bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2019‒11‒17
five papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Biochem J. 2019 Nov 11. pii: BCJ20190709. [Epub ahead of print]
    Kusuyama J, Bandow K, Ohnishi T, Amir MS, Shima K, Semba I, Matsuguchi T.
      Hypoxia in adipose tissue is regarded as a trigger that induces dysregulation of the secretory profile in adipocytes. Similarly, local dysregulation of adipocytokine secretion is an initial event in the deleterious effects of obesity on metabolism. We previously reported that CXCL13 is highly produced during adipogenesis, however little is known about the roles of CXCL13 in adipocytes. Here, we found that hypoxia, as modeled by 1% O2 or exposure to the hypoxia-mimetic reagent desferrioxamine (DFO) has strong inductive effects on the expression of CXCL13 and CXCR5, a CXCL13 receptor, in both undifferentiated and differentiated adipocytes and in organ-cultured white adipose tissue (WAT). CXCL13 was also highly expressed in WAT from high fat diet-fed mice. Hypoxic profile, typified by increased expression of IL-6 and PAI-1 and decreased expression of adiponectin, was significantly induced by CXCL13 treatment during adipogenic differentiation. Conversely, the treatment of adipocytes with a neutralizing-antibody against CXCL13 as well as CXCR5 knockdown by specific siRNA effectively inhibited DFO-induced inflammation. The phosphorylation of Akt2, a protective factor of adipose inflammation, was significantly inhibited by CXCL13 treatment during adipogenic differentiation. Mechanistically, CXCL13 induces the expression of PHLPP1, an Akt2 phosphatase, through FAK signaling; and correspondingly we show that CXCL13 and DFO-induced IL-6 and PAI-1 expression was blocked by Phlpp1 knockdown. Furthermore, we revealed the functional binding sites of PPARg2 and HIF1-a within the Cxcl13 promoter. Taken together, these results indicate that CXCL13 is an adipocytokine that facilitates hypoxia-induced inflammation in adipocytes through FAK-mediated induction of PHLPP1 in autocrine and/or paracrine manner.
    Keywords:  adipokines; hypoxia; inflammation
    DOI:  https://doi.org/10.1042/BCJ20190709
  2. Eur J Vasc Endovasc Surg. 2019 Nov 12. pii: S1078-5884(19)30530-1. [Epub ahead of print]
    Portou MJ, Yu R, Baker D, Xu S, Abraham D, Tsui J.
      OBJECTIVE: Diabetes mellitus has reached epidemic proportions. Foot ulceration is a multifactorial complication of diabetes associated with marked morbidity and mortality. Innate immune Toll-like receptor 4 (TLR4) mediated inflammation has been implicated in the systemic pathogenesis of diabetes and may contribute to impairment of wound healing. This study investigates the effect of high glucose and hypoxic conditions on TLR4 activation and signalling in vitro and in vivo.METHODS: Fibroblasts cultured at physiological glucose concentration (5.5 mM) were exposed to glucose concentrations from 0 mM to 25 mM, with duplicates placed in a hypoxic chamber. TLR4 inhibition was assessed in the 25 mM glucose groups. Diabetes was induced in wild type (WT) and TLR4 knockout (KO) C57BL/6 mice by intraperitoneal injection of low dose streptozocin (STZ). Hindlimb ischaemia was induced by femoral artery ligation four weeks post streptozocin, and a full thickness 4 mm skin wound inflicted below the knee. Wound healing was assessed via digital planimetry on days 3, 7, and 14 post surgery.
    RESULTS: Hypoxic and high glucose (25 mM) conditions led to an increase in TLR4 protein expression, apoptosis, and interleukin (IL)-6 release. Inhibition with a TLR4 neutralising antibody and specific TLR4 antagonist ameliorated the effects of high glucose and ischaemia (p < .05). In vivo, wound healing was significantly impaired in the diabetic ischaemic group at day 14 (p < .05). Diabetic ischaemic wounds in TLR4 KO mice exhibited significantly improved healing rates compared with those in WT mice at all time points.
    CONCLUSION: Hypoxia stimulates upregulation of TLR4 protein expression and this effect is exaggerated by hyperglycaemia. In TLR4 KO mice, there is a significant improvement in the healing of diabetic ischaemic wounds compared with WT. It is suggested that a synergistic effect between hypoxia and hyperglycaemia impairing wound healing exists, through TLR4 mediated inflammation.
    Keywords:  Diabetes; Hyperglycaemia; Inflammation; Ischaemia; Toll-like receptor 4; Wound healing
    DOI:  https://doi.org/10.1016/j.ejvs.2019.06.018
  3. Cell Metab. 2019 Oct 29. pii: S1550-4131(19)30559-5. [Epub ahead of print]
    Pucino V, Certo M, Bulusu V, Cucchi D, Goldmann K, Pontarini E, Haas R, Smith J, Headland SE, Blighe K, Ruscica M, Humby F, Lewis MJ, Kamphorst JJ, Bombardieri M, Pitzalis C, Mauro C.
      Accumulation of lactate in the tissue microenvironment is a feature of both inflammatory disease and cancer. Here, we assess the response of immune cells to lactate in the context of chronic inflammation. We report that lactate accumulation in the inflamed tissue contributes to the upregulation of the lactate transporter SLC5A12 by human CD4+ T cells. SLC5A12-mediated lactate uptake into CD4+ T cells induces a reshaping of their effector phenotype, resulting in increased IL17 production via nuclear PKM2/STAT3 and enhanced fatty acid synthesis. It also leads to CD4+ T cell retention in the inflamed tissue as a consequence of reduced glycolysis and enhanced fatty acid synthesis. Furthermore, antibody-mediated blockade of SLC5A12 ameliorates the disease severity in a murine model of arthritis. Finally, we propose that lactate/SLC5A12-induced metabolic reprogramming is a distinctive feature of lymphoid synovitis in rheumatoid arthritis patients and a potential therapeutic target in chronic inflammatory disorders.
    Keywords:  T cell; cytokines; immunometabolism; inflammation; lactate; lactate transporter; metabolic crosstalk; signaling; translational research
    DOI:  https://doi.org/10.1016/j.cmet.2019.10.004
  4. Med Oncol. 2019 Nov 11. 37(1): 2
    Tamura R, Tanaka T, Akasaki Y, Murayama Y, Yoshida K, Sasaki H.
      The microvasculature and immune cells are major components of the tumor microenvironment (TME). Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1α) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1α directly induces immune checkpoint molecules. VEGF/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological "cold tumors" into the "hot tumors". Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.
    Keywords:  Hypoxia; Immune checkpoint molecule; Myeloid-derived suppressor cell; Regulatory T cell; Tumor microenvironment; Tumor-associated macrophage; VEGF
    DOI:  https://doi.org/10.1007/s12032-019-1329-2
  5. Front Bioeng Biotechnol. 2019 ;7 292
    Almeria C, Weiss R, Roy M, Tripisciano C, Kasper C, Weber V, Egger D.
      Mesenchymal stem/stromal cells (MSCs) display a variety of therapeutically relevant effects, such as the induction of angiogenesis, particularly under hypoxic conditions. It is generally recognized that MSCs exert their effects by secretion of paracrine factors and by stimulation of host cells. Furthermore, there is increasing evidence that some therapeutically relevant effects of MSCs are mediated by MSC-derived extracellular vesicles (EVs). Since our current knowledge on MSC-derived EVs released under hypoxic conditions is very limited, we aimed to characterize MSC-derived EVs from normoxic vs. hypoxic conditions (5% O2). Adipose-derived MSCs were grown under normoxic and hypoxic conditions, and EVs were analyzed by flow cytometry using lactadherin as a marker for EVs exposing phosphatidylserine, CD63 and CD81 as EV markers, as well as CD73 and CD90 as MSC surface markers. Particle concentration and size distribution were measured by nanoparticle tracking analysis (NTA), and the EV surface antigen signature was characterized using bead-based multiplex flow cytometry. Furthermore, we evaluated the potential of MSC-derived EVs obtained under hypoxic conditions to support angiogenesis using an in vitro assay with an hTERT-immortalized human umbilical vein endothelial cell (HUVEC) line. Proliferation and viability of MSCs were increased under hypoxic conditions. EV concentration, size, and surface signature did not differ significantly between normoxic and hypoxic conditions, with the exception of CD44, which was significantly upregulated on normoxic EVs. EVs from hypoxic conditions exhibited increased tube formation as compared to normoxic EVs or to the corresponding supernatants from both groups, indicating that tube formation is facilitated by EVs rather than by soluble factors. In conclusion, hypoxia conditioned MSC-derived EVs appear to be functionally more potent than normoxic MSC-derived EVs regarding the induction of angiogenesis.
    Keywords:  angiogenesis; extracellular vesicles; hypoxia; mesenchymal stem cells; therapeutic potential; tube formation
    DOI:  https://doi.org/10.3389/fbioe.2019.00292