bims-stacyt 2021-01-10 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2021–01–10
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Impaired capillary tube formation induced by elevated secretion of IL8 involves altered signaling via the CXCR1/PI3K/MMP2 pathway.
Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments.
Glycolysis-induced drug resistance in tumors-A response to danger signals?
The effects of intermittent hypoxia on human nasal mucosa.
Cancer-associated adipocytes as immunomodulators in cancer.
Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion.
LncRNA HOTAIR regulates glucose transporter Glut1 expression and glucose uptake in macrophages during inflammation.
Autophagy down-regulates NLRP3-dependent inflammatory response of intestinal epithelial cells under nutrient deprivation.
Neuronal Exosomes Secreted under Oxygen-Glucose Deprivation/Reperfusion Presenting Differentially Expressed miRNAs and Affecting Neuronal Survival and Neurite Outgrowth.

Mol Biol Rep. 2021 Jan 07.

Impaired capillary tube formation induced by elevated secretion of IL8 involves altered signaling via the CXCR1/PI3K/MMP2 pathway.

Yifat Amir Levy, Theodore P Ciaraldi, Robert R Henry.

  Angiogenesis is a multistep process requiring endothelial cell activation, migration, proliferation and tube formation. We recently reported that elevated secretion of interlukin 8 (IL8) by myotubes (MT) from subjects with Type-2 Diabetes (T2D) reduced angiogenesis by human umbilical vein endothelial cells (HUVEC) and human skeletal muscle explants. This lower vascularization was mediated through impaired activation of the phosphatidylinositol 3-kinase (PI3K)-pathway. We sought to investigate additional signaling elements that might mediate reduced angiogenesis. HUVEC were exposed to levels of IL8 equal to those secreted by MT from non-diabetic (ND) and T2D subjects and the involvement of components in the angiogenic response pathway examined. Cellular content of reactive oxygen species and Nitrate secretion were similar after treatment with [ND-IL8] and [T2D-IL8]. CXCR1 protein was down-regulated after treatment with [T2D-IL8] (p < 0.01 vs [ND-IL8] treatment); CXCR2 expression was unaltered. Addition of neutralizing antibodies against CXCR1 and CXCR2 to HUVEC treated with IL8 confirmed that CXCR1 alone mediated the angiogenic response to IL8. A key modulator of angiogenesis is matrix metalloproteinase-2 (MMP2). MMP2 secretion was higher after treatment with [ND-IL8] vs [T2D-IL8] (p < 0.01). MMP2 inhibition reduced tube formation to greater extent with [ND-IL8] than with [T2D-IL8] (p < 0.005). The PI3K-pathway inhibitor LY294002 reduced IL8-induced MMP2 release. IL8 regulation of MMP2 release was CXCR1 dependent, as anti-CXCR1 significantly reduced MMP2 release (p < 0.05). These results suggest that high levels of IL8 secreted by T2D MT trigger reduced capillarization via lower activation of a CXCR1-PI3K pathway, followed by impaired release and activity of MMP2.

Keywords:  Angiogenesis; IL-8; MMP-2; Myokines; Skeletal muscle; Type 2 diabetes

DOI:  https://doi.org/10.1007/s11033-020-06104-z
Mol Cancer. 2021 Jan 04. 20(1): 7

Mechanisms of vasculogenic mimicry in hypoxic tumor microenvironments.

Xiaoxu Wei, Yunhua Chen, Xianjie Jiang, Miao Peng, Yiduo Liu, Yongzhen Mo, Daixi Ren, Yuze Hua, Boyao Yu, Yujuan Zhou, Qianjin Liao, Hui Wang, Bo Xiang, Ming Zhou, Xiaoling Li, Guiyuan Li, Yong Li, Wei Xiong, Zhaoyang Zeng.

   BACKGROUND: Vasculogenic mimicry (VM) is a recently discovered angiogenetic process found in many malignant tumors, and is different from the traditional angiogenetic process involving vascular endothelium. It involves the formation of microvascular channels composed of tumor cells; therefore, VM is considered a new model for the formation of new blood vessels in aggressive tumors, and can provide blood supply for tumor growth. Many studies have pointed out that in recent years, some clinical treatments against angiogenesis have not been satisfactory possibly due to the activation of VM. Although the mechanisms underlying VM have not been fully elucidated, increasing research on the soil "microenvironment" for tumor growth suggests that the initial hypoxic environment in solid tumors is inseparable from VM.
MAIN BODY: In this review, we describe that the stemness and differentiation potential of cancer stem cells are enhanced under hypoxic microenvironments, through hypoxia-induced epithelial-endothelial transition (EET) and extracellular matrix (ECM) remodeling to form the specific mechanism of vasculogenic mimicry; we also summarized some of the current drugs targeting VM through these processes, suggesting a new reference for the clinical treatment of tumor angiogenesis.
CONCLUSION: Overall, the use of VM inhibitors in combination with conventional anti-angiogenesis treatments is a promising strategy for improving the effectiveness of targeted angiogenesis treatments; further, considering the importance of hypoxia in tumor invasion and metastasis, drugs targeting the hypoxia signaling pathway seem to achieve good results.

Keywords:  Cancer stem cells; Epithelial-endothelial transition; Extracellular matrix remodeling; Hypoxia; Targeted angiogenesis drugs; Vascular mimicry

DOI:  https://doi.org/10.1186/s12943-020-01288-1
Neoplasia. 2021 Jan 05. pii: S1476-5586(20)30190-1. [Epub ahead of print]23(2): 234-245

Glycolysis-induced drug resistance in tumors-A response to danger signals?

Fabrizio Marcucci, Cristiano Rumio.

  Tumor cells often switch from mitochondrial oxidative metabolism to glycolytic metabolism even under aerobic conditions. Tumor cell glycolysis is accompanied by several nonenzymatic activities among which induction of drug resistance has important therapeutic implications. In this article, we review the main aspects of glycolysis-induced drug resistance. We discuss the classes of antitumor drugs that are affected and the components of the glycolytic pathway (transporters, enzymes, metabolites) that are involved in the induction of drug resistance. Glycolysis-associated drug resistance occurs in response to stimuli, either cell-autonomous (e.g., oncoproteins) or deriving from the tumor microenvironment (e.g., hypoxia or pseudohypoxia, mechanical cues, etc.). Several mechanisms mediate the induction of drug resistance in response to glycolytic metabolism: inhibition of apoptosis, induction of epithelial-mesenchymal transition, induction of autophagy, inhibition of drug influx and increase of drug efflux. We suggest that drug resistance in response to glycolysis comes into play in presence of qualitative (e.g., expression of embryonic enzyme isoforms, post-translational enzyme modifications) or quantitative (e.g., overexpression of enzymes or overproduction of metabolites) alterations of glycolytic metabolism. We also discern similarities between changes occurring in tumor cells in response to stimuli inducing glycolysis-associated drug resistance and those occurring in cells of the innate immune system in response to danger signals and that have been referred to as danger-associated metabolic modifications. Eventually, we briefly address that also mitochondrial oxidative metabolism may induce drug resistance and discuss the therapeutic implications deriving from the fact that the main energy-generating metabolic pathways may be both at the origin of antitumor drug resistance.

Keywords:  Apoptosis; Danger; Drug resistance; EMT; Glycolysis; Tumors

DOI:  https://doi.org/10.1016/j.neo.2020.12.009
Sleep Breath. 2021 Jan 02.

The effects of intermittent hypoxia on human nasal mucosa.

Seung Min In, Do-Yang Park, Ki-Il Lee, Gayoung Gu, Hyun Jun Kim.

   PURPOSE: Intermittent hypoxia (IH) is characterized by hypoxia-reoxygenation, reported to be a critical risk factor for obstructive sleep apnea (OSA). This experiment aimed to evaluate the direct effects of IH on the human nasal mucosa.
METHODS: The direct effects of IH on the human nasal mucosa was evaluated by measuring the ciliary beat frequency (CBF) and expression levels of inflammatory cytokines (granulocyte-macrophage colony-stimulating factor, transforming growth factor-β, interleukin-6, and tumor necrosis factor-α). The normoxia group was exposed to a normoxic condition for 72 h. The IH group was exposed to 288 cycles of IH (1 cycle: hypoxia, 5 min; subsequent normoxia, 10 min) for 72 h. CBF was measured using an automated computer-based video image processing technique. Changes in the expression of cytokines were assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS: The normoxia group revealed a persistent CBF pattern and a physiological range of inflammatory cytokines. However, the IH group showed a cyclic decrease in CBF and increased expression of inflammatory cytokines. Cytotoxicity assay indicated no difference in the survival rates between the two groups.
CONCLUSIONS: IH results in increased expression of inflammatory cytokines that adversely affects the mucociliary transport in the upper airway and, consequently, may result in airway inflammation.

Keywords:  Ciliary beat frequency; Cytokine; Hypoxia/reoxygenation; Inflammation; Obstructive sleep apnea

DOI:  https://doi.org/10.1007/s11325-020-02280-1
Biomark Res. 2021 Jan 07. 9(1): 2

Cancer-associated adipocytes as immunomodulators in cancer.

Qi Wu, Bei Li, Juanjuan Li, Si Sun, Jingping Yuan, Shengrong Sun.

  Cancer-associated adipocytes (CAAs), as a main component of the tumor-adipose microenvironment (TAME), have various functions, including remodeling the extracellular matrix and interacting with tumor cells or infiltrated leukocytes through a variety of mutual signals. Here, we summarize the primary interplay among CAAs, the immune response and cancer with a focus on the mechanistic aspects of these relationships. Finally, unifying our understanding of CAAs with the immune cell function may be an effective method to enhance the efficacy of immunotherapeutic and conventional treatments.

Keywords:  Cancer-associated adipocytes; Immune cells; Metabolism; Tumor

DOI:  https://doi.org/10.1186/s40364-020-00257-6
Nat Immunol. 2021 Jan 04.

Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion.

Nicole E Scharping, Dayana B Rivadeneira, Ashley V Menk, Paolo D A Vignali, B Rhodes Ford, Natalie L Rittenhouse, Ronal Peralta, Yiyang Wang, Yupeng Wang, Kristin DePeaux, Amanda C Poholek, Greg M Delgoffe.

Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8+ T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell-intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates.

DOI: https://doi.org/10.1038/s41590-020-00834-9
Sci Rep. 2021 Jan 08. 11(1): 232

LncRNA HOTAIR regulates glucose transporter Glut1 expression and glucose uptake in macrophages during inflammation.

Monira Obaid, S M Nashir Udden, Prasanna Alluri, Subhrangsu S Mandal.

Inflammation plays central roles in the immune response. Inflammatory response normally requires higher energy and therefore is associated with glucose metabolism. Our recent study demonstrates that lncRNA HOTAIR plays key roles in NF-kB activation, cytokine expression, and inflammation. Here, we investigated if HOTAIR plays any role in the regulation of glucose metabolism in immune cells during inflammation. Our results demonstrate that LPS-induced inflammation induces the expression of glucose transporter isoform 1 (Glut1) which controls the glucose uptake in macrophages. LPS-induced Glut1 expression is regulated via NF-kB activation. Importantly, siRNA-mediated knockdown of HOTAIR suppressed the LPS-induced expression of Glut1 suggesting key roles of HOTAIR in LPS-induced Glut1 expression in macrophage. HOTAIR induces NF-kB activation, which in turn increases Glut1 expression in response to LPS. We also found that HOTAIR regulates glucose uptake in macrophages during LPS-induced inflammation and its knockdown decreases LPS-induced increased glucose uptake. HOTAIR also regulates other upstream regulators of glucose metabolism such as PTEN and HIF1α, suggesting its multimodal functions in glucose metabolism. Overall, our study demonstrated that lncRNA HOTAIR plays key roles in LPS-induced Glut1 expression and glucose uptake by activating NF-kB and hence HOTAIR regulates metabolic programming in immune cells potentially to meet the energy needs during the immune response.

DOI: https://doi.org/10.1038/s41598-020-80291-4
BMB Rep. 2021 Jan 07. pii: 5185. [Epub ahead of print]

Autophagy down-regulates NLRP3-dependent inflammatory response of intestinal epithelial cells under nutrient deprivation.

Yewon Yun, Ahruem Baek, Dong-Eun Kim.

Dysregulation of inflammation induced by noninfectious stress conditions, such as nutrient deprivation, causes tissue damage and intestinal permeability, resulting in the development of inflammatory bowel diseases. We studied the effect of autophagy on cytokine secretion related to intestinal permeability under nutrient deprivation. Autophagy removes NLRP3 inflammasomes via ubiquitin-mediated degradation under starvation. When autophagy was inhibited, starvation-induced NLRP3 inflammasomes and their product, IL-1β, were significantly enhanced. A prolonged nutrient deprivation resulted in an increased epithelial mesenchymal transition (EMT), leading to intestinal permeability. Under nutrient deprivation, IL-17E/25, which is secreted by IL-1β, demolished the intestinal epithelial barrier. Our results suggest that an upregulation of autophagy maintains the intestinal barrier by suppressing the activation of NLRP3 inflammasomes and the release of their products, including proinflammatory cytokines IL-1β and IL-17E/25, under nutrient deprivation.
Neuromolecular Med. 2021 Jan 03.

Neuronal Exosomes Secreted under Oxygen-Glucose Deprivation/Reperfusion Presenting Differentially Expressed miRNAs and Affecting Neuronal Survival and Neurite Outgrowth.

Chien-Sung Chiang, Ssu-Ju Fu, Chia-Lang Hsu, Chung-Jiuan Jeng, Chih-Yung Tang, Yi-Shuian Huang, Sung-Chun Tang.

  Ischemia/reperfusion is a key feature of acute ischemic stroke, which causes neuron dysfunction and death. Exosomes, small extracellular vesicles produced by most cell types, are implicated in the mediation of cellular interactions with their environment. Here, we investigated the contents and functions of exosomes from neurons under ischemic reperfusion injury. First, rat cortical primary neuronal cell cultures were placed in an oxygen- and glucose-deprived (OGD) medium, followed by reperfusion in a normoxic conditioned medium (OGD/R) to mimic ischemia/reperfusion in vitro. The neuron-derived exosomes were harvested from the conditioned medium under normoxia and OGD/R. Through next-generation sequencing, exosomal miRNA expression levels in normoxic and OGD/R condition were compared. Their functional activity in terms of neuron viability and quantitative analysis of neurite outgrowth were examined. The expression levels of 45 exosomal miRNAs were significantly different between normoxic and OGD/R conditions. Bioinformatics analysis of dysregulated exosomal miRNAs identified multiple pathways involved in cell survival and death processes and neuronal signaling. Moreover, treatment with exosomes from OGD/R to cultured cortical neurons significantly impaired neuronal cell viability and reduced neurite outgrowth in terms of the number of primary or total neurites as well as length of primary neurites, compared with exosomes from normoxic conditions. miRNA-packed exosomes released by neurons under OGD/R challenge may contribute to post ischemic neuronal injury and provide further understanding of the effect of stressed neurons on neighboring neuronal functions.

Keywords:  Exosomes; Neurite outgrowth; Neuron; Neuronal survival; Next-generation sequencing; OGD-R; miRNA

DOI:  https://doi.org/10.1007/s12017-020-08641-z