bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒01‒19
four papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Life Sci. 2020 Jan 14. pii: S0024-3205(20)30051-5. [Epub ahead of print] 117304
    Bu L, Cao X, Zhang Z, Wu H, Guo R, Ma M.
      AIMS: Macrophages, as an important member of immune system, engulf and digest pathogens in innate immunity and help initiate adaptive immunity. However, macrophages also involve in occurrence and development of many diseases, such as obesity and type 2 diabetes. Here, we aimed to reveal how activated macrophages cause insulin resistance in skeletal muscle in vitro through simulating body environment.MAIN METHODS: We established RAW264.7 macrophages and C2C12 myotubes co-incubation model in vitro using Transwell filter to simulate body environment and investigated effects of RAW264.7 cells on insulin-regulated glucose metabolism in C2C12 myotubes. Immunofluorescence, Immunoblot and glucose uptake tests were used to assess metabolic changes in C2C12 myotubes. ELISA test detected secretions of tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) from RAW264.7 cells. In addition, RNA interference and inhibitor treatment were used.
    KEY FINDINGS: Activated RAW264.7 cells attenuated insulin response in C2C12 myotubes. Activated RAW264.7 cells secreted a lot of TNF-α and IL-6. We found that TNFα, but not IL-6, caused insulin resistance of skeletal muscle in a dose-dependent manner. The results further indicated that activation of TNF-α downstream proteins, inhibitor of nuclear factor κ-B kinase (IKK) and the jun-N-terminal kinase 1 (JNK1) led to phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser residues and insulin resistance in C2C12 myotubes.
    SIGNIFICANCE: Our research provided further and direct demonstration on activated macrophage-induced insulin resistance in skeletal muscle, suggesting TNF-α might become a therapeutic target to ameliorate and treat type 2 diabetes.
    Keywords:  Insulin resistance; Interleukin-6; Macrophages; Skeletal muscle; Tumor necrosis factor α
  2. Cytokine. 2020 Jan 14. pii: S1043-4666(20)30002-8. [Epub ahead of print]127 154986
    Strickland J, Garrison D, Copple BL.
      INTRODUCTION: Cxcl12, or stromal-derived factor-1, is a chemokine produced by several hepatic cell types, including hepatocytes, after liver injury and surgical resection. Studies have revealed that Cxcl12 is important for regeneration of the liver after surgical resection and for development of liver fibrosis during chronic liver injury. While the function of Cxcl12 in the liver is well established, the mechanism by which Cxcl12 is upregulated is not fully understood. Because regions of hypoxia develop in the liver following injury, we tested the hypothesis that hypoxia upregulates Cxcl12 in hepatocytes by a hypoxia-inducible factor (HIF)-dependent mechanism.METHODS: To test this hypothesis, primary mouse hepatocytes were isolated from the livers of HIF-1α-deficient mice or HIF-1β-deficient mice and exposed to 1% oxygen. Cxcl12 expression was increased following exposure of primary mouse hepatocytes to 1% oxygen. Previously we have shown, that in addition to HIFs, transforming growth factor-β is required for upregulation of a subset of genes in hypoxic hepatocytes. To examine the role of TGF-β in regulation of Cxcl12 during hypoxia, hepatocytes were pretreated with the TGF-β receptor I inhibitor, SB431542.
    RESULTS: Upregulation of Cxcl12 by hypoxia was partially prevented in hepatocytes from HIF-1α-deficient mice and completely prevented in hepatocytes from HIF-1β-deficient hepatocytes. This suggests that under hypoxic conditions, both HIF-1α and HIF-2α regulate Cxcl12 in hepatocytes. Pretreatment of hepatocytes with SB431542 completely prevented upregulation Cxcl12 by hypoxia. Further, treatment of hepatocytes with recombinant TGF-β1 upregulated Cxcl12 in hepatocytes cultured in room air.
    CONCLUSION: Collectively, these studies demonstrate that hypoxia upregulates Cxcl12 in primary mouse hepatocytes by a mechanism that involves HIFs and TGF-β.
    Keywords:  Cxcl12; Fibrosis; Hepatocytes; Hypoxia; Liver; TGF-β
  3. Adv Clin Chem. 2020 ;pii: S0065-2423(19)30067-8. [Epub ahead of print]94 155-218
    Gomarasca M, Banfi G, Lombardi G.
      Bone and skeletal muscle are integrated organs and their coupling has been considered mainly a mechanical one in which bone serves as attachment site to muscle while muscle applies load to bone and regulates bone metabolism. However, skeletal muscle can affect bone homeostasis also in a non-mechanical fashion, i.e., through its endocrine activity. Being recognized as an endocrine organ itself, skeletal muscle secretes a panel of cytokines and proteins named myokines, synthesized and secreted by myocytes in response to muscle contraction. Myokines exert an autocrine function in regulating muscle metabolism as well as a paracrine/endocrine regulatory function on distant organs and tissues, such as bone, adipose tissue, brain and liver. Physical activity is the primary physiological stimulus for bone anabolism (and/or catabolism) through the production and secretion of myokines, such as IL-6, irisin, IGF-1, FGF2, beside the direct effect of loading. Importantly, exercise-induced myokine can exert an anti-inflammatory action that is able to counteract not only acute inflammation due to an infection, but also a condition of chronic low-grade inflammation raised as consequence of physical inactivity, aging or metabolic disorders (i.e., obesity, type 2 diabetes mellitus). In this review article, we will discuss the effects that some of the most studied exercise-induced myokines exert on bone formation and bone resorption, as well as a brief overview of the anti-inflammatory effects of myokines during the onset pathological conditions characterized by the development a systemic low-grade inflammation, such as sarcopenia, obesity and aging.
    Keywords:  Adipokines; Inflammation; Muscle-bone crosstalk; Myokines; Physical activity
  4. Sci Rep. 2020 Jan 15. 10(1): 377
    Li R, Ong SL, Tran LM, Jing Z, Liu B, Park SJ, Huang ZL, Walser TC, Heinrich EL, Lee G, Salehi-Rad R, Crosson WP, Pagano PC, Paul MK, Xu S, Herschman H, Krysan K, Dubinett S.
      Chronic inflammation facilitates tumor progression. We discovered that a subset of non-small cell lung cancer cells underwent a gradually progressing epithelial-to-mesenchymal (EMT) phenotype following a 21-day exposure to IL-1β, an abundant proinflammatory cytokine in the at-risk for lung cancer pulmonary and the lung tumor microenvironments. Pathway analysis of the gene expression profile and in vitro functional studies revealed that the EMT and EMT-associated phenotypes, including enhanced cell invasion, PD-L1 upregulation, and chemoresistance, were sustained in the absence of continuous IL-1β exposure. We referred to this phenomenon as EMT memory. Utilizing a doxycycline-controlled SLUG expression system, we found that high expression of the transcription factor SLUG was indispensable for the establishment of EMT memory. High SLUG expression in tumors of lung cancer patients was associated with poor survival. Chemical or genetic inhibition of SLUG upregulation prevented EMT following the acute IL-1β exposure but did not reverse EMT memory. Chromatin immunoprecipitation and methylation-specific PCR further revealed a SLUG-mediated temporal regulation of epigenetic modifications, including accumulation of H3K27, H3K9, and DNA methylation, in the CDH1 (E-cadherin) promoter following the chronic IL-1β exposure. Chemical inhibition of DNA methylation not only restored E-cadherin expression in EMT memory, but also primed cells for chemotherapy-induced apoptosis.