of this study was to determine if SOCS-1 is inactivated in pancreatic ductal neoplasms, and to investigate if aberrant methylation of this gene affected the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Aberrant methylation in the CpG island of the SOCS-1 gene was detected in six of 19 (31.6%) human pancreatic cancer cell lines using methylation-specific PCR, and was associated with a loss or reduction of gene expression in five of the six methylated cell lines. Thirteen of 60 pancreatic ductal adenocarcinomas (21.7%) and two of 34 intraductal papillary mucinous neoplasms (IPMNs) (5.9%) had methylated SOCS-1. In contrast, SOCS-1 methylation was not seen in pancreatic normal ductal epithelia (zero out of 15), in pancreatic intraepithelial neoplasia (PanINs) (zero out of 49) or in the IPMNs without infiltrating cancer (zero out of 20). 5-Aza-2 0 -deoxycytidine treatment of the SOCS-1-methylated pancreatic cancer cell lines led to restoration of SOCS-1 gene expression. Interleukin-6, which has been shown to act through the JAK/STAT pathway to increase cell growth, induced modest time and dosedependent cell proliferation in a SOCS-1-methylated cell line (PL10, P ¼ 0.015) but not in two unmethylated cell lines. These results indicate that loss of SOCS-1 gene is associated with transcriptional silencing and may have growth-promoting effects, and that its methylation is a useful marker of pancreatic cancer.

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Relationship of serum levels of interleukin-6, soluble interleukin-6 receptor and tumour necrosis factor receptors to the acute-phase protein response in advanced pancreatic cancer

Cited by 47 publications

References 15 publications

Elevated tumour interleukin-1β is associated with systemic inflammation: a marker of reduced survival in gastro-oesophageal cancer

Elevated tumour interleukin-1β is associated with systemic inflammation: a marker of reduced survival in gastro-oesophageal cancer

Mechanisms of Cancer Cachexia

Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms

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