Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients

Lerner, Lorena; Hayes, Teresa G.; Tao, Nianjun; Krieger, Brian; Feng, Bin; Wu, Zhenhua; Nicoletti, Richard; Chiu, M. Isabel; Gyuris, Jenő; García, José Manuel Pérez

doi:10.1002/jcsm.12033

Cited by 161 publications

(149 citation statements)

References 32 publications

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“…body weight loss). While in many clinical studies MIC‐1 levels correlated with the severity of body weight loss in cancer patients, other studies did not observe such a correlation . Several clinical studies highlighted the potential use of MIC‐1 as a biological marker for prognosis and diagnosis of certain types of cancer (see Fairlie et al .…”

Section: Discussionmentioning

confidence: 99%

Anorexia‐cachexia syndrome in hepatoma tumour‐bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC‐1/GDF15

Borner

Arnold

Ruud

et al. 2016

J cachexia sarcopenia muscle

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BackgroundThe cancer‐anorexia‐cachexia syndrome (CACS) negatively affects survival and therapy success in cancer patients. Inflammatory mediators and tumour‐derived factors are thought to play an important role in the aetiology of CACS. However, the central and peripheral mechanisms contributing to CACS are insufficiently understood. The area postrema (AP) and the nucleus tractus solitarii are two important brainstem centres for the control of eating during acute sickness conditions. Recently, the tumour‐derived macrophage inhibitory cytokine‐1 (MIC‐1) emerged as a possible mediator of cancer anorexia because lesions of these brainstem areas attenuated the anorectic effect of exogenous MIC‐1 in mice.MethodsUsing a rat hepatoma tumour model, we examined the roles of the AP and of vagal afferents in the mediation of CACS. Specifically, we investigated whether a lesion of the AP (APX) or subdiaphragmatic vagal deafferentation (SDA) attenuate anorexia, body weight, muscle, and fat loss. Moreover, we analysed MIC‐1 levels in this tumour model and their correlation with tumour size and the severity of the anorectic response.ResultsIn tumour‐bearing sham‐operated animals mean daily food intake significantly decreased. The anorectic response was paralleled by a significant loss of body weight and muscle mass. APX rats were protected against anorexia, body weight loss, and muscle atrophy after tumour induction. In contrast, subdiaphragmatic vagal deafferentation did not attenuate cancer‐induced anorexia or body weight loss. Tumour‐bearing rats had substantially increased MIC‐1 levels, which positively correlated with tumour size and cancer progression and negatively correlated with food intake.ConclusionsThese findings demonstrate the importance of the AP in the mediation of cancer‐dependent anorexia and body weight loss and support a pathological role of MIC‐1 as a tumour‐derived factor mediating CACS, possibly via an AP‐dependent action.

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Section: Discussionmentioning

confidence: 99%

Anorexia‐cachexia syndrome in hepatoma tumour‐bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC‐1/GDF15

Borner

Arnold

Ruud

et al. 2016

J cachexia sarcopenia muscle

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“…Units for LMI, FMI, and BMD are kg/m 2 . Scans were performed after an overnight fast and before any physical performance tests on the morning of the study visit; each subject wore hospital pants and gown during the scan …”

Section: Methodsmentioning

confidence: 99%

Cancer‐driven changes link T cell frequency to muscle strength in people with cancer: a pilot study

Narsale

Moya

et al. 2019

J cachexia sarcopenia muscle

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Background Tumour growth can promote the loss of muscle mass and function. This is particularly disturbing because overall survival is significantly reduced in people with weaker and smaller skeletal muscle. The risk of cancer is also greater in people who are immune deficient. Muscle wasting in mice with cancer can be inhibited by infusion of CD4 + precursor T cells that restore balanced ratios of naïve, memory, and regulatory T cells. These data are consistent with the hypothesis that stronger anti‐cancer T cell immunity leads to improved muscle mass and function. As a first step to testing this hypothesis, we determined whether levels of circulating T cell subsets correlate with levels of muscle strength in people with cancer. Methods The frequency of circulating CD4 + and CD8 + naïve, memory, and regulatory T cell subsets was quantified in 11 men with gastrointestinal cancer (aged 59.3 ± 10.1 years) and nine men without cancer (aged 60 ± 13 years), using flow cytometry. T cell marker expression was determined using real‐time PCR and western blot analyses in whole blood and peripheral blood mononuclear cells. Handgrip strength, one‐repetition maximum chest press, and knee extension tests were used to determine muscle strength. Performance was determined using a stair climb test. Body composition was determined using dual‐energy X‐ray absorptiometry scan. The Karnofsky and ECOG scales were used to assess functional impairment. Correlations between frequencies of cell subsets with strength, performance, and body composition were determined using regression analyses. Results Our data show significant correlations between (i) higher frequencies of CD8 + naïve ( P = 0.02) and effector memory ( P = 0.003) T cells and lower frequencies of CD8 + central memory T cells ( P = 0.002) with stronger handgrip strength, (ii) lower frequency of regulatory cells with greater lean mass index ( P = 0.04), (iii) lower frequency of CD8 + T cells that express CD95 with greater stair climb power ( P = 0.003), (iv) higher frequency of T cells that co‐express CD197 and CD45RA and greater one‐repetition maximum knee extension strength ( P = 0.008), and (iv) higher expression of CD4 in whole blood with greater functional impairment ( P = 0.004) in people with cancer. Conclusions We have identified significant correlations between levels of T cell populations and muscle strength, performance, and body composition in people with cancer. These data justify a follow‐up study with a larger cohort to test the validity of the findings.

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“…As well, STAT3 inhibits TLR signaling in macrophages [119]. Which of these functions is important in cancer cachexia has not been tested directly, however data in parallel studies are suggestive.…”

Section: Stat3 Outside Muscle In Cachexiamentioning

confidence: 99%

STAT3 in the systemic inflammation of cancer cachexia

Zimmers

Fishel

Bonetto

2016

Seminars in Cell & Developmental Biology

194

166

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Weight loss is diagnostic of cachexia, a debilitating syndrome contributing mightily to morbidity and mortality in cancer. Most research has probed mechanisms leading to muscle atrophy and adipose wasting in cachexia; however cachexia is a truly systemic phenomenon. Presence of the tumor elicits an inflammatory response and profound metabolic derangements involving not only muscle and fat, but also the hypothalamus, liver, heart, blood, spleen and likely other organs. This global response is orchestrated in part through circulating cytokines that rise in conditions of cachexia. Exogenous Interleukin-6 (IL6) and related cytokines can induce most cachexia symptomatology, including muscle and fat wasting, the acute phase response and anemia, while IL-6 inhibition reduces muscle loss in cancer. Although mechanistic studies are ongoing, certain of these cachexia phenotypes have been causally linked to the cytokine-activated transcription factor, STAT3, including skeletal muscle wasting, cardiac dysfunction and hypothalamic inflammation. Correlative studies implicate STAT3 in fat wasting and the acute phase response in cancer cachexia. Parallel data in non-cancer models and disease states suggest both contributory and protective functions for STAT3 in other organs during cachexia. Finally, STAT3 contributes to cancer cachexia through enhancing tumorigenesis, metastasis and immune suppression, particularly in tumors associated with high prevalence of cachexia. This review examines the evidence linking STAT3 to multi-organ manifestations of cachexia in cancer and evidence for targeting STAT3 for anti-cachexia therapies.

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Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients

Cited by 161 publications

References 32 publications

Anorexia‐cachexia syndrome in hepatoma tumour‐bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC‐1/GDF15

Anorexia‐cachexia syndrome in hepatoma tumour‐bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC‐1/GDF15

Cancer‐driven changes link T cell frequency to muscle strength in people with cancer: a pilot study

STAT3 in the systemic inflammation of cancer cachexia

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