Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90

Zhang, Guohua; Liu, Zhelong; Ding, Hui; Zhou, Yong; Doan, Hoang Anh; Sin, Ka Wai Thomas; Zhu, Zhiren J.; Flores, Rene; Wen, Yu; Gong, Xing; Liu, Qingyun; Li, Yi-Ping

doi:10.1038/s41467-017-00726-x

Cited by 187 publications

(255 citation statements)

References 57 publications

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“…Cancer cachexia is initiated by tumour‐derived factors . There is general consensus that many of these factors are proteins . We previously showed that LIF is not only sufficient to induce myotube atrophy, but it is entirely responsible for atrophy due to treatment with C26 tumour cell CM .…”

Section: Discussionmentioning

confidence: 99%

“…Not all preclinical models of cachexia involve LIF. The Lewis Lung Carcinoma (LLC) is another well‐studied mouse model of cancer cachexia, and several tumour‐secreted proteins, other than LIF, have been implicated in causing wasting from LLC . Our own evaluation of CM from LLC shows that they secrete very low levels of LIF, not enough to contribute to wasting (see ).…”

Section: Discussionmentioning

confidence: 99%

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Tumour‐derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour‐bearing mice

Kandarian

Nosacka

Delitto

et al. 2018

J cachexia sarcopenia muscle

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BackgroundCancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour‐derived LIF is required for cancer cachexia in mice by knockout of Lif in C26 cells.MethodsA C26 Lif null tumour cell line was made using CRISPR‐Cas9. Measurements of cachexia were compared in mice inoculated with C26 vs. C26Lif−/− tumour cells, and atrophy was compared in myotubes treated with medium from C26 vs. C26Lif−/− tumour cells. Levels of 25 cytokines/chemokines were compared in serum of mice bearing C26 vs. C26Lif−/− tumours and in the medium from these tumour cell lines.ResultsAt study endpoint, C26 mice showed outward signs of sickness while mice with C26Lif−/− tumours appeared healthy. Mice with C26Lif−/− tumours showed a 55–75% amelioration of body weight loss, muscle loss, fat loss, and splenomegaly compared with mice with C26 tumours (P < 0.05). The heart was not affected by LIF levels because the loss of cardiac mass was the same in C26 and C26Lif−/− tumour‐bearing mice. LIF levels in mouse serum was entirely dependent on secretion from the tumour cells. Serum levels of interleukin‐6 and G‐CSF were increased by 79‐fold and 68‐fold, respectively, in C26 mice but only by five‐fold and two‐fold, respectively, in C26Lif−/− mice, suggesting that interleukin‐6 and G‐CSF increases are dependent on tumour‐derived LIF.ConclusionsThis study shows the first use of CRISPR‐Cas9 knockout of a candidate cachexia factor in tumour cells. The results provide direct evidence for LIF as a major cachexia initiating factor for the C26 tumour in vivo. Tumour‐derived LIF was also a regulator of multiple cytokines in C26 tumour cells and in C26 tumour‐bearing mice. The identification of tumour‐derived factors such as LIF that initiate the cachectic process is immediately applicable to the development of therapeutics to treat cachexia. This is a proof of principle for studies that when carried out in human cells, will make possible an understanding of the factors causing cachexia in a patient‐specific manner.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tumour‐derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour‐bearing mice

Kandarian

Nosacka

Delitto

et al. 2018

J cachexia sarcopenia muscle

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“…Heat shock protein 70 (Hsp70) is a predominantly intracellular protein, but can be released externally, especially under disease or stress conditions to stimulate a proinflammatory response . Increased levels of Hsp70 were found in secreted exosomes in different disease states, including cancer, bacterial infection, and sarcoidosis, and these exosomes could induce pro‐inflammatory or immunostimulatory responses, such as NF‐κB activation and TNF‐α release or increased IFN‐γ and IL‐13 production …”

Section: Role Of Exosomesmentioning

confidence: 99%

Exosomes in Inflammation and Inflammatory Disease

et al. 2019

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Exosomes are a subset of extracellular vesicles released by all cell types and involved in local and systemic intercellular communication. In the past decade, research into exosomes has swelled as their important role in the mediation of health and disease has been increasingly established and acknowledged. Exosomes carry a diverse range of cargo including proteins, nucleic acids, and lipids derived from their parental cell that, when delivered to the recipient cell, can confer pathogenic or therapeutic effects through modulation of immunity and inflammation. In this review, the role of exosomes on mediation of immune and inflammatory responses, and their participation in diseases with a significant inflammatory component is discussed. The considerable potential for exosomes in therapy and diagnosis of inflammatory diseases is also highlighted.

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“…Zhang et al . (2017) suggested that tumour‐derived exosomes may be responsible for the induction of cachexia . A plethora of studies show that inflammatory mediators, including tumour necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ), interleukin (IL)‐1 and IL‐6, myostatin, and transforming growth factor β (TGF‐β) are involved in the etiology of the loss of skeletal muscle and adipose tissue mass.…”

Section: Introductionmentioning

confidence: 99%

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

Lima

Simoes

Castro

et al. 2019

J cachexia sarcopenia muscle

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Background Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro‐environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro‐environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients. Methods 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components. Results Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte–macrophage colony‐stimulating factor, interferon‐α, and interleukin (IL)‐8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight‐stable counterparts. Also, IL‐8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of α‐smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)‐β1, TGF‐β2, and TGF‐β3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen‐activated protein kinase alteration. Hypoxia‐inducible factor‐1α mRNA content was significantly increased in the tumour of cachectic patients, when compared with weight‐stable group (P = 0.005). Conclusions Our results demonstrate TGF‐β pathway activation in the tumour in cachexia, through the (non‐canonical) mitogen‐activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF‐β‐induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.

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Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90

Cited by 187 publications

References 57 publications

Tumour‐derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour‐bearing mice

Tumour‐derived leukaemia inhibitory factor is a major driver of cancer cachexia and morbidity in C26 tumour‐bearing mice

Exosomes in Inflammation and Inflammatory Disease

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

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