bims-stacyt 2024-06-02 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2024–06–02
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Overview of growth differentiation factor 15 (GDF15) in metabolic diseases.
EDA2R-NIK signaling in cancer cachexia.
Extracellular vesicles in cancer cachexia: deciphering pathogenic roles and exploring therapeutic horizons.
Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health.
Survival strategies: How tumor hypoxia microenvironment orchestrates angiogenesis.
HIF-1α Pathway Orchestration by LCN2: A Key Player in Hypoxia-Mediated Colitis Exacerbation.
An IFNγ-dependent immune-endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response.

Biomed Pharmacother. 2024 May 28. pii: S0753-3322(24)00693-0. [Epub ahead of print]176 116809

Overview of growth differentiation factor 15 (GDF15) in metabolic diseases.

Jian Li, Xiangjun Hu, Zichuan Xie, Jiajin Li, Chen Huang, Yan Huang.

  GDF15 is a stress response cytokine and a distant member of the transforming growth factor beta (TGFβ) superfamily, its levels increase in response to cell stress and certain diseases in the serum. To exert its effects, GDF15 binds to glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL), which was firstly identified in 2017 and highly expressed in the brain stem. Many studies have demonstrated that elevated serum GDF15 is associated with anorexia and weight loss. Herein, we focus on the biology of GDF15, specifically how this circulating protein regulates appetite and metabolism in influencing energy homeostasis through its actions on hindbrain neurons to shed light on its impact on diseases such as obesity and anorexia/cachexia syndromes. It works as an endocrine factor and transmits metabolic signals leading to weight reduction effects by directly reducing appetite and indirectly affecting food intake through complex mechanisms, which could be a promising target for the treatment of energy-intake disorders.

Keywords:  Anorexia; Appetite regulation; GDF15; GFRAL; Metabolism; Obesity

DOI:  https://doi.org/10.1016/j.biopha.2024.116809
Curr Opin Support Palliat Care. 2024 May 27.

EDA2R-NIK signaling in cancer cachexia.

Samet Agca, Serkan Kir.

PURPOSE OF REVIEW: Cachexia is a debilitating condition causing weight loss and skeletal muscle wasting that negatively influences treatment and survival of cancer patients. The objective of this review is to describe recent discoveries on the role of a novel signaling pathway involving ectodysplasin A2 receptor (EDA2R) and nuclear factor κB (NFκB)-inducing kinase (NIK) in muscle atrophy.
RECENT FINDINGS: Studies identified tumor-induced upregulation of EDA2R expression in muscle tissues in pre-clinical cachexia models and patients with various cancers. Activation of EDA2R by its ligand promoted atrophy in cultured myotubes and muscle tissue, which depended on NIK activity. The non-canonical NFκB pathway via NIK also stimulated muscle atrophy. Mice lacking EDA2R or NIK were protected from muscle loss due to tumors. Tumor-induced cytokine oncostatin M (OSM) upregulated EDA2R expression in muscles whereas OSM receptor-deficient mice were resistant to muscle wasting.
SUMMARY: Recent discoveries revealed a mechanism involving EDA2R-NIK signaling and OSM that drives cancer-associated muscle loss, opening up new directions for designing anti-cachexia treatments. The therapeutic potential of targeting this mechanism to prevent muscle loss should be further investigated. Future research should also explore broader implications of the EDA2R-NIK pathway in other muscle wasting diseases and overall muscle health.

DOI: https://doi.org/10.1097/SPC.0000000000000705
J Transl Med. 2024 May 27. 22(1): 506

Extracellular vesicles in cancer cachexia: deciphering pathogenic roles and exploring therapeutic horizons.

Yifeng Wang, Shengguang Ding.

  Cancer cachexia (CC) is a debilitating syndrome that affects 50-80% of cancer patients, varying in incidence by cancer type and significantly diminishing their quality of life. This multifactorial syndrome is characterized by muscle and fat loss, systemic inflammation, and metabolic imbalance. Extracellular vesicles (EVs), including exosomes and microvesicles, play a crucial role in the progression of CC. These vesicles, produced by cancer cells and others within the tumor environment, facilitate intercellular communication by transferring proteins, lipids, and nucleic acids. A comprehensive review of the literature from databases such as PubMed, Scopus, and Web of Science reveals insights into the formation, release, and uptake of EVs in CC, underscoring their potential as diagnostic and prognostic biomarkers. The review also explores therapeutic strategies targeting EVs, which include modifying their release and content, utilizing them for drug delivery, genetically altering their contents, and inhibiting key cachexia pathways. Understanding the role of EVs in CC opens new avenues for diagnostic and therapeutic approaches, potentially mitigating the syndrome's impact on patient survival and quality of life.

Keywords:  Adipose atrophy; Cancer cachexia; Extracellular vesicles; Muscle wasting; Systemic inflammation; Therapeutic agents

DOI:  https://doi.org/10.1186/s12967-024-05266-9
Front Endocrinol (Lausanne). 2024 ;15 1404047

Different roles of circulating and intramuscular GDF15 as markers of skeletal muscle health.

Antonio Chiariello, Giuseppe Conte, Luca Rossetti, Lorenzo Trofarello, Stefano Salvioli, Maria Conte.

   Introduction: Growth Differentiation Factor 15 (GDF15) is a mitokine expressed in response to various stresses whose circulating levels increase with age and are associated with numerous pathological conditions, including muscle wasting and sarcopenia. However, the use of circulating GDF15 (c-GDF15) as a biomarker of sarcopenia is still debated. Moreover, the role of GDF15 intracellular precursor, pro-GDF15, in human skeletal muscle (SM-GDF15) is not totally understood. In order to clarify these points, the association of both forms of GDF15 with parameters of muscle strength, body composition, metabolism and inflammation was investigated.
Methods: the levels of c-GDF15 and SM-GDF15 were evaluated in plasma and muscle biopsies, respectively, of healthy subjects (HS) and patients with lower limb mobility impairment (LLMI), either young (<40 years-old) or old (>70 years-old). Other parameters included in the analysis were Isometric Quadriceps Strength (IQS), BMI, lean and fat mass percentage, Vastus lateralis thickness, as well as circulating levels of Adiponectin, Leptin, Resistin, IGF-1, Insulin, IL6, IL15 and c-PLIN2. Principal Component Analysis (PCA), Canonical Discriminant Analysis (CDA) and Receiving Operating Characteristics (ROC) analysis were performed.
Results: c-GDF15 but not SM-GDF15 levels resulted associated with decreased IQS and IGF-1 levels in both HS and LLMI, while only in LLMI associated with increased levels of Resistin. Moreover, in LLMI both c-GDF15 and SM-GDF15 levels were associated with IL-6 levels, but interestingly SM-GDF15 is lower in LLMI with respect to HS. Furthermore, a discrimination of the four groups of subjects based on these parameters was possible with PCA and CDA. In particular HS, LLMI over 70 years or under 40 years of age were discriminated based on SM-GDF15, c-GDF15 and Insulin levels, respectively.
Conclusion: our data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength. Moreover, it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15, which is likely linked to a healthy and active state.

Keywords:  GDF15; aging; biomarkers; inflammaging; muscle health

DOI:  https://doi.org/10.3389/fendo.2024.1404047
Biomed Pharmacother. 2024 May 25. pii: S0753-3322(24)00667-X. [Epub ahead of print]176 116783

Survival strategies: How tumor hypoxia microenvironment orchestrates angiogenesis.

Mengrui Yang, Yufeng Mu, Xiaoyun Yu, Dandan Gao, Wenfeng Zhang, Ye Li, Jingyang Liu, Changgang Sun, Jing Zhuang.

  During tumor development, the tumor itself must continuously generate new blood vessels to meet their growth needs while also allowing for tumor invasion and metastasis. One of the most common features of tumors is hypoxia, which drives the process of tumor angiogenesis by regulating the tumor microenvironment, thus adversely affecting the prognosis of patients. In addition, to overcome unsuitable environments for growth, such as hypoxia, nutrient deficiency, hyperacidity, and immunosuppression, the tumor microenvironment (TME) coordinates angiogenesis in several ways to restore the supply of oxygen and nutrients and to remove metabolic wastes. A growing body of research suggests that tumor angiogenesis and hypoxia interact through a complex interplay of crosstalk, which is inextricably linked to the TME. Here, we review the TME's positive contribution to angiogenesis from an angiogenesis-centric perspective while considering the objective impact of hypoxic phenotypes and the status and limitations of current angiogenic therapies.

Keywords:  VEGF; hypoxia, angiogenesis; non-VEGF-dependent angiogenesis; tumor microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2024.116783
Inflammation. 2024 May 31.

HIF-1α Pathway Orchestration by LCN2: A Key Player in Hypoxia-Mediated Colitis Exacerbation.

Yun-Han Yang, Fang Yan, Peng-Shuang Shi, Liu-Chan Yang, De-Jun Cui.

  In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention.

Keywords:  HIF-1α signaling pathway; M1 macrophages; chronic inflammatory bowel disease; glycolysis; hypoxia; lipocalin 2

DOI:  https://doi.org/10.1007/s10753-024-01990-y
Nat Immunol. 2024 May 29.

An IFNγ-dependent immune-endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response.

Marko Šestan, Sanja Mikašinović, Ante Benić, Stephan Wueest, Christoforos Dimitropoulos, Karlo Mladenić, Mia Krapić, Lea Hiršl, Yossef Glantzspiegel, Ana Rasteiro, Maria Aliseychik, Đurđica Cekinović Grbeša, Tamara Turk Wensveen, Marina Babić, Irit Gat-Viks, Henrique Veiga-Fernandes, Daniel Konrad, Felix M Wensveen, Bojan Polić.

Viral infection makes us feel sick as the immune system alters systemic metabolism to better fight the pathogen. The extent of these changes is relative to the severity of disease. Whether blood glucose is subject to infection-induced modulation is mostly unknown. Here we show that strong, nonlethal infection restricts systemic glucose availability, which promotes the antiviral type I interferon (IFN-I) response. Following viral infection, we find that IFNγ produced by γδ T cells stimulates pancreatic β cells to increase glucose-induced insulin release. Subsequently, hyperinsulinemia lessens hepatic glucose output. Glucose restriction enhances IFN-I production by curtailing lactate-mediated inhibition of IRF3 and NF-κB signaling. Induced hyperglycemia constrained IFN-I production and increased mortality upon infection. Our findings identify glucose restriction as a physiological mechanism to bring the body into a heightened state of responsiveness to viral pathogens. This immune-endocrine circuit is disrupted in hyperglycemia, possibly explaining why patients with diabetes are more susceptible to viral infection.

DOI: https://doi.org/10.1038/s41590-024-01848-3