bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒04‒26
six papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Proc Natl Acad Sci U S A. 2020 Apr 20. pii: 201913707. [Epub ahead of print]
    Püschel F, Favaro F, Redondo-Pedraza J, Lucendo E, Iurlaro R, Marchetti S, Majem B, Eldering E, Nadal E, Ricci JE, Chevet E, Muñoz-Pinedo C.
      Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.
    Keywords:  cancer immunity; cancer metabolism; cytokines; glucose
    DOI:  https://doi.org/10.1073/pnas.1913707117
  2. Apoptosis. 2020 Apr 24.
    Cao X, Li B, Han X, Zhang X, Dang M, Wang H, Du F, Zeng X, Guo C.
      Soluble receptor for advanced glycation end-products (sRAGE), which exerts cardioprotective effect through inhibiting cardiomyocyte apoptosis and autophagy during ischemia/reperfusion (I/R) injury, is also known to enhance angiogenesis in post-ischemic reperfusion injury-critical limb ischemia (PIRI-CLI) mice. However, whether sRAGE protects the heart from myocardial I/R injury via promoting angiogenesis remains unclear. Myocardial model of I/R injury was conducted by left anterior descending (LAD) ligation for 30 min and reperfusion for 2 weeks in C57BL/6 mice. And I/R injury in cardiac microvascular endothelial cells (CMECs) was duplicated by oxygen and glucose deprivation. The results showed that I/R-induced cardiac dysfunction, inflammation and myocardial fibrosis were all reversed by sRAGE. CD31 immunohistochemistry staining showed that sRAGE increased the density of vessels after I/R injury. The results from cultured CMECs showed that sRAGE inhibited apoptosis and increased proliferation, migration, angiogenesis after exposure to I/R. These effects were dependent on signal transducer and activator of transcription 3 (STAT3) pathway. Together, the present study demonstrated that activation of STAT3 contributed to the protective effects of sRAGE on myocardial I/R injury via promoting angiogenesis.
    Keywords:  Angiogenesis; Endothelial cells; Ischemia/reperfusion injury; Signal transducer and activator of transcription 3; Soluble receptor for advanced glycation end-products
    DOI:  https://doi.org/10.1007/s10495-020-01602-8
  3. Gen Physiol Biophys. 2020 Mar;39(2): 169-177
    Yang Q, Li S, Zhou Z, Fu M, Yang X, Hao K, Liu Y.
      The present study aimed to investigate the effects of histone deacetylase 6 (HDAC6) inhibitor Cay10603 (Cay) on high glucose (HG)-stimulated human retinal pigment epithelium (RPE) cells and its underlying mechanisms. ARPE-19 cells were cultured under normal glucose (NG) or high glucose (HG) conditions. The results revealed that HDAC6 was upregulated in HG-stimulated ARPE-19 cells. Cay treatment caused a decrease in intracellular reactive oxygen species (ROS). The levels of malondialdehyde (MDA) and myeloperoxidase (MPO) were reduced accompanied by increase in the activities of superoxide dismutase (SOD) and catalase (CAT) after treatment with Cay. Besides, Cay decreased the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 and monocyte chemoattractant protein-1 (MCP-1) in supernatant. Meanwhile, the apoptotic rate in Cay-treated ARPE-19 cells notably reduced, coupled with an upregulation in Bcl-2 expression and a downregulation in cleaved caspase-3 and cleaved caspase-9 expression. Cay decreased the expression of phospho (p)-NF-κB p65, p-IκB-α, NLRP3, cleaved caspase-1 and ASC while increased the expression of NF-κB p65 (cytoplasm). Taken together, these findings demonstrated that Cay suppressed HG-induced oxidative stress, inflammation and apoptosis via regulating NF-κB and NLRP3 inflammasome pathway in HG-induced ARPE-19 cells, suggesting that Cay might be a therapeutic agent for the treatment of diabetic retinopathy.
    DOI:  https://doi.org/10.4149/gpb_2019058
  4. Cells. 2020 Apr 22. pii: E1043. [Epub ahead of print]9(4):
    Kadye R, Stoffels M, Fanucci S, Mbanxa S, Prinsloo E.
      Metabolic remodelling of the tumour microenvironment is a major mechanism by which cancer cells survive and resist treatment. The pro-oncogenic inflammatory cascade released by adipose tissue promotes oncogenic transformation, proliferation, angiogenesis, metastasis and evasion of apoptosis. STAT3 has emerged as an important mediator of metabolic remodelling. As a downstream effector of adipocytokines and cytokines, its canonical and non-canonical activities affect mitochondrial functioning and cancer metabolism. In this review, we examine the central role played by the crosstalk between the transcriptional and mitochondrial roles of STAT3 to promote survival and further oncogenesis within the tumour microenvironment with a particular focus on adipose-breast cancer interactions.
    Keywords:  STAT3; adipocytokine signalling; adipose tissue; cancer; inflammation; mitochondrial STAT3; oncogenesis
    DOI:  https://doi.org/10.3390/cells9041043
  5. FASEB J. 2020 Apr 25.
    Contreras-Lopez R, Elizondo-Vega R, Paredes MJ, Luque-Campos N, Torres MJ, Tejedor G, Vega-Letter AM, Figueroa-Valdés A, Pradenas C, Oyarce K, Jorgensen C, Khoury M, Garcia-Robles MLA, Altamirano C, Djouad F, Luz-Crawford P.
      Hypoxia-inducible factor 1 α (HIF1α), a regulator of metabolic change, is required for the survival and differentiation potential of mesenchymal stem/stromal cells (MSC). Its role in MSC immunoregulatory activity, however, has not been completely elucidated. In the present study, we evaluate the role of HIF1α on MSC immunosuppressive potential. We show that HIF1α silencing in MSC decreases their inhibitory potential on Th1 and Th17 cell generation and limits their capacity to generate regulatory T cells. This reduced immunosuppressive potential of MSC is associated with a metabolic switch from glycolysis to OXPHOS and a reduced capacity to express or produce some immunosuppressive mediators including Intercellular Adhesion Molecule (ICAM), IL-6, and nitric oxide (NO). Moreover, using the Delayed-Type Hypersensitivity murine model (DTH), we confirm, in vivo, the critical role of HIF1α on MSC immunosuppressive effect. Indeed, we show that HIF1α silencing impairs MSC capacity to reduce inflammation and inhibit the generation of pro-inflammatory T cells. This study reveals the pivotal role of HIF1α on MSC immunosuppressive activity through the regulation of their metabolic status and identifies HIF1α as a novel mediator of MSC immunotherapeutic potential.
    Keywords:  HIF1α; MSCs; glycolytic; immunomodulation; immunosuppression; metabolic reprogramming; metabolism
    DOI:  https://doi.org/10.1096/fj.201902232R
  6. Kidney Int. 2020 Feb 04. pii: S0085-2538(20)30113-7. [Epub ahead of print]
    Wang F, Yin J, Lin Y, Zhang F, Liu X, Zhang G, Kong Y, Lu Z, Wu R, Wang N, Xing T, Qian Y.
      Cytokines are necessary to trigger the inflammatory response in kidney ischemia/reperfusion injury. Interleukin-17C (IL-17C), a unique member of the IL-17 family, is a cytokine produced by epithelial cells implicated in host defense and autoimmune diseases. However, little is known about the role of IL-17C in acute kidney injury. We investigated this and found that IL-17C was significantly increased in kidney biopsies of patients and mice with acute kidney injury. Exposure to hypoxia induced upregulation of IL-17C in kidney tubular epithelial cells. To further investigate the role of IL-17C, kidney ischemia/reperfusion injury was induced in mice. Inhibition of IL-17C action with a neutralizing antibody or IL-17 receptor E (IL-17RE) knockout attenuated tubular injury, kidney oxidative stress, and kidney inflammation. Mechanistically, both IL-17C neutralization and IL-17RE knockout attenuated TH17 activation and IL-17A expression in kidneys of mice with acute kidney injury. TNF-α and IL-1β, downstream cytokines of IL-17C, were also reduced in IL-17C antibody pretreated and IL-17RE knockout mice. Additionally, IL-17C knockdown with siRNA decreased hypoxia-induced inflammation in kidney tubular cells and silencing IL-17RE abrogated the effects of IL-17C in kidney tubular cells. Thus, IL-17C may participate in the inflammatory response of acute kidney injury and inhibition of IL-17C or blockade of IL-17 RE may be a novel therapeutic strategy for the treatment of acute kidney injury.
    Keywords:  IL-17C; IL-17RE; acute kidney injury; inflammation; ischemia reperfusion injury
    DOI:  https://doi.org/10.1016/j.kint.2020.01.015