bims-stacyt 2020-09-20 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2020–09–20
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages.
Obese Adipose Tissue Secretion Induces Inflammation in Preadipocytes: Role of Toll-Like Receptor-4.
Metabolic regulation of exercise-induced angiogenesis.
Leukemia Inhibitory Factor (LIF) Overexpression Increases the Angiogenic Potential of Bone Marrow Mesenchymal Stem/Stromal Cells.
Hypoxia-Induced Adipose Lipolysis Requires Fibroblast Growth Factor 21.
IGF2BP1 silencing inhibits proliferation and induces apoptosis of high glucose-induced non-small cell lung cancer cells by regulating Netrin-1.
Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer.

Metabolites. 2020 Sep 15. pii: E372. [Epub ahead of print]10(9):

Succinate Is an Inflammation-Induced Immunoregulatory Metabolite in Macrophages.

Karl J Harber, Kyra E de Goede, Sanne G S Verberk, Elisa Meinster, Helga E de Vries, Michel van Weeghel, Menno P J de Winther, Jan Van den Bossche.

  Immunometabolism revealed the crucial role of cellular metabolism in controlling immune cell phenotype and functions. Macrophages, key immune cells that support progression of numerous inflammatory diseases, have been well described as undergoing vast metabolic rewiring upon activation. The immunometabolite succinate particularly gained a lot of attention and emerged as a crucial regulator of macrophage responses and inflammation. Succinate was originally described as a metabolite that supports inflammation via distinct routes. Recently, studies have indicated that succinate and its receptor SUCNR1 can suppress immune responses as well. These apparent contradictory effects might be due to specific experimental settings and particularly the use of distinct succinate forms. We therefore compared the phenotypic and functional effects of distinct succinate forms and receptor mouse models that were previously used for studying succinate immunomodulation. Here, we show that succinate can suppress secretion of inflammatory mediators IL-6, tumor necrosis factor (TNF) and nitric oxide (NO), as well as inhibit Il1b mRNA expression of inflammatory macrophages in a SUCNR1-independent manner. We also observed that macrophage SUCNR1 deficiency led to an enhanced inflammatory response without addition of exogenous succinate. While our study does not reveal new mechanistic insights into how succinate elicits different inflammatory responses, it does indicate that the inflammatory effects of succinate and its receptor SUCNR1 in macrophages are clearly context dependent.

Keywords:  SUCNR1; immunometabolite; inflammation; macrophage; metabolite; succinate

DOI:  https://doi.org/10.3390/metabo10090372
Nutrients. 2020 Sep 16. pii: E2828. [Epub ahead of print]12(9):

Obese Adipose Tissue Secretion Induces Inflammation in Preadipocytes: Role of Toll-Like Receptor-4.

Mariana Renovato-Martins, Catharina Moreira-Nunes, Georgia C Atella, Christina Barja-Fidalgo, João Alfredo de Moraes.

  In obesity, the dysfunctional adipose tissue (AT) releases increased levels of proinflammatory adipokines such as TNFα, IL-6, and IL-1β and free fatty acids (FFAs), characterizing a chronic, low-grade inflammation. Whilst FFAs and proinflammatory adipokines are known to elicit an inflammatory response within AT, their relative influence upon preadipocytes, the precursors of mature adipocytes, is yet to be determined. Our results demonstrated that the conditioned medium (CM) derived from obese AT was rich in FFAs, which guided us to evaluate the role of TLR4 in the induction of inflammation in preadipocytes. We observed that CM derived from obese AT increased reactive oxygen species (ROS) levels and NF-ĸB nuclear translocation together with IL-6, TNFα, and IL-1β in 3T3-L1 cells in a TLR4-dependent manner. Furthermore, TLR4 signaling was involved in the increased expression of C/EBPα together with the release of leptin, adiponectin, and proinflammatory mediators, in response to the CM derived from obese AT. Our results suggest that obese AT milieu secretes lipokines, which act in a combined paracrine/autocrine manner, inducing inflammation in preadipocytes via TLR4 and ROS, thus creating a paracrine loop that facilitates the differentiation of adipocytes with a proinflammatory profile.

Keywords:  TLR4; adipose tissue; free fatty acid; inflammation; obesity; preadipocyte

DOI:  https://doi.org/10.3390/nu12092828
Vasc Biol. 2019 ;1(1): H1-H8

Metabolic regulation of exercise-induced angiogenesis.

Tatiane Gorski, Katrien De Bock.

  Skeletal muscle relies on an ingenious network of blood vessels, which ensures optimal oxygen and nutrient supply. An increase in muscle vascularization is an early adaptive event to exercise training, but the cellular and molecular mechanisms underlying exercise-induced blood vessel formation are not completely clear. In this review, we provide a concise overview on how exercise-induced alterations in muscle metabolism can evoke metabolic changes in endothelial cells (ECs) that drive muscle angiogenesis. In skeletal muscle, angiogenesis can occur via sprouting and splitting angiogenesis and is dependent on vascular endothelial growth factor (VEGF) signaling. In the resting muscle, VEGF levels are controlled by the estrogen-related receptor γ (ERRγ). Upon exercise, the transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC1α) orchestrates several adaptations to endurance exercise within muscle fibers and simultaneously promotes transcriptional activation of Vegf expression and increased muscle capillary density. While ECs are highly glycolytic and change their metabolism during sprouting angiogenesis in development and disease, a similar role for EC metabolism in exercise-induced angiogenesis in skeletal muscle remains to be elucidated. Nonetheless, recent studies have illustrated the importance of endothelial hydrogen sulfide and sirtuin 1 (SIRT1) activity for exercise-induced angiogenesis, suggesting that EC metabolic reprogramming may be fundamental in this process. We hypothesize that the exercise-induced angiogenic response can also be modulated by metabolic crosstalk between muscle and the endothelium. Defining the underlying molecular mechanisms responsible for skeletal muscle angiogenesis in response to exercise will yield valuable insight into metabolic regulation as well as the determinants of exercise performance.

Keywords:  angiogenesis; endothelial metabolism; exercise; metabolism; microvasculature

DOI:  https://doi.org/10.1530/VB-19-0008
Front Cell Dev Biol. 2020 ;8 778

Leukemia Inhibitory Factor (LIF) Overexpression Increases the Angiogenic Potential of Bone Marrow Mesenchymal Stem/Stromal Cells.

Girlaine Café Santos, Daniela Nascimento Silva, Vitor Fortuna, Brysa Mariana Silveira, Iasmim Diniz Orge, Thaís Alves de Santana, Gabriela Louise Sampaio, Bruno Diaz Paredes, Ricardo Ribeiro-Dos-Santos, Milena Botelho Pereira Soares.

  Mesenchymal stem/stromal cells (MSCs) have the ability to secrete bioactive molecules, exerting multiple biological effects, such as tissue regeneration, reduction of inflammation, and neovascularization. The therapeutic potential of MSCs can be increased by genetic modification to overexpress cytokines and growth factors. Here we produced mouse MSCs overexpressing human leukemia inhibitory factor (LIF) to assess their proangiogenic potential in vitro and in vivo. Mouse bone marrow-derived MSCs were transduced by using a second-generation lentiviral system to express human LIF. Leukemia inhibitory factor expression was confirmed by RT-qPCR and by ELISA, allowing the quantification of the transcript and secreted protein, respectively. Flow cytometry analysis and trilineage differentiation assay showed that the MSC_LIF cell line maintained the immunophenotype and a multipotency characteristic of MSCs. The immunosuppressive activity of MSC_LIF was confirmed using a lymphoproliferation assay. Moreover, gene expression analysis demonstrated upregulation of genes coding for strategic factors in the neovascularization process, such as angiogenin, IL-8, MCP-1, and VEGF, and for the perivascular cell markers αSMA, Col4a1, SM22, and NG2. To evaluate the pro-angiogenic potential of MSC_LIF, we first tested its effects on endothelial cells obtained from umbilical vein in a scratch wound healing assay. Conditioned medium (CM) from MSC_LIF promoted a significant increase in cell migration compared to CM from control MSC. Additionally, in vitro tube formation of endothelial cells was increased by the presence of MSC_LIF, as shown in microvessel sprouting in aortic ring cultures. Finally, an in vivo Matrigel plug assay was performed, showing that MSC_LIF were more potent in promoting in vivo angiogenesis and tissue vascularization than control MSCs. In conclusion, LIF overexpression is a promising strategy to increase the proangiogenic potential of MSCs and sets precedents for future investigations of their potential applications for the treatment of ischemic diseases and tissue repair.

Keywords:  LIF; angiogenesis; genetic modification; mesenchymal stem/stromal cells; proangiogenico factors

DOI:  https://doi.org/10.3389/fcell.2020.00778
Front Pharmacol. 2020 ;11 1279

Hypoxia-Induced Adipose Lipolysis Requires Fibroblast Growth Factor 21.

Guicheng Wu, Yanlong Liu, Wenke Feng, Xuan An, Wenhui Lin, Chengwei Tang.

  Fibroblast growth factor 21 (FGF21) is a recently discovered hepatokine that regulates lipid and glucose metabolism and is upregulated in response to numerous physiological and pathological stimuli. Herein, we demonstrate that both physical and chemical hypoxia increase the systemic and hepatic expression of FGF21 in mice; by contrast, hypoxia induces a reduction of FGF21 expression in hepatocytes, indicating that hypoxia-induced FGF21 expression is differentially regulated in intact animals and in hepatocytes. Furthermore, we demonstrate that hypoxia treatment increases hormone-sensitive lipase-mediated adipose tissue lipolysis in mice, which is reduced in Fgf21 knockout mice, thereby implying that FGF21 plays a critical role in hypoxia-related adipose lipolysis. Adipose tissue lipolysis causes an increase in the amount of circulating free fatty acids, which leads to the activation of peroxisome proliferators-activated receptor alpha and an increased expression of FGF21 in hepatocytes. We further show that hypoxia-induced elevation of reactive oxygen species, but not the hypoxia-inducible factor, is responsible for the lipolysis and FGF21 expression. In conclusion, our data clearly demonstrate that FGF21 plays a critical role in hypoxia-induced adipose lipolysis, which induces hepatic expression of FGF21. Clarification of hypoxia-regulated FGF21 regulation will enhance our understanding of the pathophysiology of hypoxia-related diseases, such as sleep disorders and metabolic diseases.

Keywords:  fibroblast growth factor 21; free fatty acid; hormone sensitive lipase; hypoxia-inducible factor; lipolysis

DOI:  https://doi.org/10.3389/fphar.2020.01279
Arch Biochem Biophys. 2020 Sep 11. pii: S0003-9861(20)30590-7. [Epub ahead of print] 108581

IGF2BP1 silencing inhibits proliferation and induces apoptosis of high glucose-induced non-small cell lung cancer cells by regulating Netrin-1.

Jiawen Zhang, Wen Luo, Xiaowen Chi, Lijuan Zhang, Qiu Ren, Hui Wang, Wei Zhang.

  Non-small cell lung cancer (NSCLC) accompanied by diabetes is an important risk factor affecting the prognosis of patients with NSCLC in clinical practice. However, the effect of high glucose (HG) in the pathogenesis of NSCLC remains elusive. It has been found that the RNA-binding protein Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) plays important roles in various diseases, including NSCLC and diabetes. The aim of this study was to explore the role of IGF2BP1 in HG-treated NSCLC cells, and further investigate its underlying molecular mechanism. Results showed that IGF2BP1 was highly expressed in HG-treated NSCLC cells. Knockdown of IGF2BP1 inhibited cancer cell proliferation, migration and invasion, as well as induced cell cycle arrest and apoptosis. Besides, IGF2BP1 silencing decreased the Netrin-1 level in HG-treated NSCLC cells. Reintroduction of Netrin-1 expression rescued IGF2BP1 deficiency-induced cell proliferation reduction, migration suppression, cell cycle arrest and apoptosis. These findings suggest that IGF2BP1 silencing inhibits the occurrence of tumor events through down-regulating Netrin-1 expression, indicating that the IGF2BP1/Netrin-1 axis exerts an oncogenic role in HG-treated NSCLC cells.

Keywords:  Apoptosis; High glucose; IGF2BP1; Netrin-1; Non-small cell lung cancer; Proliferation

DOI:  https://doi.org/10.1016/j.abb.2020.108581
J Immunol. 2020 Sep 16. pii: ji2000185. [Epub ahead of print]

Hypoxia-Inducible Factor α Subunits Regulate Tie2-Expressing Macrophages That Influence Tumor Oxygen and Perfusion in Murine Breast Cancer.

Kayla J Steinberger, Mary A Forget, Andrey A Bobko, Nicole E Mihalik, Marieta Gencheva, Julie M Roda, Sara L Cole, Xiaokui Mo, E Hannah Hoblitzell, Randall Evans, Amy C Gross, Leni Moldovan, Clay B Marsh, Valery V Khramstov, Timothy D Eubank.

Tie2-expressing monocytes/macrophages (TEMs) are a distinct subset of proangiogenic monocytes selectively recruited to tumors in breast cancer. Because of the hypoxic nature of solid tumors, we investigated if oxygen, via hypoxia-inducible transcription factors HIF-1α and HIF-2α, regulates TEM function in the hypoxic tumor microenvironment. We orthotopically implanted PyMT breast tumor cells into the mammary fat pads of syngeneic LysMcre, HIF-1α fl/fl /LysMcre, or HIF-2α fl/fl /LysMcre mice and evaluated the tumor TEM population. There was no difference in the percentage of tumor macrophages among the mouse groups. In contrast, HIF-1α fl/fl /LysMcre mice had a significantly smaller percentage of tumor TEMs compared with control and HIF-2α fl/fl /LysMcre mice. Proangiogenic TEMs in macrophage HIF-2α-deficient tumors presented significantly more CD31+ microvessel density but exacerbated hypoxia and tissue necrosis. Reduced numbers of proangiogenic TEMs in macrophage HIF-1α-deficient tumors presented significantly less microvessel density but tumor vessels that were more functional as lectin injection revealed more perfusion, and functional electron paramagnetic resonance analysis revealed more oxygen in those tumors. Macrophage HIF-1α-deficient tumors also responded significantly to chemotherapy. These data introduce a previously undescribed and counterintuitive prohypoxia role for proangiogenic TEMs in breast cancer which is, in part, suppressed by HIF-2α.

DOI: https://doi.org/10.4049/jimmunol.2000185