bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2020–02–02
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Glycolytic reprogramming of macrophages activated by NOD1 and TLR4 agonists: no association with proinflammatory cytokine production in normoxia.
  2. Local intracerebral immunomodulation using interleukin-expressing mesenchymal stem cells in glioblastoma.
  3. Endothelial and T cell crosstalk: targeting metabolism as a therapeutic approach in chronic inflammation.
  4. Regulation of immune cell metabolism by cancer cell oncogenic mutations.
  5. Knockdown of MALAT1 attenuates high-glucose-induced angiogenesis and inflammation via endoplasmic reticulum stress in human retinal vascular endothelial cells.
  6. The Role of Tumor-Derived Vesicles in the Regulation of Antitumor Immunity.
  7. Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4.
  1. J Biol Chem. 2020 Jan 31. pii: jbc.RA119.010589. [Epub ahead of print]
    Glycolytic reprogramming of macrophages activated by NOD1 and TLR4 agonists: no association with proinflammatory cytokine production in normoxia.
    Nina E Murugina, Anna S Budikhina, Yulia A Dagil, Polina V Maximchik, Lyudmila S Balyasova, Vladimir V Murugin, Mikhail V Melnikov, Viktoriya S Sharova, Anna M Nikolaeva, Georgy Z Chkadua, Boris V Pinegin, Mikhail V Pashenkov.
      Upon activation with pathogen-associated molecular patterns, metabolism of macrophages and dendritic cells is shifted from oxidative phosphorylation to aerobic glycolysis, which is considered important for proinflammatory cytokine production. Fragments of bacterial peptidoglycan (muramyl peptides) activate innate immune cells through nucleotide-binding oligomerization domain (NOD) 1 and/or NOD2 receptors. Here, we show that NOD1 and NOD2 agonists induce early glycolytic reprogramming of human monocyte-derived macrophages (MDM), which is similar to that induced by the Toll-like receptor (TLR) 4 agonist, lipopolysaccharide. This glycolytic reprogramming is dependent on Akt kinases, independent of mTOR complex 1, and is efficiently inhibited by 2-deoxy-D-glucose (2-DG) or by glucose starvation. 2-DG inhibits proinflammatory cytokine production by MDM and monocyte-derived dendritic cells activated by NOD1 or TLR4 agonists, except for tumor necrosis factor (TNF) production by MDM, which is inhibited initially, but augmented 4 hours after addition of agonists and later. However, 2-DG exerts these effects by inducing unfolded protein response (UPR) rather than by inhibiting glycolysis. By contrast, glucose starvation does not cause UPR and, in normoxic conditions, only marginally affects proinflammatory cytokine production triggered through NOD1 or TLR4. In hypoxia mimicked by treating MDM with oligomycin (a mitochondrial ATP synthase inhibitor), both 2-DG and glucose starvation strongly suppress TNF and interleukin-6 production, and compromise cell viability. In summary, the requirement of glycolytic reprogramming for proinflammatory cytokine production in normoxia is not obvious, and effects of 2-DG on cytokine responses should be interpreted cautiously. In hypoxia, however, glycolysis becomes critical for cytokine production and cell survival.
    Keywords:  2-deoxy-D-glucose; NOD1; NOD2; Nod-like receptor (NLR); cytokine; dendritic cell; glucose metabolism; macrophage; metabolic reprogramming; unfolded protein response (UPR)
    DOI:  https://doi.org/10.1074/jbc.RA119.010589
  2. Clin Cancer Res. 2020 Jan 27. pii: clincanres.0803.2019. [Epub ahead of print]
    Local intracerebral immunomodulation using interleukin-expressing mesenchymal stem cells in glioblastoma.
    Malte Mohme, Cecile L Maire, Ulf Geumann, Simon Schliffke, Lasse Dührsen, Krystian D Fita, Nuray Akyüz, Mascha Binder, Manfred Westphal, Christine Guenther, Katrin Lamszus, Felix G Hermann, Nils Ole Schmidt.
       PURPOSE: Mesenchymal stem cells (MSCs) show an inherent brain tumor tropism that can be exploited for targeted delivery of therapeutic genes to invasive glioma. We assessed whether a motile MSC-based local immunomodulation is able to overcome the immunosuppressive glioblastoma microenvironment and to induce an antitumor immune response.
    EXPERIMENTAL DESIGN: We genetically modified MSCs to co-express high levels of IL-12 and IL-7 (MSCIL7/12, Apceth-301). Therapeutic efficacy was assessed in two immunocompetent orthotopic C57BL/6 glioma models using GL261 and CT2A. Immunomodulatory effects were assessed by multicolor flow-cytometry to profile immune activation and exhaustion of tumor-infiltrating immune cells. Diversity of the tumor-specific immune response as analyzed using T-cell receptor sequencing (TCRseq).
    RESULTS: Intratumoral administration of MSCIL7/12 induced significant tumor growth inhibition and remission of established intracranial tumors, as demonstrated by MR imaging. Notably, up to 50% of treated mice survived long-term. Re-challenging of survivors confirmed long-lasting tumor immunity. Local treatment with MSCIL7/12 was well tolerated and led to a significant inversion of the CD4+/CD8+ T-cell ratio with an intricate, predominantly CD8+ effector T-cell mediated anti-tumor response. T-cell receptor sequencing demonstrated an increased diversity of TILs in MSCIL7/12-treated mice, indicating a broader tumor-specific immune response with subsequent oligoclonal specification during generation of long-term immunity.
    CONCLUSION: Local MSC-based immunomodulation is able to efficiently alter the immunosuppressive microenvironment in glioblastoma. The long-lasting therapeutic effects warrant a rapid clinical translation of this concept and have led to planning of a phase I/II study of apceth-301 in recurrent glioblastoma.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-19-0803
  3. Br J Pharmacol. 2020 Jan 30.
    Endothelial and T cell crosstalk: targeting metabolism as a therapeutic approach in chronic inflammation.
    Michelangelo Certo, Hagar Elkafrawy, Valentina Pucino, Danilo Cucchi, Kenneth C P Cheung, Claudio Mauro.
      The role of metabolic reprogramming in the coordination of the immune response has gained increasing consideration in recent years. Indeed, it has become clear that changes in the metabolic status of immune cells can alter their functional properties. During inflammation, T cells need to generate sufficient energy and biomolecules to support growth, proliferation and effector functions. Therefore, T cells need to rearrange their metabolism to meet these demands. A similar metabolic reprogramming has been described in endothelial cells which have the ability to interact with and modulate the function of immune cells. In this overview, we will discuss recent insights in the complex crosstalk between endothelial and T cells as well as their metabolic reprogramming following activation. We highlight key components of this metabolic switch that can lead to the development of new therapeutics against chronic inflammatory disorders.
    DOI:  https://doi.org/10.1111/bph.15002
  4. Int J Cancer. 2020 Jan 29.
    Regulation of immune cell metabolism by cancer cell oncogenic mutations.
    Alaa Madi, Guoliang Cui.
      In noncancerous tissues, neighboring cells coexist in metabolic harmony. This metabolic harmony is disrupted in cancerous tissues, often accompanied by genetic mutations. Tumor cells fundamentally change the metabolite profiles in the tumor microenvironment to favor their own growth. In this review, we will discuss several examples in which genetic mutations reprogram tumor cell metabolic pathways, leading to the consumption of essential nutrients in the tumor microenvironment, production of toxic byproducts, and suppression of antitumor immune cell metabolic fitness and tumor-killing function. Finally, we will briefly discuss how immune checkpoint blockade overcomes the metabolic suppression of tumor-infiltrating immune cells. This article is protected by copyright. All rights reserved.
    Keywords:  T cell metabolism; immunometabolism; oncogenic mutations
    DOI:  https://doi.org/10.1002/ijc.32888
  5. Biomed Pharmacother. 2020 Jan 24. pii: S0753-3322(19)35321-1. [Epub ahead of print]124 109699
    Knockdown of MALAT1 attenuates high-glucose-induced angiogenesis and inflammation via endoplasmic reticulum stress in human retinal vascular endothelial cells.
    Yuan Wang, Ling Wang, Hui Guo, Yun Peng, Danyao Nie, Jinsong Mo, Lin Ye.
      Diabetic retinopathy (DR) is one of the most severe complications of diabetes mellitus, and retinal endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis of DR. However, the exact mechanisms by which ERS mediates DR remain unclear. In this study, human retinal vascular endothelial cells (RVECs) were cultured in high-glucose (HG) medium to mimic the environment of DR. The expression of long non-coding RNA (lncRNA)-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was determined by quantitative real time PCR. ERS markers (glucose-regulated protein 78 [GRP78] and C/EBP homologous protein [CHOP]) were measured by immunofluorescence and western blotting. Cell viability was analyzed by the CCK-8 assay. The angiogenesis of RVECs was evaluated by tube formation assays. The levels of pro-inflammation cytokines TNF-α and IL-6 in RVECs were determined by ELISA assays. We found that exposure to HG levels upregulated MALAT1 and GRP78 expression in RVECs. While, GRP78 overexpression strengthened CHOP expression, cell proliferation suppression, capillary morphogenesis and inflammation in HG-treated RVECs. Importantly, knockdown of MALAT1 reversed HG-induced cell proliferation suppression, inhibited capillary morphogenesis, and inflammation in RVECs, and those effects were reversed by GRP78 overexpression. These results suggest that MALAT1 promotes HG-induced angiogenesis and inflammation in RVECs by upregulating ER stress, and might be target for treating DR.
    Keywords:  Diabetic retinopathy; GRP78; MALAT1; Retinal vascular endothelial cells
    DOI:  https://doi.org/10.1016/j.biopha.2019.109699
  6. Acta Naturae. 2019 Oct-Dec;11(4):11(4): 33-41
    The Role of Tumor-Derived Vesicles in the Regulation of Antitumor Immunity.
    V M Ukrainskaya, Y P Rubtsov, V D Knorre, M A Maschan, A G Gabibov, A V Stepanov.
      In this article, we present a comprehensive, updated, and elucidative review of the current knowledge on the function played by tumor-derived vesicles (TDVs) in the crosstalk between tumor and immune cells. Characterization of the structure, biogenesis, and the major functions of TDVs is reported. The review focuses on particular ways of suppression or activation of CD4+/CD8+ T cells by tumor-derived vesicles. Tumor-derived vesicles play an important role in the suppression of antitumor immunity. During the last 15 years, vesicle research has elucidated and improved our knowledge about the role of the vesicles in intercellular communication. Nevertheless, there are still blinds spots concerning vesicle heterogeneity and isolation methods, their uptake by target cells, and the role of mRNA in T-cell transformation or suppression. Along with the substantial progress in understanding of the role of tumor-derived vesicles in intercellular communication, novel antitumor therapy strategies based on vesicle inhibition in a tumor microenvironment are likely to appear very soon.
    Keywords:  CD4+/CD8+ T cells; exosomes; immune response; tumor microenvironment; vesicles
    DOI:  https://doi.org/10.32607/20758251-2019-11-4-33-41
  7. Cancer Lett. 2020 Jan 28. pii: S0304-3835(20)30037-9. [Epub ahead of print]
    Tumor-derived exosomal miR-619-5p promotes tumor angiogenesis and metastasis through the inhibition of RCAN1.4.
    Dong Ha Kim, Sojung Park, HyeongRyul Kim, Yun Jung Choi, Seon Ye Kim, Ki Jung Sung, Young Hoon Sung, Chang-Min Choi, Miyong Yun, Young-Su Yi, Chae Won Lee, Sang-Yeob Kim, Jae Cheol Lee, Jin Kyung Rho.
      Tumor-derived exosomes (TEXs) contain enriched miRNAs that act as novel non-invasive biomarkers for cancer diagnosis and play a role in cancer progression. We investigated the exosomal miRNAs that affect cancer progression in non-small cell lung cancer (NSCLC) and identified the specific molecules involved. We identified that specific miRNAs in NSCLC cell-released exosomes can modulate angiogenesis, among which miR-619-5p was the most potent inducer. RCAN1.4 was identified as a target of miR-619-5p and its suppression promoted angiogenesis. Furthermore, the suppression of RCAN1.4 induced cell proliferation and metastasis in NSCLC cells. In patients with NSCLC, the level of RCAN1.4 expression was significantly lower, and that of miR-619-5p significantly higher, in tumor than normal lung tissues. miR-619-5p expression was higher than normal in exosomes isolated from the plasma of NSCLC patients. Finally, hypoxic conditions induced miR-619-5p upload into NSCLC cell-derived exosomes. Our findings indicate that exosomal miR-619-5p promotes the growth and metastasis of NSCLCs by regulating RCAN1.4 and can serve as a diagnostic indicator for these lung cancers.
    Keywords:  RCAN1; exosomal miRNAs; exosome; non-small cell lung cancer; tumor growth
    DOI:  https://doi.org/10.1016/j.canlet.2020.01.023
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