bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–02–05
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Adipokines and epithelial-mesenchymal transition (EMT) in cancer.
  2. Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia.
  3. Lactate from glycolysis regulates inflammatory macrophage polarization in breast cancer.
  4. Adipocyte-hepatocyte crosstalk in cellular models of obesity: Role of soluble factors.
  5. TSC2 regulates tumor susceptibility to TRAIL-mediated T-cell killing by orchestrating mTOR signaling.
  6. Interleukin 8 in plasma is an efficacy marker for advanced non-small cell lung cancer treated with hypofractionated radiotherapy and PD-1 blockade.
  1. Mol Cell Biochem. 2023 Jan 30.
    Adipokines and epithelial-mesenchymal transition (EMT) in cancer.
    Ioanna Akrida, Helen Papadaki.
      Obesity is a significant risk factor for cancer development. Within the tumor microenvironment, adipocytes interact with cancer cells, immune cells, fibroblasts and endothelial cells, and orchestrate several signaling pathways by secreting bioactive molecules, including adipokines. Adipokines or adipocytokines are produced predominantly by adipocytes and function as autocrine, paracrine and endocrine mediators. Adipokines can exert pro- and anti-inflammatory functions, and they play a pivotal role in the state of chronic low-grade inflammation that characterizes obesity. Epithelial-mesenchymal transition (EMT), a complex biological process whereby epithelial cells acquire the invasive, migratory mesenchymal phenotype is well-known to be implicated in cancer progression and metastasis. Emerging evidence suggests that there is a link between adipokines and EMT. This may contribute to the correlation that has been documented between obesity and cancer progression. This review summarizes the existing body of evidence supporting an association between the process of EMT in cancer and the adipokines leptin, adiponectin, resistin, visfatin/NAMPT, lipocalin-2/NGAL, as well as other newly discovered adipokines including chemerin, nesfatin-1/nucleobindin-2, AZGP1, SFRP5 and FABP4.
    Keywords:  Adiponectin; Epithelial to mesenchymal transition; Leptin; Lipocalin-2; Resistin; Visfatin
    DOI:  https://doi.org/10.1007/s11010-023-04670-x
  2. bioRxiv. 2023 Jan 14. pii: 2023.01.12.523716. [Epub ahead of print]
    Area postrema neurons mediate interleukin-6 function in cancer-associated cachexia.
    Qingtao Sun, Daniëlle van de Lisdonk, Miriam Ferrer, Bruno Gegenhuber, Melody Wu, Jessica Tollkuhn, Tobias Janowitz, Bo Li.
      Interleukin-6 (IL-6) has been long considered a key player in cancer-associated cachexia 1-15 . It is believed that sustained elevation of IL-6 production during cancer progression causes brain dysfunctions, which ultimately result in cachexia 16-20 . However, how peripheral IL-6 influences the brain remains poorly understood. Here we show that neurons in the area postrema (AP), a circumventricular structure in the hindbrain, mediate the function of IL-6 in cancer-associated cachexia in mice. We found that circulating IL-6 can rapidly enter the AP and activate AP neurons. Peripheral tumor, known to increase circulating IL-6 1-5,15,18,21-23 , leads to elevated IL-6 and neuronal hyperactivity in the AP, and causes potentiated excitatory synaptic transmission onto AP neurons. Remarkably, neutralization of IL-6 in the brain of tumor-bearing mice with an IL-6 antibody prevents cachexia, reduces the hyperactivity in an AP network, and markedly prolongs lifespan. Furthermore, suppression of Il6ra , the gene encoding IL-6 receptor, specifically in AP neurons with CRISPR/dCas9 interference achieves similar effects. Silencing of Gfral-expressing AP neurons also ameliorates the cancer-associated cachectic phenotypes and AP network hyperactivity. Our study identifies a central mechanism underlying the function of peripheral IL-6, which may serve as a target for treating cancer-associated cachexia.
    DOI:  https://doi.org/10.1101/2023.01.12.523716
  3. Cancer Immunol Immunother. 2023 Feb 02.
    Lactate from glycolysis regulates inflammatory macrophage polarization in breast cancer.
    Chao Wang, Linxuan Xue, Wenqiang Zhu, Lina Liu, Shuhua Zhang, Daya Luo.
      Globally, breast cancer is one of the leading causes of cancer death in women. Metabolic reprogramming and immune escape are two important mechanisms supporting the progression of breast cancer. Lactate in tumors mainly comes from glycolysis and glutaminolysis. Using multiomics data analysis, we found that lactate is mainly derived from glycolysis in breast cancer. Single-cell transcriptome analysis found that breast cancer cells with higher malignancy, especially those in the cell cycle, have higher expression levels of glycolytic metabolic enzymes. Combined with clinical data analysis, it was found that the expression of the lactate transporter SLC16A3 is correlated with breast cancer molecular subtypes and immune infiltration. Among 22 immune cells, macrophages are the most abundant immune cells in breast cancer tissues, and the proportion of M1 macrophages is lower in the high SLC16A3 expression group. Finally, in vitro experiments confirmed that lactate could inhibit the expression of M1 macrophage markers at both RNA and protein levels. In conclusion, we found that lactate produced by glycolysis regulates the polarization of inflammatory macrophages in breast cancer.
    Keywords:  Breast cancer; Lactate; Macrophage polarization; Metabolic reprogramming; Multiomics
    DOI:  https://doi.org/10.1007/s00262-023-03382-x
  4. Life Sci. 2023 Jan 31. pii: S0024-3205(23)00098-X. [Epub ahead of print]317 121464
    Adipocyte-hepatocyte crosstalk in cellular models of obesity: Role of soluble factors.
    Francesca Baldini, Farah Diab, Nadia Serale, Lama Zeaiter, Piero Portincasa, Alberto Diaspro, Laura Vergani.
      Hepatic steatosis is often a consequence of obesity. Adipose tissue is an important endocrine regulator of metabolic homeostasis in the body. In obesity, adipocytes become hypertrophic and develop an inflammatory phenotype, altering the panel of secreted adipokines. Moreover, excess fatty acids are, in part, released by adipocytes and delivered to the liver. These multiple pathways of adipose-liver crosstalk contribute to the development and progression of liver disease: TNFα induces hepatocyte dysfunction, excess of circulating fatty acids promotes hepatic steatosis and inflammation, whilst adipokines mediate and exacerbate liver injury. In this study, we investigated in vitro the effects and mechanisms of the crosstalk between adipocytes and hepatocytes, as a function of the different adipocyte status (mature vs hypertrophic) being mediated by soluble factors. We employed the conditioned medium method to test how mature and hypertrophic adipocytes distinctively affect the liver, leading to metabolic dysfunction. The media collected from adipocytes were characterized by high triglyceride content and led to lipid accumulation and fat-dependent dysfunction in hepatocytes. The present findings seem to suggest that, in addition to triglycerides, other soluble mediators, cytokines, are released by mature and hypertrophic adipocytes and influence the metabolic status of liver cells. Understanding the precise factors involved in the pathogenesis and pathophysiology of NAFLD in obesity will provide important insights into the mechanisms responsible for the metabolic complications of obesity, paving the way for new possible approaches.
    Keywords:  Adipocyte hypertrophy; Co-culture; Conditioned medium; Hepatocytes dysfunction; Obesity
    DOI:  https://doi.org/10.1016/j.lfs.2023.121464
  5. EMBO J. 2023 Jan 30. e111614
    TSC2 regulates tumor susceptibility to TRAIL-mediated T-cell killing by orchestrating mTOR signaling.
    Chun-Pu Lin, Joleen J H Traets, David W Vredevoogd, Nils L Visser, Daniel S Peeper.
      Resistance to cancer immunotherapy continues to impair common clinical benefit. Here, we use whole-genome CRISPR-Cas9 knockout data to uncover an important role for Tuberous Sclerosis Complex 2 (TSC2) in determining tumor susceptibility to cytotoxic T lymphocyte (CTL) killing in human melanoma cells. TSC2-depleted tumor cells had disrupted mTOR regulation following CTL attack, which was associated with enhanced cell death. Wild-type tumor cells adapted to CTL attack by shifting their mTOR signaling balance toward increased mTORC2 activity, circumventing apoptosis, and necroptosis. TSC2 ablation strongly augmented tumor cell sensitivity to CTL attack in vitro and in vivo, suggesting one of its functions is to critically protect tumor cells. Mechanistically, TSC2 inactivation caused elevation of TRAIL receptor expression, cooperating with mTORC1-S6 signaling to induce tumor cell death. Clinically, we found a negative correlation between TSC2 expression and TRAIL signaling in TCGA patient cohorts. Moreover, a lower TSC2 immune response signature was observed in melanomas from patients responding to immune checkpoint blockade. Our study uncovers a pivotal role for TSC2 in the cancer immune response by governing crosstalk between TSC2-mTOR and TRAIL signaling, aiding future therapeutic exploration of this pathway in immuno-oncology.
    Keywords:  T-cell sensitivity; TRAIL; TSC2; mTOR; tumor cells
    DOI:  https://doi.org/10.15252/embj.2022111614
  6. Cytokine. 2023 Jan 30. pii: S1043-4666(23)00011-X. [Epub ahead of print]163 156133
    Interleukin 8 in plasma is an efficacy marker for advanced non-small cell lung cancer treated with hypofractionated radiotherapy and PD-1 blockade.
    Pengyuan Kang, Dan Liu, Lin Li, Xiyuan Guo, Yingchun Ye, Yunfei Li, Qin Jiang, Sheng Lin, Qing Yuan.
       BACKGROUND: Programmed death-1 (PD-1) blockade promotes combination therapy in advanced non-small cell lung cancer (NSCLC), hypofractionated radiotherapy (HFRT) and chemotherapy combined with immunotherapy improves the outcome of prognosis in advanced NSCLC, while effective biomarkers to follow prognostic efficacy are still to be found.
    METHODS: We enrolled 44 NSCLC patients with HFRT combined with PD-1 blockade, 13 patients with chemotherapy combined with immunotherapy, additionally collected tissue samples from 8 patients with earlystage NSCLC without therapy, and peripheral whole blood from 16 healthy donors, detected the expression differences of cytokines Interleukin 6 (IL-6), Interleukin 8 (IL-8) and Interleukin 17A (IL-17A) in the peripheral plasma and tissues by flow cytometry, immunofluorescence, and real-time fluorescence quantitative PCR. Cultured peripheral blood mononuclear cell (PBMC) and tumor-infiltrating T cells with recombinant human IL-8 in vitro to observe the changes of immune memory T cell subtypes and apoptosis.
    RESULTS: Our results show that IL-6, IL-8, and IL-17A are highly expressed in advanced NSCLC, high levels of IL-8 are significantly associated with poor prognosis in advanced NSCLC patients treated with HFRT + PD1 blockade, high circulating IL-8 in NSCLC increased apoptosis of effector memory RA (TemRA; CD45RA+CCR7-) T cell subsets and CD8+ T cell subsets in tissues, resulting in decreased peripheral TemRA and stem cell-like memory T cells (TSCM: CD45RA +CCR7 + CD95 +) in tissue.
    CONCLUSION: We suggest that IL-8 can impair immune memory function in NSCLC. It is a useful biomarker to evaluate the efficacy of HFRT + PD1 blockade in advanced NSCLC. Further exploration of easily available plasma biomarkers for personalized treatment of NSCLC is required.
    Keywords:  Hypofractionated radiotherapy; Interleukin 8; Memory T cells; PD-1 blockade
    DOI:  https://doi.org/10.1016/j.cyto.2023.156133
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