Understanding cachexia in the context of metastatic progression

Biswas, Anup; Acharyya, Swarnali

doi:10.1038/s41568-020-0251-4

Cited by 138 publications

(120 citation statements)

References 143 publications

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“…[4] Cancer-associated cachexia leads to progressive functional impairment, treatmentrelated complications, poor quality of life and cancer-related mortality. [12] The universally accepted diagnostic criterion for cancer-associated cachexia was weight loss greater than 5% within six months, or weight loss greater than 2% in individuals already showing depletion according to current body weight and height (BMI < 20 kg/m 2 ) or skeletal muscle mass (sarcopenia). [5] Therefore, weight loss is a key factor in identifying cancer-associated cachexia.…”

Section: Discussionmentioning

confidence: 99%

Relationships Among Circulating TNF-α, Skeletal Muscle and Peripheral CD8+ T Cells During Cachexia in Gastric Cancer

Zhao

Wan

Lin

et al. 2020

Preprint

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Background: Cancer-associated cachexia is characterized by ongoing loss of skeletal muscle and has a high incidence in gastric cancer. Although studies have focused on the effect of inflammatory cytokines on skeletal muscle loss, it is not clear whether inflammatory cytokines affect other physiological functions, particularly immunity in gastric cancer. Thus, we aim to investigate the relationships between circulating TNF-α, skeletal muscle and peripheral immune status in gastric cancer.Methods: Totally 392 gastric cancer patients in cohort A and 60 gastric cancer patients in cohort B were selected from the prospective cohort study NCT03115931 and ChiCTR1900026578 in West China Hospital, Sichuan University, respectively. Besides, human skeletal muscle myoblasts (HSMMs) and peripheral CD8+ T cells completed about 7 to 9 days successive TNF-α intervention with different concentrations. Results: From data in cohort A, multivariate analysis showed that preoperative weight loss ≥5% was associated with circulating TNF-α (P =0.001) and TNM stage (P =0.002). ROC curve indicated that cut-off point of 9.96 pg/ml for circulating TNF-α was an important warning of weight loss ≥5% in patient with gastric cancer. Before surgery, high circulating TNF-α (≥ 9.96 pg/ml) was associated with significantly lower body weight, skeletal muscle mass and handgrip strength but not fat mass. After radical surgery, high circulating TNF-α was also associated with significantly more loss of body weight and skeletal muscle mass instead of fat mass. In cohort B and vitro experiments, immunohistochemistry, western blot and flow cytometry identified that high TNF-α led to myofiber change, decreased expression of AMP-dependent protein kinase (AMPK) and phosphate-AMPK in skeletal muscle and increased myoblast apoptosis. Flow cytometry found that circulating TNF-α was not correlated with PD-1, LAG-3, TIM-3 and TIGIT expressed on peripheral CD8+ T cells, and TNF-α not only promoted the proliferation of CD8+ T cells but also increased their apoptosis ratio at higher concentration.Conclusions: In our study, we found that TNF-α could result in myofiber change, interfered glycometabolism of skeletal muscle, whereas promoted the proliferation of CD8+ T cells in gastric cancer during cachexia, and preoperative circulating TNF-α of more than 9.96 pg/ml could indicate a high risk of weight loss.

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Section: Discussionmentioning

confidence: 99%

Relationships Among Circulating TNF-α, Skeletal Muscle and Peripheral CD8+ T Cells During Cachexia in Gastric Cancer

Zhao

Wan

Lin

et al. 2020

Preprint

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“…Moreover, skeletal muscle mass is sensitive to the several systemic disruptions associated with cancer including insulin resistance, chronic inflammation, anorexia, and hypogonadism ( Baracos et al, 2018 ). There also has been significant interest in investigating tumor derived factors that can directly drive skeletal muscle catabolism, and numerous factors have been identified ( Biswas and Acharyya, 2020 ). Despite our vastly improved mechanistic understanding of cancer-induced muscle wasting through established and well-defined preclinical cachexia and in vitro atrophy models, the complexity and heterogeneity of cancer cachexia have hindered the development of effective treatments for the cancer patient ( Anderson et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

The Impact of Immune Cells on the Skeletal Muscle Microenvironment During Cancer Cachexia

2020

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Progressive weight loss combined with skeletal muscle atrophy, termed cachexia, is a common comorbidity associated with cancer that results in adverse consequences for the patient related to decreased chemotherapy responsiveness and increased mortality. Cachexia’s complexity has provided a barrier for developing successful therapies to prevent or treat the condition, since a large number of systemic disruptions that can regulate muscle mass are often present. Furthermore, considerable effort has focused on investigating how tumor derived factors and inflammatory mediators directly signal skeletal muscle to disrupt protein turnover regulation. Currently, there is developing appreciation for understanding how cancer alters skeletal muscle’s complex microenvironment and the tightly regulated interactions between multiple cell types. Skeletal muscle microenvironment interactions have established functions in muscle response to regeneration from injury, growth, aging, overload-induced hypertrophy, and exercise. This review explores the growing body of evidence for immune cell modulation of the skeletal muscle microenvironment during cancer-induced muscle wasting. Emphasis is placed on the regulatory network that integrates physiological responses between immune cells with other muscle cell types including satellite cells, fibroblast cells, and endothelial cells to regulate myofiber size and plasticity. The overall goal of this review is to provide an understanding of how different cell types that constitute the muscle microenvironment and their signaling mediators contribute to cancer and chemotherapy-induced muscle wasting.

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“…A recent article published in Nature Reviews demonstrated that extracellular vesicles packing cargo reach subpopulations of muscle cells and mediate cachexia. While the effects of GC exosomes on adipogenesis have not been elucidated [15].…”

Section: Introductionmentioning

confidence: 99%

Exosomes from Gastric Cancer Suppressed Adipo-differentiation of Adipose Mesenchymal Stem Cells to Promote Cancer-associated Cachexia via miR-155/ C/EPBβ pathway

Liu

Lin

Wang

et al. 2020

Preprint

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BACKGROUND: Cancer-associated cachexia (CAC) is defined as a multifactorial syndrome including depletion of adipose tissue and skeletal muscle. Adipose tissue wasting, as a key characteristic of CAC, occurs early and is related with poor survival. However, the influence of exosomes on adipo-differentiation in CAC remained be mysterious.METHODS: Oil-red staining, western blotting, and real-time polymerase chain reaction (RT-PCR) were used to investigate the adipo-differentiation capacity of A-MSCs from GC patients and healthy donors. Adipo-differentiation capacity of A-MSCs treated with exosomes from GES-1 or GC cell lines was also detected. To further explore the effects of exosomal miR-155 on adipo-differentiation in vitro, we carried out luciferase reporter assay. Finally, to evaluate the function of exosomal miR-155 in vivo, BALB/c mice were subcutaneously transplanted with SGC7901 cells transfected with lentivirus containing a miR-155 overexpressing (miR-155 OE) sequence or miR-155 shRNA (miR-155 KO) or control lentivirus(NC) to observe the change of adipo-differentiation of A-MSCs.RESULTS: We showed that miR-155 was high expressed in adipose mesenchymal stem cells (A-MSCs) isolated from GC patients, which exhibited significantly suppressed adipo-differentiation. Mechanistically, targeting C/EPBβ and suppressing C/EPBα and PPARγ by GC exosomal miR-155 was demonstrated to be involved in impairing the differentiation of A-MSCs into adipocytes. The expression of C/EPBβ C/EPBα and PPARγ were rescued through downregulating miR-155 in GC exosomes. Moreover, overexpression of miR-155 improved cancer cachexia in tumor-implanted mice, charactered by weight loss, tumor progression and low expression of C/EPBβ, C/EPBα, and PPARγ in A-MSCs as well as FABP4 in tumor-related adipose tissue. Decreasing level of miR-155 in implanted tumor blocked the anti-adipogenic effects of GC. CONCLUSION: GC exosomsal miR-155 suppressed adipo-differentiation of A-MSCs via targeting C/EPBβ of A-MSCs plays a crucial role in CAC.

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Understanding cachexia in the context of metastatic progression

Cited by 138 publications

References 143 publications

Relationships Among Circulating TNF-α, Skeletal Muscle and Peripheral CD8+ T Cells During Cachexia in Gastric Cancer

Relationships Among Circulating TNF-α, Skeletal Muscle and Peripheral CD8+ T Cells During Cachexia in Gastric Cancer

The Impact of Immune Cells on the Skeletal Muscle Microenvironment During Cancer Cachexia

Exosomes from Gastric Cancer Suppressed Adipo-differentiation of Adipose Mesenchymal Stem Cells to Promote Cancer-associated Cachexia via miR-155/ C/EPBβ pathway

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