bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒08‒16
eight papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Prog Lipid Res. 2020 Aug 10. pii: S0163-7827(20)30035-7. [Epub ahead of print] 101055
    Corn KC, Windham MA, Rafat M.
      Over the past decade, the study of metabolic abnormalities in cancer cells has risen dramatically. Cancer cells can thrive in challenging environments, be it the hypoxic and nutrient-deplete tumor microenvironment or a distant tissue following metastasis. The ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment and adjacent stroma. Adipocytes can be activated by cancer cells to lipolyze their triglyceride stores, delivering secreted fatty acids to cancer cells for uptake through numerous fatty acid transporters. Cancer-associated fibroblasts are also implicated in lipid secretion for cancer cell catabolism and lipid signaling leading to activation of mitogenic and migratory pathways. As these cancer-stromal interactions are exacerbated during tumor progression, fatty acids secreted into the microenvironment can impact infiltrating immune cell function and phenotype. Lipid metabolic abnormalities such as increased fatty acid oxidation and de novo lipid synthesis can provide survival advantages for the tumor to resist chemotherapeutic and radiation treatments and alleviate cellular stresses involved in the metastatic cascade. In this review, we highlight recent literature that demonstrates how lipids can shape each part of the cancer lifecycle and show that there is significant potential for therapeutic intervention surrounding lipid metabolic and signaling pathways.
    Keywords:  Immune Response; Lipid Metabolism; Lipid Signaling; Metastasis; Radiation Therapy; Tumor Microenvironment
  2. Biomed Pharmacother. 2020 Aug 10. pii: S0753-3322(20)30816-7. [Epub ahead of print]130 110623
    Sun X, Lv X, Yan Y, Zhao Y, Ma R, He M, Wei M.
      Drug resistance is a major obstacle in the treatment of tumors, which easily lead to relapse or poor prognosis. Cancer stem cells (CSCs) are regarded as one of the important targets that mediate tumor resistance. Increasing evidence shows that the tumor hypoxia microenvironment is closely related to the resistance of CSCs to chemotherapy and radiotherapy. In this review, we intend to review the articles that have described how the hypoxic microenvironment affects CSC stemness and mediates tumor resistance and provide new directions and methods in the clinical treatment of tumors. Here, we also discuss the feasibility and development prospects of using hypoxia-inducible factors (HIFs) that regulate the hypoxic microenvironment of tumors as targeted agents to treat tumors, as well as to reduce or even reverse the resistance of tumors to chemotherapy and radiotherapy.
    Keywords:  Cancer stem cells (CSCs); HIF inhibitors; Hypoxia inducible factors (HIFs); Tumor resistance
  3. Cell Metab. 2020 Aug 04. pii: S1550-4131(20)30411-3. [Epub ahead of print]
    Hooftman A, Angiari S, Hester S, Corcoran SE, Runtsch MC, Ling C, Ruzek MC, Slivka PF, McGettrick AF, Banahan K, Hughes MM, Irvine AD, Fischer R, O'Neill LAJ.
      The Krebs cycle-derived metabolite itaconate is highly upregulated in inflammatory macrophages and exerts immunomodulatory effects through cysteine modifications on target proteins. The NLRP3 inflammasome, which cleaves IL-1β, IL-18, and gasdermin D, must be tightly regulated to avoid excessive inflammation. Here we provide evidence that itaconate modifies NLRP3 and inhibits inflammasome activation. Itaconate and its derivative, 4-octyl itaconate (4-OI), inhibited NLRP3 inflammasome activation, but not AIM2 or NLRC4. Conversely, NLRP3 activation was increased in itaconate-depleted Irg1-/- macrophages. 4-OI inhibited the interaction between NLRP3 and NEK7, a key step in the activation process, and "dicarboxypropylated" C548 on NLRP3. Furthermore, 4-OI inhibited NLRP3-dependent IL-1β release from PBMCs isolated from cryopyrin-associated periodic syndrome (CAPS) patients, and reduced inflammation in an in vivo model of urate-induced peritonitis. Our results identify itaconate as an endogenous metabolic regulator of the NLRP3 inflammasome and describe a process that may be exploited therapeutically to alleviate inflammation in NLRP3-driven disorders.
    Keywords:  IL-1β; NEK7; NLRP3; cysteine modification; immunometabolism; inflammasome; itaconate; macrophage; metabolite; pyroptosis
  4. Cell Biol Int. 2020 Aug 08.
    Deng J, Zhang N, Chen F, Yang C, Ning H, Xiao C, Sun K, Liu Y, Yang M, Hu T, Zhang Z, Jiang W.
      High glucose (HG)-induced cardiomyocytes (CMs) injury is a leading cause of diabetic cardiomyopathy with little treatment options. Irisin, a new myokine, which is cleaved from its precursor fibronectin type III domain-containing protein 5 (FNDC5), has aroused great attentions as an essential cardioprotective factor and glucose metabolism regulator but little was known on diabetic cardiomyopathy yet. Here, we aim to clarify the role of irisin in the HG-induced CMs injury. Neonatal Sprague-Dawley (SD) rat CMs were cultured in a normal or high glucose medium for 12, 24 and 48 h respectively before exposing to irisin. The apoptosis level was determined by Terminal-deoxynucleotidyl transferase mediated-dUTP Nick End Labeling (TUNEL) assay. Cell viability was measured with the conventional methylthiazolyl tetrazolium (MTT) assay. Moreover, reactive oxygen species (ROS) production was evaluated by dihydroethidium (DHE) staining. Inflammatory factors, namely TNF-ɑ, IL-6, IL-1β were determined by enzyme-linked immunosorbent assay (ELISA) kits. Furthermore, protein and mRNA expressions were measured by Western blot and qRT-PCR respectively. HG increases the apoptosis of CMs and activated the inflammatory responses and oxidative stress in CMs. Meanwhile, the mRNA and protein expressions of FNDC5 are decreased after HG exposure. Nevertheless, the increased apoptosis is alleviated by irisin treatment. Notably, irisn suppresses the inflammatory responses and oxidative stress in injured CMs. Mechanically, after administration of Compound C, AMPK inhibitor, these cardioprotective effects resulting from irisin are reversed. Irisin plays a significant role in anti-apoptosis, anti-inflammation, anti-oxidative stress in HG-induced CMs via AMPK/mTOR signaling pathway. This article is protected by copyright. All rights reserved.
    Keywords:  Apoptosis; Cardiomyocytes (CMs); High glucose (HG); Inflammatory responses; Irisin; Oxidative stress
  5. Endocrinology. 2020 Sep 01. pii: bqaa116. [Epub ahead of print]161(9):
    Vinaik R, Barayan D, Jeschke MG.
      Inflammasomes are multiprotein complexes that respond to pathogen or host associated damage markers, leading to caspase-1 maturation and processing of pro-inflammatory cytokines. Initially, inflammasomes were implicated primarily in inflammatory and infectious conditions. However, increasing evidence demonstrates broader roles beyond inflammation, including regulation of adipose tissue metabolism after burns. Here, we conducted a search for articles on PubMed, Web of Science, Embase, Scopus, and UpToDate with applied search strategies including a combination of "burns," "trauma," "(NLRP3) inflammasome," "metabolic conditions," "white adipose tissue," "macrophages," "browning," and "lipolysis" and included papers from 2000 to 2020. We discuss unexpected roles for NLRP3, the most characterized inflammasome to date, as a key metabolic driver in a variety of conditions. In particular, we highlight the function of NLRP3 inflammasome in burn trauma, which is characterized by both hyperinflammation and hypermetabolism. We identify a critical part for NLRP3 activation in macrophage dynamics and delineate a novel role in postburn white adipose tissue remodeling, a pathological response associated with hypermetabolism and poor clinical outcomes. Mechanistically, how inflammation and inflammasome activation is linked to postburn hypermetabolism is a novel concept to contemplate, and herein we provide evidence of an immunometabolic crosstalk between adipocytes and infiltrating macrophages.
    Keywords:  NLRP3 inflammasome; browning; burns; hypermetabolism; lipolysis; macrophages
  6. Front Oncol. 2020 ;10 1197
    Jiang Z, Hsu JL, Li Y, Hortobagyi GN, Hung MC.
      Immune checkpoint inhibitors (ICIs) targeting immune checkpoint proteins, such as CTLA-4 and PD-1/PD-L1, have demonstrated remarkable and durable clinical responses in various cancer types. However, a considerable number of patients receiving ICIs eventually experience a relapse due to diverse resistance mechanisms. As a result, there have been increasing research efforts to elucidate the molecular mechanisms behind resistance to ICIs and improve patient outcomes. There is growing evidence that the dysregulated metabolic activity of tumor cells generates an immunosuppressive tumor microenvironment (TME) that orchestrates an impaired anti-tumor immune response. Notably, the immunosuppressive TME is characterized by nutrient shortage, hypoxia, an acidic extracellular milieu, and abundant immunosuppressive molecules. A detailed understanding of the TME remains a major challenge in mounting a more effective anti-tumor immune response. Herein, we discuss how tumor cells reprogram metabolism to modulate a pro-tumor TME, driving disease progression and immune evasion; in particular, we highlight potential approaches to target metabolic vulnerabilities in the context of anti-tumor immunotherapy.
    Keywords:  cancer cell metabolite; cancer metabolism; immune checkpoint inhibitors; immune evasion; tumor microenvironment
  7. Lung. 2020 Aug 12.
    Zou F, Su X, Pan P.
      PURPOSE: Intermittent hypoxia (IH) is a recognized risk factor for multiple organs damage, resulting in lung injury. Its pathophysiology is still poorly understood. Toll-like receptor 4 (TLR4) signaling plays a critical role in host immune response to invading pathogen and non-infectious tissue injury. The role of TLR4-mediated inflammation in IH-induced lung injury was investigated in this study.METHODS: Lean adult male TLR4-deficient (TLR4-/-) mice and their controls (C57BL/6 mice) were exposed to either IH (FiO2 6-8% for 25 s, 150 s/cycle, 8 h/day) or air (normoxic mice) for 6 weeks. Animals were sacrificed after 6-week exposure, and the lung tissues were harvested for morphological and inflammatory analyses. The expression of TLR4 and nuclear factor kappa-B (NF-κB) P65 were examined by real-time quantitative polymerase chain reaction and immunohistochemical method. Serum cytokine levels of interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α) were analyzed by enzyme-linked immunosorbent assay.
    RESULTS: IH induced morphological and inflammation changes in the lung. IH for 6 weeks induced higher expression of TLR4 (C57BL/6-N vs C57BL/6-IH, P < 0.05) and resulted in higher release of TNF-α, IL-6 (P < 0.05), and NF-κB P65 (P < 0.05). These alterations were remitted by TLR4 deletion.
    CONCLUSIONS: TLR4-mediated inflammation plays an important role in the development of IH-induced lung injury in mice, possibly through mechanisms involving nuclear factor-κB. Targeting TLR4/NF-κB pathway could represent a further therapeutic option for sleep apnea patients.
    Keywords:  Intermittent hypoxia; Lung injury; Obstructive sleep apnea; Toll-like receptor 4
  8. Int J Mol Sci. 2020 Aug 06. pii: E5647. [Epub ahead of print]21(16):
    Korbecki J, Kojder K, Barczak K, Simińska D, Gutowska I, Chlubek D, Baranowska-Bosiacka I.
      Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we have gathered all the available data about the impact of hypoxia on β chemokines. In the introduction, we present the chronic (continuous, non-interrupted) and cycling (intermittent, transient) hypoxia together with the mechanisms of activation of hypoxia inducible factors (HIF-1 and HIF-2) and NF-κB. Then we describe the effect of hypoxia on the expression of chemokines with the CC motif: CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 together with CC chemokine receptors: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10. To better understand the effect of hypoxia on neoplastic processes and changes in the expression of the described proteins, we summarize the available data in a table which shows the effect of individual chemokines on angiogenesis, lymphangiogenesis, and recruitment of eosinophils, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and tumor-associated macrophages (TAM) to a tumor niche.
    Keywords:  NF-κB; cancer; chemokine; hypoxia; hypoxia inducible factor