bims-stacyt Biomed news
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒03‒31
eleven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Nat Rev Clin Oncol. 2019 Mar 26.
    Li X, Wenes M, Romero P, Huang SC, Fendt SM, Ho PC.
      The development of immunotherapies over the past decade has resulted in a paradigm shift in the treatment of cancer. However, the majority of patients do not benefit from immunotherapy, presumably owing to insufficient reprogramming of the immunosuppressive tumour microenvironment (TME) and thus limited reinvigoration of antitumour immunity. Various metabolic machineries and nutrient-sensing mechanisms orchestrate the behaviour of immune cells in response to nutrient availability in the TME. Notably, tumour-infiltrating immune cells typically experience metabolic stress as a result of the dysregulated metabolic activity of tumour cells, leading to impaired antitumour immune responses. Moreover, the immune checkpoints that are often exploited by tumour cells to evade immunosurveillance have emerging roles in modulating the metabolic and functional activity of T cells. Thus, repurposing of drugs targeting cancer metabolism might synergistically enhance immunotherapy via metabolic reprogramming of the TME. In addition, interventions targeting the metabolic circuits that impede antitumour immunity have been developed, with several clinical trials underway. Herein, we discuss how these metabolic circuits regulate antitumour immunity and the possible approaches to targeting these pathways in the context of anticancer immunotherapy. We also describe hypothetical combination treatments that could be used to better unleash the potential of adoptive cell therapies by enhancing T cell metabolism.
    DOI:  https://doi.org/10.1038/s41571-019-0203-7
  2. Clin Exp Immunol. 2019 Mar 28.
    Jaiswal N, Agrawal S, Agrawal A.
      Dendritic cells (DCs) are critical antigen presenting cells which are the initiators and regulators of the immune response. Numerous studies support the idea that dietary sugars influence DC functions. Increased consumption of fructose has been thought to be the leading cause of metabolic disorders. Though evidences support their association with immune dysfunction, the specific mechanisms are not well understood. Fructose is one of the main dietary sugars in our diet. Therefore, here we compared the effect of fructose and glucose on the functions of human DCs. High levels of D-fructose as compared to D-glucose led to activation of DCs in vitro by promoting IL-6 and IL-1β production. Moreover, fructose exposed DCs also induced IFN-γ secretion from T cells. Pro-inflammatory response of DCs in high fructose environment was found to be independent of the major known metabolic regulators or glycolytic control. Instead, DC activation on acute exposure to fructose was via activation of RAGE (Receptor for advanced Glycation End product) in response to increased accumulation of advanced glycation end products (AGE). However, chronic exposure of DCs to high fructose environment induced a shift towards glycolysis as compared to glucose cultured DCs. Further investigations revealed that the AGEs formed by fructose induced increased levels of inflammatory cytokines in DCs as compared to AGEs from glucose. In summary, understanding the link between metabolic changes and fructose induced DC activation as compared to glucose has broad implications for immune dysfunction associated with metabolic disorders. This article is protected by copyright. All rights reserved.
    Keywords:  Advanced glycation end products (AGE); Dendritic cells; Fructose; glucose; human; inflammation
    DOI:  https://doi.org/10.1111/cei.13299
  3. Neural Plast. 2019 ;2019 7675496
    Lu D, Shen L, Mai H, Zang J, Liu Y, Tsang CK, Li K, Xu A.
      Ischemic stroke is usually followed by inflammatory responses mediated by microglia. However, the effect of statins on directly preventing posthypoxia microglia inflammatory factors to prevent injury to surrounding healthy neurons is unclear. Atorvastatin and rosuvastatin, which have different physical properties regarding their lipid and water solubility, are the most common HMG-CoA reductase inhibitors (statins) and might directly block posthypoxia microglia inflammatory factors to prevent injury to surrounding neurons. Neuronal damage and microglial activation of the peri-infarct areas were investigated by Western blotting and immunofluorescence after 24 hours in a middle cerebral artery occlusion (MCAO) rat model. The decrease in neurons was in accordance with the increase in microglia, which could be reversed by both atorvastatin and rosuvastatin. The effects of statins on blocking secretions from posthypoxia microglia and reducing the secondary damage to surrounding normal neurons were studied in a coculture system in vitro. BV2 microglia were cultured under oxygen glucose deprivation (OGD) for 3 hours and then cocultured following reperfusion for 24 hours in the upper wells of transwell plates with primary neurons being cultured in the bottom wells. Inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and cyclooxygenase-2 (COX2), which are activated by the nuclear factor-kappa B (NF-κB) signaling pathway in OGD-induced BV2 microglia, promoted decreased release of the anti-inflammatory cytokine IL-10 and apoptosis of neurons in the coculture systems according to ELISA and Western blotting. However, pretreatment with atorvastatin or rosuvastatin significantly reduced neuronal death, synaptic injury, and amyloid-beta (Aβ) accumulation, which might lead to increased low-density lipoprotein receptors (LDLRs) in BV2 microglia. We concluded that the proinflammatory mediators released from postischemia damage could cause damage to surrounding normal neurons, while HMG-CoA reductase inhibitors prevented neuronal apoptosis and synaptic injury by inactivating microglia through blocking the NF-κB signaling pathway.
    DOI:  https://doi.org/10.1155/2019/7675496
  4. Cancer Metastasis Rev. 2019 Mar 26.
    Pillai SR, Damaghi M, Marunaka Y, Spugnini EP, Fais S, Gillies RJ.
      While cancer is commonly described as "a disease of the genes," it is also associated with massive metabolic reprogramming that is now accepted as a disease "Hallmark." This programming is complex and often involves metabolic cooperativity between cancer cells and their surrounding stroma. Indeed, there is emerging clinical evidence that interrupting a cancer's metabolic program can improve patients' outcomes. The most commonly observed and well-studied metabolic adaptation in cancers is the fermentation of glucose to lactic acid, even in the presence of oxygen, also known as "aerobic glycolysis" or the "Warburg Effect." Much has been written about the mechanisms of the Warburg effect, and this remains a topic of great debate. However, herein, we will focus on an important sequela of this metabolic program: the acidification of the tumor microenvironment. Rather than being an epiphenomenon, it is now appreciated that this acidosis is a key player in cancer somatic evolution and progression to malignancy. Adaptation to acidosis induces and selects for malignant behaviors, such as increased invasion and metastasis, chemoresistance, and inhibition of immune surveillance. However, the metabolic reprogramming that occurs during adaptation to acidosis also introduces therapeutic vulnerabilities. Thus, tumor acidosis is a relevant therapeutic target, and we describe herein four approaches to accomplish this: (1) neutralizing acid directly with buffers, (2) targeting metabolic vulnerabilities revealed by acidosis, (3) developing acid-activatable drugs and nanomedicines, and (4) inhibiting metabolic processes responsible for generating acids in the first place.
    Keywords:  Anti-acidic therapy; Cancer; Exosomes; Microenvironment acidity
    DOI:  https://doi.org/10.1007/s10555-019-09792-7
  5. Int J Radiat Oncol Biol Phys. 2019 Mar 21. pii: S0360-3016(19)30381-5. [Epub ahead of print]
    Li A, Barsoumian HB, Schoenhals JE, Caetano MS, Wang X, Menon H, Valdecanas DR, Niknam S, Younes AI, Cortez MA, Welsh JW.
      PURPOSE: The limitation of hypofractionated radiation efficacy is due partly to the immunosuppressive tumor microenvironment. Indoleamine-2,3-dioxygenase 1 (IDO1) is an important regulator of tumor immune suppression. We evaluated the effects of IDO1 in hypofractionated radiation using a Lewis lung carcinoma (LLC) mouse model and tested whether IDO1 inhibition could sensitize those tumors to hypofractionated radiation.METHODS AND MATERIALS: Bilateral LLC tumors were established in C57BL/6 mice. Primary tumors were treated with 3 fractions of either 12-Gy or 6-Gy, and the IDO1 inhibitor INCB023843 was given starting on the first day of radiation. Plasma tryptophan (Trp) and kynurenine (Kyn) levels were quantified by liquid chromatography/tandem mass spectrometry. Tumor-infiltrating immune cells were isolated from the tumors, stained, and quantified by flow cytometry.
    RESULTS: The combination of INCB023843 and three 12-Gy fractions led to better tumor control and survival than radiation alone; INCB023843 plus three 6-Gy fractions had no benefit. IDO1 expression by tumor-infiltrating immune cells were increased by three 12-Gy doses and inhibited by the addition of INCB023843. Nearly all IDO1+ immune cells were also F4/80+. Percentages of IDO1+F4/80+ immune cells were drastically increased by three 12-Gy fractions and also by three 6-Gy fractions, but only INCB023843 combined with three 12-Gy fractions reduced those percentages. IDO1+F4/80+ immune cells were further found to be CD11b+, Gr1-intermediate-expressing, CD206-, and CD11c-, i.e., myeloid-derived suppressor cells (MDSCs). Three 12-Gy fractions also increased the percentages of tumor-infiltrating T regulatory cells and CD8+ T cells but adding INCB023843 did not affect those percentages.
    CONCLUSIONS: In addition to its immune activation effects, hypofractionated radiation induced "rebound immune suppression" in the tumor microenvironment by activating and recruiting IDO1-expressing MDSCs in a dose-dependent manner. Adding an IDO1 inhibitor to hypofractionated radiation reduced the percentages of these cells, overcame the immune suppression, and sensitized LLC tumors to hypofractionated radiation.
    DOI:  https://doi.org/10.1016/j.ijrobp.2019.03.022
  6. Mediators Inflamm. 2019 ;2019 1082497
    Leng B, Zhang Y, Liu X, Zhang Z, Liu Y, Wang H, Lu M.
      Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1β (IL-1β), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1β expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1β expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.
    DOI:  https://doi.org/10.1155/2019/1082497
  7. Mol Cancer. 2019 Mar 30. 18(1): 57
    Meng W, Hao Y, He C, Li L, Zhu G.
      Hypoxic tumor microenvironment is a common feature of solid tumors and is associated with aggressiveness and poor patient outcomes. A continuous interference between cancer cells and stromal cells within the hypoxic microenvironment has been uncovered for its importance in cancer development and treatment responsiveness. Exosomes, initially considered as "garbage bins" for unwanted material from cells, are now elucidated to perform a variety of functions that involve interactions within the cellular microenvironment due to their ability to carry numerous cargoes, including lipids, proteins, nucleic acids, and metabolites. Exosome-mediated continuous interference between cancer cells and stroma are believed to regulate hypoxia-adaptation and to rebuild the microenvironment in return. In this review, we will discuss the knowledge in literature with respect to the exosome-mediated multi-directional and mutual signal transmission among the variety of cell types within hypoxic cancer microenvironment.
    Keywords:  Exosome; Extracellular vesicle; Hypoxia; Non-coding RNA; Tumor microenvironment; miRNA
    DOI:  https://doi.org/10.1186/s12943-019-0982-6
  8. Cell Metab. 2019 Mar 05. pii: S1550-4131(19)30102-0. [Epub ahead of print]
    Wu Z, Isik M, Moroz N, Steinbaugh MJ, Zhang P, Blackwell TK.
      Chronic inflammation predisposes to aging-associated disease, but it is unknown whether immunity regulation might be important for extending healthy lifespan. Here we show that in C. elegans, dietary restriction (DR) extends lifespan by modulating a conserved innate immunity pathway that is regulated by p38 signaling and the transcription factor ATF-7. Longevity from DR depends upon p38-ATF-7 immunity being intact but downregulated to a basal level. p38-ATF-7 immunity accelerates aging when hyperactive, influences lifespan independently of pathogen exposure, and is activated by nutrients independently of mTORC1, a major DR mediator. Longevity from reduced insulin/IGF-1 signaling (rIIS) also involves p38-ATF-7 downregulation, with signals from DAF-16/FOXO reducing food intake. We conclude that p38-ATF-7 is an immunometabolic pathway that senses bacterial and nutrient signals, that immunity modulation is critical for DR, and that DAF-16/FOXO couples appetite to growth regulation. These conserved mechanisms may influence aging in more complex organisms.
    Keywords:  ATF-7; C. elegans; aging; dietary restriction; food intake; immunometabolism; innate immunity; insulin/IGF-1 signaling; longevity; p38 signaling
    DOI:  https://doi.org/10.1016/j.cmet.2019.02.013
  9. Cell Physiol Biochem. 2019 ;52(4): 668-680
    Ou K, Mertsch S, Theodoropoulou S, Wu J, Liu J, Copland DA, Scott LM, Dick AD, Schrader S, Liu L.
      BACKGROUND/AIMS: Hypoxia of the retina is a common pathogenic drive leading to vision loss as a result of tissue ischemia, increased vascular permeability and ultimately retinal neovascularisation. Here we tested the hypothesis that Müller cells stabilize the neurovascular unit, microvasculature by suppression of HIF-1α activation as a result of hypoxic preconditioning.METHODS: Tube Formation Assay and In vitro Vascular Permeability Image Assay were used to analyze angiogenesis and vascular integrity. Seahorse XF Cell Mito Stress Test was used to measure mitochondrial respiration. Gene and protein expression were examined by qRTPCR, ELISA and western blot.
    RESULTS: Hypoxic insult induces a significant induction of proangiogenic factors including vascular endothelial growth factor (VEGF) and angiopoietinlike 4 (ANGPTL-4) resulting in angiogenesis and increased vascular permeability of vascular endothelial cells. Hypoxic preconditioning of a human retinal Müller glia cell line significantly attenuates HIF-1α activation through the inhibition of mTOR and concomitant induction of aerobic glycolysis, stabilizing endothelial cells.
    CONCLUSION: Hypoxic preconditioning of Müller cells confers a robust protection to endothelial cells, through the suppression of HIF1α activation and its downstream regulation of VEGF and ANGPTL-4.
    Keywords:  Angiogenesis; Hypoxia; Hypoxic preconditioning; Müller cells; Vascular permeability
    DOI:  https://doi.org/10.33594/000000047
  10. Cell Physiol Biochem. 2019 ;52(4): 708-727
    Wang C, Qu Y, Wang D, Zhu Y.
      BACKGROUND/AIMS: With advances in RNA-sequencing (RNA-seq), exploring the expression and transcripts of different classes of genes are now possible. Our purpose was to analyse to the long non-coding RNAs (lncRNAs) in mouse brain microvascular endothelial cells (bEnd.3) after oxygen-glucose deprivation/re-oxygenation (OGD/R).METHODS: RNA-seq was employed to explore the expression of lncRNAs, and quantitative real-time PCR (qRT-PCR) was used to identify the results of RNA-seq. Furthermore, the biological functions of the lncRNAs were identified by cell viability, wound healing, transwell, tube formation and immunofluorescent staining assays. Finally, the molecular mechanisms involving the differentially expressed lncRNAs were further explored by bioinformatics and Western blotting (WB).
    RESULTS: In total, 2710 lncRNAs were found, 33 of which were significantly differentially expressed, with 18 upregulated lncRNAs and 15 downregulated lncRNAs in brain microvascular endothelial cells following OGD/R. Among the dysregulated genes, G protein-coupled receptor 137b-pseudogene (Gpr137b-ps), predicted gene 32856 (Gm32856), small nucleolar RNA host gene 17 (snhg17), chaperonin containing Tcp1 and subunit 6a (Cct6a) were significantly upregulated lncRNAs; this finding was further validated using qRT-PCR. Moreover, Gene Ontology (GO) and Kyoto Encyclopaedia of Genes (KEGG) pathway analyses were employed to decipher the potential target genes and signaling pathways of the differentially expressed lncRNAs. Finally, we selected pseudogene-expressed lncRNA Gpr137b-ps as a candidate gene, and report for the first time that pseudogenes can mediate angiogenesis and their potential target genes, namely, 15-lipoxygenase1 (15-LOX1), Signal Transducer and Activator of Transcription 3 (S TAT3) and vascular endothelial growth factor (VEGF).
    CONCLUSION: Therefore, our study revealed that Gpr137b-ps plays critical roles in the process of angiogenesis, suggesting avenues for the development of future therapeutic strategies that contribute to promoting angiogenesis following I/R.
    Keywords:  Angiogenesis; Endothelial cells; Long non-coding RNAs; Oxygen-glucose deprivation/reoxygenation; Pseudogenes; RNA-sequencing
    DOI:  https://doi.org/10.33594/000000050
  11. Biochem Biophys Res Commun. 2019 Mar 26. pii: S0006-291X(19)30510-8. [Epub ahead of print]
    Showalter MR, Wancewicz B, Fiehn O, Archard JA, Clayton S, Wagner J, Deng P, Halmai J, Fink KD, Bauer G, Fury B, Perotti NH, Apperson M, Butters J, Belafsky P, Farwell G, Kuhn M, Nolta JA, Anderson JD.
      Mesenchymal stem cell (MSC) based therapies are currently being evaluated as a putative therapeutic in numerous human clinical trials. Recent reports have established that exosomes mediate much of the therapeutic properties of MSCs. Exosomes are nanovesicles which mediate intercellular communication, transmitting signals between cells which regulate a diverse range of biological processes. MSC-derived exosomes are packaged with numerous types of proteins and RNAs, however, their metabolomic and lipidomic profiles to date have not been well characterized. We previously reported that MSCs, in response to priming culture conditions that mimic the in vivo microenvironmental niche, substantially modulate cellular signaling and significantly increase the secretion of exosomes. Here we report that MSCs exposed to such priming conditions undergo glycolytic reprogramming, which homogenizes MSCs' metabolomic profile. In addition, we establish that exosomes derive from primed MSCs are packaged with numerous metabolites that have been directly associated with immunomodulation, including M2 macrophage polarization and regulatory T lymphocyte induction.
    Keywords:  Exosomes; Lipidomics; Mesenchymal stem cells; Metabolomics
    DOI:  https://doi.org/10.1016/j.bbrc.2019.03.119