bims-stacyt 2021-08-01 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2021–08–01
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Lactic acid in macrophage polarization: The significant role in inflammation and cancer.
Signal transducer and activator of transcription-3 mediated neuroprotective effect of interleukin-6 on cobalt chloride mimetic hypoxic cell death in R28 cells.
Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies.
Exosomes derived from astrocytes after oxygen-glucose deprivation promote differentiation and migration of oligodendrocyte precursor cells in vitro.
Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis.
Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.
Diabetes Impaired Ischemia-Induced PDGF (Platelet-Derived Growth Factor) Signaling Actions and Vessel Formation Through the Activation of Scr Homology 2-Containing Phosphatase-1.
TGF-β links glycolysis and immunosuppression in glioblastoma.

Int Rev Immunol. 2021 Jul 25. 1-15

Lactic acid in macrophage polarization: The significant role in inflammation and cancer.

Hai-Cun Zhou, Xin-Yan Yan, Wen-Wen Yu, Xiao-Qin Liang, Xiao-Yan Du, Zhi-Chang Liu, Jian-Ping Long, Guang-Hui Zhao, Hong-Bin Liu.

Metabolite lactic acid has always been regarded as a metabolic by-product rather than a bioactive molecule. Recently, this view has changed since it was discovered that lactic acid can be used as a signal molecule and has novel signal transduction functions both intracellular and extracellular, which can regulate key functions in the immune system. In recent years, more and more evidence has shown that lactic acid is closely related to the metabolism and polarization of macrophages. During inflammation, lactic acid is a regulator of macrophage metabolism, and it can prevent excessive inflammatory responses; In malignant tumors, lactic acid produced by tumor tissues promotes the polarization of tumor-associated macrophages, which in turn promotes tumor progression. In this review, we examined the relationship between lactic acid and macrophage metabolism. We further discussed how lactic acid plays a role in maintaining the homeostasis of macrophages, as well as the biology of macrophage polarization and the M1/M2 imbalance in human diseases. Potential methods to target lactic acid in the treatment of inflammation and cancer will also be discussed so as to provide new strategies for the treatment of diseases.

DOI: https://doi.org/10.1080/08830185.2021.1955876
Mol Biol Rep. 2021 Jul 27.

Signal transducer and activator of transcription-3 mediated neuroprotective effect of interleukin-6 on cobalt chloride mimetic hypoxic cell death in R28 cells.

Nanamika Thakur, Rajeev Kumar Pandey, Sanjana Mehrotra.

   BACKGROUND: Hypoxic injury to retinal ganglionic cells and adjoining glia is implicated in glaucomatous optic neuropathy. The present study evaluates the effect of IL-6 on R28 retinal precursor cell line exposed to hypoxic injury.
METHODS AND RESULTS: Apoptotic cell death induced by hypoxia mimetic CoCl2 in R28 cells with or without IL-6 treatment was measured using cell viability assays and apoptotic markers. Oxidative stress was also measured. Hypoxia induced by mimetic CoCl2 led to a time and concentration dependent apoptosis of cells mediated by disruption of mitochondrial membrane potential and activation of caspase 3. Cells pre-treated with IL-6 demonstrated significantly higher viability and mitochondrial integrity under hypoxic conditions. A critical role of STAT3 was observed in mediating the cytoprotective effects of IL-6. Treatment of cells with IL-6 led to STAT3-mediated expression of the Bcl-2 family proteins and MnSOD.
CONCLUSIONS: The data from the present study indicate cytoprotective role of IL-6 and suggest a previously unreported mechanism of neuroprotection via STAT3 mediated signaling.

Keywords:  Glaucoma; Hypoxia; IL-6; Neuroprotection; Retinal ganglion cells; STAT3

DOI:  https://doi.org/10.1007/s11033-021-06586-5
Front Oncol. 2021 ;11 697894

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies.

Guofeng Ma, Chun Li, Zhilei Zhang, Ye Liang, Zhijuan Liang, Yuanbin Chen, Liping Wang, Dan Li, Manqin Zeng, Wenhong Shan, Haitao Niu.

  Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tumor immune escape. Generally, the limited amount of metabolites in the tumor microenvironment leads to nutritional competition between tumors and immune cells. Metabolism regulates tumor cell expression of PD-L1, and the PD-1/PD-L1 immune checkpoint regulates the metabolism of tumor and T cells, which suggests that targeted tumor metabolism may have a synergistic therapeutic effect together with immunotherapy. However, the targeting of different metabolic pathways in different tumors may have different effects on tumor immune escape. Herein, we discuss the influence of glucose metabolism and glutamine metabolism on tumor immune escape and describe the theoretical basis for strategies targeting glucose or glutamine metabolism in combination with PD-1/PD-L1 checkpoint blockade immunotherapy.

Keywords:  PD-1/PD-L1 immune checkpoint; combination therapy; glucose metabolism; glutamine metabolism; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.697894
Mol Biol Rep. 2021 Jul 26.

Exosomes derived from astrocytes after oxygen-glucose deprivation promote differentiation and migration of oligodendrocyte precursor cells in vitro.

Yaping Xu, Yeye Tian, Yao Wang, Li Xu, Guini Song, Qiao Wu, Wei Wang, Minjie Xie.

   BACKGROUND: Excessive release of glutamate, oxidative stress, inflammation after ischemic brain injury can lead to demyelination. Astrocytes participate in the maturation and differentiation of oligodendrocyte precursor cells (OPCs), and play multiple roles in the process of demyelination and remyelination. Here, we studied the role of Astrocyte-derived exosomes (AS-Exo) under ischemic conditions in proliferation, differentiation and migration of OPCs in vitro.
METHODS AND RESULTS: Exosomes were collected from astrocytes supernatant by differential centrifugation from control astrocytes (CTexo), mild hypoxia astrocytes (O2R24exo) which were applied oxygen-glucose deprivation for 2 h and reperfusion for 24 h (OGD2hR24h) and severe hypoxia astrocytes (O4R24exo) which were applied oxygen-glucose deprivation for 4 h and reperfusion for 24 h (OGD4hR24h). Exosomes (20 µg/ml) were co-cultured with OPCs for 24 h and their proliferation, differentiation and migration were detected. The results showed that AS-Exo under severe hypoxia (O4R24exo) inhibit the proliferation of OPCs. Meanwhile, all exosomes from three groups can promote OPCs differentiation and migration. Compared to control, the expressions of MAG and MBP, markers of mature oligodendrocytes, were significantly increased in AS-Exo treatment groups. AS-Exo treatment significantly increased chemotaxis for OPCs.
CONCLUSIONS: AS-Exo improve OPCs' differentiation and migration, whereas AS-Exo with severe hypoxic precondition suppress OPCs' proliferation. AS-Exo may be a potential therapeutic target for myelin regeneration and repair in white matter injury or other demyelination related diseases.

Keywords:  Astrocyte-derived exosomes; Differentiation; Migration; Oligodendrocyte precursor cells; Oxygen-glucose deprivation; Proliferation

DOI:  https://doi.org/10.1007/s11033-021-06557-w
Front Oncol. 2021 ;11 692142

Tumor-Induced Inflammatory Cytokines and the Emerging Diagnostic Devices for Cancer Detection and Prognosis.

Apriliana E R Kartikasari, Cesar S Huertas, Arnan Mitchell, Magdalena Plebanski.

  Chronic inflammation generated by the tumor microenvironment is known to drive cancer initiation, proliferation, progression, metastasis, and therapeutic resistance. The tumor microenvironment promotes the secretion of diverse cytokines, in different types and stages of cancers. These cytokines may inhibit tumor development but alternatively may contribute to chronic inflammation that supports tumor growth in both autocrine and paracrine manners and have been linked to poor cancer outcomes. Such distinct sets of cytokines from the tumor microenvironment can be detected in the circulation and are thus potentially useful as biomarkers to detect cancers, predict disease outcomes and manage therapeutic choices. Indeed, analyses of circulating cytokines in combination with cancer-specific biomarkers have been proposed to simplify and improve cancer detection and prognosis, especially from minimally-invasive liquid biopsies, such as blood. Additionally, the cytokine signaling signatures of the peripheral immune cells, even from patients with localized tumors, are recently found altered in cancer, and may also prove applicable as cancer biomarkers. Here we review cytokines induced by the tumor microenvironment, their roles in various stages of cancer development, and their potential use in diagnostics and prognostics. We further discuss the established and emerging diagnostic approaches that can be used to detect cancers from liquid biopsies, and additionally the technological advancement required for their use in clinical settings.

Keywords:  biomarkers; cancer; cytokines; diagnosis; inflammation; point of care; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.692142
EMBO J. 2021 Jul 26. e107336

Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.

Rojyar Khezri, Petter Holland, Todd Andrew Schoborg, Ifat Abramovich, Szabolcs Takáts, Caroline Dillard, Ashish Jain, Fergal O'Farrell, Sebastian Wolfgang Schultz, William M Hagopian, Eduardo Martin Quintana, Rachel Ng, Nadja Sandra Katheder, Mohammed Mahidur Rahman, José Gerardo Teles Reis, Andreas Brech, Heinrich Jasper, Nasser M Rusan, Anne Hope Jahren, Eyal Gottlieb, Tor Erik Rusten.

  During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12 ; scrib-/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.

Keywords:   Drosophila ; autophagy; cancer cachexia; muscle; tumor; wasting

DOI:  https://doi.org/10.15252/embj.2020107336
Arterioscler Thromb Vasc Biol. 2021 Jul 29. ATVBAHA121316638

Diabetes Impaired Ischemia-Induced PDGF (Platelet-Derived Growth Factor) Signaling Actions and Vessel Formation Through the Activation of Scr Homology 2-Containing Phosphatase-1.

Clément Mercier, Tristan Brazeau, Jérémy Lamoureux, Elizabeth Boisvert, Stéphanie Robillard, Valérie Breton, Martin Paré, Andréanne Guay, Farah Lizotte, Marc-Antoine Despatis, Pedro Geraldes.

   OBJECTIVE: Critical limb ischemia is a major complication of diabetes characterized by insufficient collateral vessel development and proper growth factor signaling unresponsiveness. Although mainly deactivated by hypoxia, phosphatases are important players in the deregulation of proangiogenetic pathways. Previously, SHP-1 (Scr homology 2-containing phosphatase-1) was found to be associated with the downregulation of growth factor actions in the diabetic muscle. Thus, we aimed to gain further understanding of the impact of SHP-1 on smooth muscle cell (SMC) function under hypoxic and diabetic conditions. Approach and Results: Despite being inactivated under hypoxic conditions, high glucose level exposure sustained SHP-1 phosphatase activity in SMC and increased its interaction with PDGFR (platelet-derived growth factor receptor)-β, thus reducing PDGF proangiogenic actions. Overexpression of an inactive form of SHP-1 fully restored PDGF-induced proliferation, migration, and signaling pathways in SMC exposed to high glucose and hypoxia. Nondiabetic and diabetic mice with deletion of SHP-1 specifically in SMC were generated. Ligation of the femoral artery was performed, and blood flow was measured for 4 weeks. Blood flow reperfusion, vascular density and maturation, and limb survival were all improved while vascular apoptosis was attenuated in diabetic SMC-specific SHP-1 null mice as compared to diabetic mice.
CONCLUSIONS: Diabetes and high glucose level exposure maintained SHP-1 activity preventing hypoxia-induced PDGF actions in SMC. Specific deletion of SHP-1 in SMC partially restored blood flow reperfusion in the diabetic ischemic limb. Therefore, local modulation of SHP-1 activity in SMC could represent a potential therapeutic avenue to improve the proangiogenic properties of SMC under ischemia and diabetes.

Keywords:  hypoxia; ischemia; muscle cells; peripheral arterial disease; platelet-derived growth factor

DOI:  https://doi.org/10.1161/ATVBAHA.121.316638
Histol Histopathol. 2021 Jul 29. 18366

TGF-β links glycolysis and immunosuppression in glioblastoma.

Lingli Gong, Li Ji, Daxing Xu, Jingjing Wang, Jian Zou.

Glioblastoma (GBM) is the most common and aggressive brain tumor in adults, characterized by diffuse infiltration, dysplasia, and resistance to therapy. Metabolic remodeling and immunosuppression are typical events which contribute to GBM progression, but the molecular link between these two events remains largely undetermined. Studies have shown that high levels of transforming growth factor-β (TGF-β) and its receptors are associated with glioma malignancy and a poor prognosis. TGF-β plays an important role in cell metabolism and immunity. During tumorigenesis, TGF-β induces a shift in cell metabolism from oxidative phosphorylation to aerobic glycolysis, providing a favorable environment for tumor growth. Locally, TGF-β creates an immunosuppressive microenvironment and promotes the malignant phenotype of GBM. In this review, we aim to link GBM aerobic glycolysis and immunosuppression through TGF-β to provide new ideas for the study of GBM.

DOI: https://doi.org/10.14670/HH-18-366