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      Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer

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          Abstract

          Background:

          Macrophage inhibitory cytokine-1(MIC-1) is a potential modulator of systemic inflammation and nutritional depletion, both of which are adverse prognostic factors in oesophago-gastric cancer (OGC).

          Methods:

          Plasma MIC-1, systemic inflammation (defined as plasma C-reactive protein (CRP) of ⩾10 mg l –1 or modified Glasgow prognostic score (mGPS) of ⩾1), and nutritional status were assessed in newly diagnosed OGC patients ( n=293). Healthy volunteers ( n=35) served as controls.

          Results:

          MIC-1 was elevated in patients (median=1371 pg ml –1; range 141–39 053) when compared with controls (median=377 pg ml –1; range 141–3786; P<0.001). Patients with gastric tumours (median=1592 pg ml –1; range 141–12 643) showed higher MIC-1 concentrations than patients with junctional (median=1337 pg ml –1; range 383–39 053) and oesophageal tumours (median=1180 pg ml –1; range 258–31 184; P=0.015). Patients showed a median weight loss of 6.4% (range 0.0–33.4%), and 42% of patients had an mGPS of ⩾1 or plasma CRP of ⩾10 mg l –1 (median=9 mg l –1; range 1–200). MIC-1 correlated positively with disease stage ( r 2=0.217; P<0.001), age ( r 2=0.332; P<0.001), CRP ( r 2=0.314; P<0.001), and mGPS ( r 2=0.336; P<0.001), and negatively with Karnofsky Performance Score ( r 2=−0.269; P<0.001). However, although MIC-1 correlated weakly with dietary intake (r 2=0.157; P=0.031), it did not correlate with weight loss, BMI, or anthropometry. Patients with MIC-1 levels in the upper quartile showed reduced survival (median=204 days; 95% CI 157–251) when compared with patients with MIC-1 levels in the lower three quartiles (median=316 days; 95% CI 259–373; P=0.036), but MIC-1 was not an independent prognostic indicator.

          Conclusions:

          There is no independent link between plasma MIC-1 levels and depleted nutritional status or survival in OGC.

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          Most cited references46

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          MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily.

          Macrophages play a key role in both normal and pathological processes involving immune and inflammatory responses, to a large extent through their capacity to secrete a wide range of biologically active molecules. To identify some of these as yet not characterized molecules, we have used a subtraction cloning approach designed to identify genes expressed in association with macrophage activation. One of these genes, designated macrophage inhibitory cytokine 1 (MIC-1), encodes a protein that bears the structural characteristics of a transforming growth factor beta (TGF-beta) superfamily cytokine. Although it belongs to this superfamily, it has no strong homology to existing families, indicating that it is a divergent member that may represent the first of a new family within this grouping. Expression of MIC-1 mRNA in monocytoid cells is up-regulated by a variety of stimuli associated with activation, including interleukin 1beta, tumor necrosis factor alpha (TNF-alpha), interleukin 2, and macrophage colony-stimulating factor but not interferon gamma, or lipopolysaccharide (LPS). Its expression is also increased by TGF-beta. Expression of MIC-1 in CHO cells results in the proteolytic cleavage of the propeptide and secretion of a cysteine-rich dimeric protein of Mr 25 kDa. Purified recombinant MIC-1 is able to inhibit lipopolysaccharide -induced macrophage TNF-alpha production, suggesting that MIC-1 acts in macrophages as an autocrine regulatory molecule. Its production in response to secreted proinflammatory cytokines and TGF-beta may serve to limit the later phases of macrophage activation.
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            Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1.

            Anorexia and weight loss are part of the wasting syndrome of late-stage cancer, are a major cause of morbidity and mortality in cancer, and are thought to be cytokine mediated. Macrophage inhibitory cytokine-1 (MIC-1) is produced by many cancers. Examination of sera from individuals with advanced prostate cancer showed a direct relationship between MIC-1 abundance and cancer-associated weight loss. In mice with xenografted prostate tumors, elevated MIC-1 levels were also associated with marked weight, fat and lean tissue loss that was mediated by decreased food intake and was reversed by administration of antibody to MIC-1. Additionally, normal mice given systemic MIC-1 and transgenic mice overexpressing MIC-1 showed hypophagia and reduced body weight. MIC-1 mediates its effects by central mechanisms that implicate the hypothalamic transforming growth factor-beta receptor II, extracellular signal-regulated kinases 1 and 2, signal transducer and activator of transcription-3, neuropeptide Y and pro-opiomelanocortin. Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.
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              Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis.

              Cancer cachexia is a multifactorial syndrome that is poorly defined. Our objective was to evaluate whether a 3-factor profile incorporating weight loss (> or = 10%), low food intake ( or = 10 mg/L) might relate better to the adverse functional aspects of cachexia and to a patient's overall prognosis than will weight loss alone. One hundred seventy weight-losing (> or = 5%) patients with advanced pancreatic cancer were screened for nutritional status, functional status, performance score, health status, and quality of life. Patients were followed for a minimum of 6 mo, and survival was noted. Patients were characterized by using the individual factors, > or = 2 factors, or all 3 factors. Weight loss alone did not define a population that differed in functional aspects of self-reported quality of life or health status and differed only in objective factors of physical function. The 3-factor profile identified both reduced subjective and objective function. In the overall population, the 3 factors, > or = 2 factors, and individual profile factors (except weight loss) all carried adverse prognostic significance (P < 0.01). Subgroup analysis showed that the 3-factor profile carried adverse prognostic significance in localized (hazard ratio: 4.9; P < 0.001) but not in metastatic disease. Weight loss alone does not identify the full effect of cachexia on physical function and is not a prognostic variable. The 3-factor profile (weight loss, reduced food intake, and systemic inflammation) identifies patients with both adverse function and prognosis. Shortened survival applies particularly to cachectic patients with localized disease, thereby reinforcing the need for early intervention.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                26 January 2010
                16 February 2010
                16 February 2010
                : 102
                : 4
                : 665-672
                Affiliations
                [1 ]Clinical and Surgical Sciences (Surgery), University of Edinburgh, Royal Infirmary of Edinburgh 51 Little France Crescent, Edinburgh EH16 4SA, UK
                [2 ]St Vincent's Centre for Applied Medical Research, St Vincent's Hospital and University of New South Wales Victoria Street, Sydney, New South Wales 2010, Australia
                Author notes
                [* ]Author for correspondence: k.fearon@ 123456ed.ac.uk
                Article
                6605532
                10.1038/sj.bjc.6605532
                2837566
                20104227
                44d00264-a74c-47d3-9cfe-194b3e658f8a
                Copyright 2010, Cancer Research UK
                History
                : 19 November 2009
                : 02 December 2009
                Categories
                Clinical Studies

                Oncology & Radiotherapy
                gastric cancer,nutrition,macrophage inhibitory cytokine 1,oesophageal cancer,survival,cachexia

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