bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒06‒30
eight papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Biochemistry (Mosc). 2019 May;84(5): 553-561
    Stafeev IS, Michurina SS, Podkuychenko NV, Menshikov MY, Parfyonova YV, Vorotnikov AV.
      Obesity is accompanied by dyslipidemia, hypoxia, endoplasmic reticulum (ER) stress, and inflammation, representing the major risk factor for the development of insulin resistance (IR) and type 2 diabetes. We modeled these conditions in cultured 3T3-L1 adipocytes and studied their effect on insulin signaling, glucose uptake, and inflammatory response via activation of stress-dependent JNK1/2 kinases. Decreased insulin-induced phosphorylation of the insulin cascade components IRS, Akt, and AS160 was observed under all tested conditions (lipid overloading of cells by palmitate, acute inflammation induced by bacterial lipopolysaccharide, hypoxia induced by Co2+, and ER stress induced by brefeldin A). In all the cases, except the acute inflammation, glucose uptake by adipocytes was reduced, and the kinetics of JNK1/2 activation was bi-phasic exhibiting sustained activation for 24 h. By contrast, in acute inflammation, JNK1/2 phosphorylation increased transiently and returned to the basal level within 2-3 h of stimulation. These results suggest a critical role of sustained (latent) vs. transient (acute) inflammation in the induction of IR and impairment of glucose utilization by adipose tissue. The components of the inflammatory signaling can be promising targets in the development of new therapeutic approaches for preventing IR and type 2 diabetes.
  2. Diabetes Metab J. 2019 Apr 23.
    Wang Y, Lee MYK, Mak JCW, Ip MSM.
      BACKGROUND: The relationship between obstructive sleep apnoea (OSA) and metabolic disorders is complex and highly associated. The impairment of adipogenic capacity in pre-adipocytes may promote adipocyte hypertrophy and increase the risk of further metabolic dysfunction. We hypothesize that intermittent hypoxia (IH), as a pathophysiologic feature of OSA, may regulate adipogenesis by promoting macrophage polarization.METHODS: Male C57BL/6N mice were exposed to either IH (240 seconds of 10% O₂ followed by 120 seconds of 21% O₂, i.e., 10 cycles/hour) or intermittent normoxia (IN) for 6 weeks. Stromal-vascular fractions derived from subcutaneous (SUB-SVF) and visceral (VIS-SVF) adipose tissues were cultured and differentiated. Conditioned media from cultured RAW 264.7 macrophages after air (Raw) or IH exposure (Raw-IH) were incubated with SUB-SVF during adipogenic differentiation.
    RESULTS: Adipogenic differentiation of SUB-SVF but not VIS-SVF from IH-exposed mice was significantly downregulated in comparison with that derived from IN-exposed mice. IH-exposed mice compared to IN-exposed mice showed induction of hypertrophic adipocytes and increased preferential infiltration of M1 macrophages in subcutaneous adipose tissue (SAT) compared to visceral adipose tissue. Complementary in vitro analysis demonstrated that Raw-IH media significantly enhanced inhibition of adipogenesis of SUB-SVF compared to Raw media, in agreement with corresponding gene expression levels of differentiation-associated markers and adipogenic transcription factors.
    CONCLUSION: Low frequency IH exposure impaired adipogenesis of SAT in lean mice, and macrophage polarization may be a potential mechanism for the impaired adipogenesis.
    Keywords:  Adipogenesis; Hypoxia; Inflammation; Macrophages
  3. Glia. 2019 Jun 24.
    Karunakaran I, Alam S, Jayagopi S, Frohberger SJ, Hansen JN, Kuehlwein J, Hölbling BV, Schumak B, Hübner MP, Gräler MH, Halle A, van Echten-Deckert G.
      Microglia mediated responses to neuronal damage in the form of neuroinflammation is a common thread propagating neuropathology. In this study, we investigated the microglial alterations occurring as a result of sphingosine 1-phosphate (S1P) accumulation in neural cells. We evidenced increased microglial activation in the brains of neural S1P-lyase (SGPL1) ablated mice (SGPL1fl/fl/Nes ) as shown by an activated and deramified morphology and increased activation markers on microglia. In addition, an increase of pro-inflammatory cytokines in sorted and primary cultured microglia generated from SGPL1 deficient mice was noticed. Further, we assessed autophagy, one of the major mechanisms in the brain that keeps inflammation in check. Indeed, microglial inflammation was accompanied by defective microglial autophagy in SGPL1 ablated mice. Rescuing autophagy by treatment with rapamycin was sufficient to decrease interleukin 6 (IL-6) but not tumor necrosis factor (TNF) secretion in cultured microglia. Rapamycin mediated decrease of IL-6 secretion suggests a particular mechanistic target of rapamycin (mTOR)-IL-6 link and appeared to be microglia specific. Using pharmacological inhibitors of the major receptors of S1P expressed in the microglia, we identified S1P receptor 2 (S1PR2) as the mediator of both impaired autophagy and proinflammatory effects. In line with these results, the addition of exogenous S1P to BV2 microglial cells showed similar effects as those observed in the genetic knock out of SGPL1 in the neural cells. In summary, we show a novel role of the S1P-S1PR2 axis in the microglia of mice with neural-targeted SGPL1 ablation and in BV2 microglial cell line exogenously treated with S1P.
    Keywords:  autophagy; inflammation; microglia; sphingosine 1-phosphate
  4. Cells. 2019 Jun 21. pii: E624. [Epub ahead of print]8(6):
    Knowles HJ.
      Osteoclast-mediated bone destruction is amplified in the hypoxic synovial microenvironment of rheumatoid arthritis (RA). This increased bone resorption is driven by the hypoxia-inducible transcription factor HIF. We identified hypoxic induction of the HIF-regulated adenosine A2B receptor in primary human osteoclasts (mRNA, 3.8-fold increase, p < 0.01) and sought to identify the role(s) of purinergic signaling via this receptor in the bone resorption process. Primary human osteoclasts were differentiated from CD14+ monocytes and exposed to hypoxia (2% O2) and A2B receptor inhibitors (MRS1754, PSB603). The hypoxic increase in bone resorption was prevented by the inhibition of the A2B receptor, at least partly by the attenuation of glycolytic and mitochondrial metabolism via inhibition of HIF. A2B receptor inhibition also reduced osteoclastogenesis in hypoxia by inhibiting early cell fusion (day 3-4, p < 0.05). The A2B receptor is only functional in hypoxic or inflammatory environments when the extracellular concentrations of adenosine (1.6-fold increase, p < 0.05) are sufficient to activate the receptor. Inhibition of the A2B receptor under normoxic conditions therefore did not affect any parameter tested. Reciprocal positive regulation of HIF and the A2B receptor in a hypoxic microenvironment thus enhances glycolytic and mitochondrial metabolism in osteoclasts to drive increased bone resorption. A2B receptor inhibition could potentially prevent the pathological osteolysis associated with hypoxic diseases such as rheumatoid arthritis.
    Keywords:  ATP; adenosine; adenosine A2B receptor; bone resorption; glycolysis; hypoxia; hypoxia-inducible factor (HIF); osteoclast
  5. Curr Opin Immunol. 2019 Jun 20. pii: S0952-7915(19)30018-4. [Epub ahead of print]60 111-116
    Knight M, Stanley S.
      Hypoxia-inducible transcription factor-1α (HIF-1α) was originally identified as a master regulator of cellular responses to hypoxia. More recently, HIF-1α has emerged as a critical regulator of immune cell function that couples shifts in cellular metabolism to cell type-specific transcriptional outputs. Activation of macrophages with inflammatory stimuli leads to induction of the metabolic program aerobic glycolysis and to HIF-1α stabilization, which reinforce one another in a positive feedback loop that helps drive macrophage activation. This activation of aerobic glycolysis and HIF-1α is important both for production of inflammatory cytokines, such as IL-1β, and for cell intrinsic control of infection. Here, we review the importance of HIF-1α for control of bacterial, fungal, and protozoan intracellular pathogens, highlighting recent findings that reveal mechanisms by which HIF-1α is activated during infection and how HIF-1α coordinates antimicrobial responses of macrophages.
  6. Cancer Res. 2019 Jun 25. pii: canres.3436.2018. [Epub ahead of print]
    Zuazo-Gaztelu I, Pàez-Ribes M, Carrasco P, Martin L, Soler A, Martínez-Lozano M, Pons R, Llena J, Palomero L, Graupera M, Casanovas O.
      One of the main consequences of inhibition of neovessel growth and vessel pruning produced by angiogenesis inhibitors is increased intratumor hypoxia. Growing evidence indicates that tumor cells escape from this hypoxic environment to better nourished locations, presenting hypoxia as a positive stimulus for invasion. In particular, anti-VEGF/R therapies produce hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer (PanNET), RIP1-Tag2. Here, a novel vascular targeting agent targeting Semaphorin 4D (Sema4D) demonstrated impaired tumor growth and extended survival in the RIP1-Tag2 model. Surprisingly, although there was no induction of intratumor hypoxia by anti-Sema4D therapy, the increase in local invasion and distant metastases were comparable with the ones produced by VEGFR inhibition. Mechanistically, the antitumor effect was due to an alteration in vascular function by modification of pericyte coverage involving PDGF-B. On the other hand, the aggressive phenotype involved a macrophage-derived Sema4D signaling engagement which induced their recruitment to the tumor invasive fronts and secretion of stromal derived factor 1 (SDF1) that triggered tumor cell invasive behavior via CXCR4. A comprehensive clinical validation of the targets in different stages of PanNETs demonstrated the implication of both Sema4D and CXCR4 in tumor progression. Taken together, we demonstrate beneficial anti-tumor and pro-survival effects of anti-Sema4D antibody but also unravel a novel mechanism of tumor aggressivity. This mechanism implicates recruitment of Sema4D positive macrophages to invasive fronts and their secretion of pro-invasive molecules that ultimately induce local tumor invasion and distant metastasis in PanNETs.
  7. Cytokine Growth Factor Rev. 2019 Jun 15. pii: S1359-6101(19)30045-0. [Epub ahead of print]
    Liang W, Ye DD.
      Over the past decades, there has been a major increase in type 2 diabetes (T2D) prevalence in most regions of the world. Diabetic patients are more prone to cardiovascular complications. Accumulating evidence suggests that adipose tissue is not simply an energy storage tissue but it also functions as a secretory tissue producing a variety of bioactive substances, also referred to as adipokines. The balance between pro-inflammatory adipokines and protective adipokines is disturbed in type 2 diabetes, this can be regarded as adipose tissue dysfunction which partly promote the pathogenesis of diabetes complications. In this review, we not only discuss the favorable adipokines like adiponectin, omentin, C1q tumor necrosis factor-related proteins, but also unfavorable ones like resisitin and visfatin, in the aim of finding potential biomarkers recommended for the clinical use in the diagnosis, prognosis and follow up of patients with T2D at high risk of developing cardiovascular diseases as well as leading to new therapeutic approaches.
    Keywords:  Adipokines; Adipose tissue; Cardiovascular disease; Type 2 diabetes; Vascular endothelial dysfunction
  8. Diabetes Metab Syndr Obes. 2019 ;12 801-811
    Liu B, Mao X, Huang D, Li F, Dong N.
      Background: The liver coordinates a series of metabolic adaptations to maintain the energy balance of the system and provide adequate nutrients to key organs, tissues and cells during starvation. However, the mediators and underlying molecular mechanisms that mediate these fasting-induced adaptive responses remain unclear. Materials and methods: Male wild-type C57BL/6J littermates (8-weeks-old) were intraperitoneally injected with MCC950 or vehicle, and then randomly divided into three groups: fed, fasted, and refed. Plasma IL1β and insulin levels were detected by ELISA kits. Plasma and hepatic metabolites were determined using commercial assay kits. HepaRG cell line was applied to verify the regulation of NLRP3 on lipogenesis. Results: NOD-like receptor protein 3 (NLRP3) and its downstream inflammatory cytokines were significantly suppressed after 24 h fasting and recovered upon 6 h refeeding in plasma and liver tissues of mice. Moreover, fasting-induced hepatic steatosis and accompanied liver injury were ameliorated when mice were intraperitoneally injected with MCC950 (a selective NLRP3 inhibitor). Further study revealed that MCC950 suppressed sterol regulatory element-binding protein-1c (SREBP-1c) expression and transcriptional activity, thus inhibited lipogenesis in the liver, which may explain its role in stabilizing lipid metabolism. Conclusion: The NLRP3 inhibitor-MCC950 protects against fasting-induced hepatic steatosis. The novel and critical role of NLRP3 in lipogenesis may explain its importance in regulating the adaptive responses of the liver upon starvation stress and may provide therapeutic value.
    Keywords:  MCC950; NLRP3; SREBP-1c; metabolic homeostasis; starvation stress