bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒05‒17
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Cancer Lett. 2020 May 05. pii: S0304-3835(20)30202-0. [Epub ahead of print]
    Eisenberg L, Eisenberg-Bord M, Eisenberg-Lerner A, Sagi-Eisenberg R.
      Metabolic reprogramming is a characteristic feature of both cancer cells and their neighbouring cells in the tumor microenvironment (TME). The latter include stroma fibroblasts and adipocytes, that respectively differentiate to become cancer associated fibroblasts (CAFs) and cancer associated adipocytes (CAAs), and infiltrated immune cells, that collaborate with the stromal cells to provide the tumor a pro-tumorigenic niche. Here we discuss the association between the reprogramming of glucose metabolism in the TME and oncogenic signaling and its reflection in the non-canonical functions of metabolic enzymes. We also discuss the non-canonical actions of oncometabolites and the contribution to oncogenesis of external metabolites that accumulate in the TME as result of crosstalk between the tumor and the TME. Special emphasis is given in this regard to lysophosphatidic acid (LPA) and adenosine, two powerful metabolites, the concentrations of which rise in the TME due to altered metabolism of the tumor and its surrounding cells, allowing their action as external signals.
    Keywords:  Adenosine; Aerobic glycolysis; Cancer; Lysophosphatidic acid (LPA); Metabolic reprogramming; Oncometabolites; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2020.04.016
  2. Int Immunopharmacol. 2020 May 07. pii: S1567-5769(20)30117-X. [Epub ahead of print]84 106551
    Zhu M, Sun X, Qi X, Xia L, Wu Y.
      There is increasing evidence that macrophages play an important role in the development and pathogenesis of diabetic nephropathy (DN) by secreting inflammatory cytokines. Exosomes are a family of extracellular vesicles that are secreted from almost all types of cells and associated with cell-to-cell communications. In this article, we try to investigate whether high glucose (HG)-treated macrophages-derived exosomes could activate macrophages and induce inflammatory responses in vivo and in vitro. We incubated the exosomes from high glucose-treated Raw264.7 cells (HG-Exo) and Raw264.7 cells for 24 h. The expression levels of related inflammatory molecules and NF-κB p65 signaling pathway were identified, as well as the intracellular localization of NF-κB p65 was detected. In vivo, HG-Exo was injected into mice via tail vein and the related parameters of kidneys were detected. Compared with the exosomes from normal glucose-treated Raw264.7 cells (NG-Exo), HG-Exo contained higher concentrations of IL-1β and iNOS. HG-Exo-treated Raw264.7 cells secreted higher level of related inflammatory molecules and promoted NF-κB p65 signaling pathway expression. HG-Exo induced the production of intracellular iNOS and α-SMA. In the HG-Exo group, NF-κB p65 positive signals were mainly distributed in the nucleus area. HG-Exo treated mice kidneys displayed a significantly mesangial expansion and proliferation. NF-κB p65 protein expression levels in mice renal tissue treated with HG-Exo was significantly up-regulated. These findings suggest that high glucose treated macrophages-derived exosomes may activate macrophages and accelerate kidney injury via NF-κB p65 signaling pathway.
    Keywords:  Exosomes; High glucose; Inflammatory responses; Macrophages; NF-κB signaling pathway
    DOI:  https://doi.org/10.1016/j.intimp.2020.106551
  3. Cancer Immunol Immunother. 2020 May 09.
    Yu S, Li Q, Yu Y, Cui Y, Li W, Liu T, Liu F.
      Chemotherapy is the preferred treatment for advanced stage gastric cancer (GC) patients, and developing chemoresistance is a tremendous challenge to efficacy of GC treatment. The treatments of anti-tumor chemo-agents recruit more tumor-associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that hypoxia-inducible factor 1α (HIF1α) in GC cells is activated upon 5-fluorouracil (5-FU) treatment and results in much more accumulation of M2-type TAMs which protect tumor cells from chemo-agents. Mechanistically, in the GC cells under the 5-FU treatment, reactive oxygen species is accumulated and then induces the activation of HIF1α signaling to drive the expression of high-mobility group box 1, which leads to more macrophage's infiltration into GC tumor. In turn, the recruited TAMs exhibit tumor-protected M2-type phenotype and promote the chemoresistance of GC cells via producing growth differentiation factor 15 (GDF15) to exacerbate the fatty acid β-oxidation in tumor cells. Blocking GDF15 using antibody or inhibiting FAO of tumor cells by etomoxir efficiently gave rise to the tumor cell sensitivity to 5-FU. Therefore, our study demonstrates a novel insight in understanding the cross talking between tumor cells and immune microenvironment and provides new therapeutic targets for clinic treatments of gastric cancer.
    Keywords:  Chemoresistance; GDF15; Gastric cancer; HIF1α; HMGB1; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s00262-020-02598-5
  4. Nat Metab. 2019 Sep 30. 1 966-974
    Martin JL, Costa ASH, Gruszczyk AV, Beach TE, Allen FM, Prag HA, Hinchy EC, Mahbubani K, Hamed M, Tronci L, Nikitopoulou E, James AM, Krieg T, Robinson AJ, Huang MH, Caldwell ST, Logan A, Pala L, Hartley RC, Frezza C, Saeb-Parsy K, Murphy MP.
      During heart transplantation, storage in cold preservation solution is thought to protect the organ by slowing metabolism; by providing osmotic support; and by minimising ischaemia-reperfusion (IR) injury upon transplantation into the recipient1,2. Despite its widespread use our understanding of the metabolic changes prevented by cold storage and how warm ischaemia leads to damage is surprisingly poor. Here, we compare the metabolic changes during warm ischaemia (WI) and cold ischaemia (CI) in hearts from mouse, pig, and human. We identify common metabolic alterations during WI and those affected by CI, thereby elucidating mechanisms underlying the benefits of CI, and how WI causes damage. Succinate accumulation is a major feature within ischaemic hearts across species, and CI slows succinate generation, thereby reducing tissue damage upon reperfusion caused by the production of mitochondrial reactive oxygen species (ROS)3,4. Importantly, the inevitable periods of WI during organ procurement lead to the accumulation of damaging levels of succinate during transplantation, despite cooling organs as rapidly as possible. This damage is ameliorated by metabolic inhibitors that prevent succinate accumulation and oxidation. Our findings suggest how WI and CI contribute to transplant outcome and indicate new therapies for improving the quality of transplanted organs.
    DOI:  https://doi.org/10.1038/s42255-019-0115-y
  5. Front Cell Dev Biol. 2020 ;8 282
    Wu Q, Li B, Sun S, Sun S.
      Senescence is characterized by a permanent cell cycle arrest that is elicited in response to different stresses. In addition, senescent cells undergo multiple other phenotypic alterations, such as autophagy modulation, metabolic reprogramming, and the senescence-associated secretory phenotype (SASP). These senescence-related and inflammatory effects prevail within tumors and are strongly controlled by cancer properties, and inflammatory mediators further maintain and propagate the senescence process to adjacent cells. It is important to consider these detrimental effects that may drive tumorigenesis or cancer relapse. Importantly, cancer-associated adipocytes (CAAs) are one of the primary stromal cells in various tumor microenvironments and favor tumor progression by releasing various factors that can mediate local and systemic effects. However, it remains unclear whether CAAs possess senescent features. In this review, we discuss the complex relationship between senescence and CAAs and highlight important considerations for therapeutics.
    Keywords:  adipocytes; cancer; inflammation; senescence; tumor microenvironment (TEM)
    DOI:  https://doi.org/10.3389/fcell.2020.00282
  6. Ren Fail. 2020 Nov;42(1): 463-473
    Zhang YL, Wang JM, Yin H, Wang SB, He CL, Liu J.
      Objective: This report was designed to assess the functional role of miR-218/dachshund family transcription factor 1 (DACH1) in diabetic kidney disease (DKD) and investigate its possible molecular mechanism.Materials and Methods: From the GEO database, we downloaded different datasets for analyzing the expression of miR-218 and DACH1 in DKD. TargetScan was adopted to predict the binding sites between miR-218 and DACH1, which was further verified by dual-luciferase reporter assays. The renal proximal tubule cells (HK-2) treated with high glucose (HG) were used as an in vitro model. QRT-PCR and western blot were used to determine the expression of DACH1 and other relative factors. Cell counting kit-8 and flow cytometer were applied to detect cell viability and apoptosis. The levels of inflammatory cytokines were determined by an ELISA assay.Results: A prominent raise of miR-218 was observed in DKD through bioinformatics analysis, which was further confirmed in the HG-induced model. DACH1 is a target of miR-218. miR-218 reduced cell viability and induced apoptosis by negatively regulating DACH1. Moreover, upregulating miR-218 in HG models increased the concentrations of pro-inflammatory cytokines TNF-α and IL-1β, reduced the level of anti-inflammatory cytokine IL-10, and promoted the epithelial-mesenchymal transition (EMT) process, which is possibly achieved by targeting DACH1. While downregulating miR-218 showed the opposite results.Conclusion: These data demonstrated that, under an in vitro HG environment, miR-218 suppressed the HK-2 cells proliferation, promoted apoptosis, caused an inflammatory response, and facilitated the EMT process largely by targeting DACH1, providing an insight into the therapeutic intervention of DKD.
    Keywords:  DACH1; Diabetic kidney disease; inflammation; microRNA-218; proliferation
    DOI:  https://doi.org/10.1080/0886022X.2020.1762647
  7. Biotechnol Appl Biochem. 2020 May 12.
    Shomali N, Mahmoudi J, Mahmoodpoor A, Zamiri RE, Akbari M, Xu H, Shotorbani SS.
      Release and storage of energy can be regulated by the metabolic parameter dependent on the CNS (Central nervous system). Macrophages are one of the most professional APCs (antigen-presenting cells) that are formed by the accumulation of dead or damaged cells or in response to the infection, which the main function is phagocytosis, secretion of cytokines and presenting antigen to T cells. The proper immune response needs to the production of effector cytokines along with comprehensive and rapid cell proliferation and growth. Activation of the immune system and immune cells need to increased glucose metabolism. When the immune system responds to pathogens, chemokines inform immune cells such as macrophages and T cells to travel to the infected area. Although glucose is vital for the proper function of immune cells and their proliferation, a high amount of glucose may lead to impaired function of the immune system and pathological conditions. However, a suitable amount of glucose is indispensable for the immune system, but its elevated amount leads to excessive pro-inflammatory cytokines production. In this study, we focused on the master regulatory role of glucose on the immune system. This article is protected by copyright. All rights reserved.
    Keywords:  Glucose, Immune system; Metabolic regulation
    DOI:  https://doi.org/10.1002/bab.1938