bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2023–10–08
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Role of growth differentiation factor 15 in cancer cachexia (Review).
  2. Hypoxia-induced exosomes facilitate lung pre-metastatic niche formation in hepatocellular carcinoma through the miR-4508-RFX1-IL17A-p38 MAPK-NF-κB pathway.
  3. GCN2 is required to maintain core body temperature in mice during acute cold.
  4. The role of angiogenic growth factors in the immune microenvironment of glioma.
  5. The effect of leptin on trained innate immunity and on systemic inflammation in subjects with obesity.
  6. Adipose Mesenchymal Stem Cell-derived Exosomes Enhanced Glycolysis through the SIX1/HBO1 Pathway against Oxygen and Glucose Deprivation Injury in Human Umbilical Vein Endothelial Cells.
  1. Oncol Lett. 2023 Nov;26(5): 462
    Role of growth differentiation factor 15 in cancer cachexia (Review).
    Tingting Ling, Jing Zhang, Fuwan Ding, Lanlan Ma.
      Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-β family, is a stress-induced cytokine. Under normal circumstances, the expression of GDF15 is low in most tissues. It is highly expressed during tissue injury, inflammation, oxidative stress and cancer. GDF15 has been established as a biomarker in patients with cancer, and is associated with cancer cachexia (CC) and poor survival. CC is a multifactorial metabolic disorder characterized by severe muscle and adipose tissue atrophy, loss of appetite, anemia and bone loss. Cachexia leads to reductions in quality of life and tolerance to anticancer therapy, and results in a poor prognosis in cancer patients. Dysregulated GDF15 levels have been discovered in patients with CC and animal models, where they have been found to be involved in anorexia and weight loss. Although studies have suggested that GDF15 mediates anorexia and weight loss in CC through its neuroreceptor, glial cell-lineage neurotrophic factor family receptor α-like, the effects of GDF15 on CC and the potential regulatory mechanisms require further elucidation. In the present review, the characteristics of GDF15 and its roles and molecular mechanisms in CC are elaborated. The targeting of GDF15 as a potential therapeutic strategy for CC is also discussed.
    Keywords:  anemia; anorexia; bone loss; cancer cachexia; fat loss; growth differentiation factor 15; muscle atrophy
    DOI:  https://doi.org/10.3892/ol.2023.14049
  2. Int J Biol Sci. 2023 ;19(15): 4744-4762
    Hypoxia-induced exosomes facilitate lung pre-metastatic niche formation in hepatocellular carcinoma through the miR-4508-RFX1-IL17A-p38 MAPK-NF-κB pathway.
    Wentao Jia, Shufang Liang, Wanfu Lin, Shu Li, Jiaying Yuan, Mingming Jin, Shuchang Nie, Ya'ni Zhang, Xiaofeng Zhai, Liping Zhou, Changquan Ling, Binbin Cheng, Chen Ling.
      Background: Hypoxia plays an important role in the lung metastasis of hepatocellular carcinoma (HCC). However, the process by which hypoxia promotes the formation of a pre-metastatic niche (PMN) and its underlying mechanism remain unclear. Methods: Exosomes derived from normoxic and hypoxic HCC cells were collected to induce fibroblast activation in vitro and PMN formation in vivo. The micro RNA (miR) profiles of the exosomes were sequenced to identify differentially expressed miRNAs. Gain- and loss-of-function analyses were performed to investigate miR-4508 function. Dual-luciferase, western blotting, and real-time reverse transcription-PCR analyses were used to identify the direct targets of miR-4508 and its downstream signaling pathways. To demonstrate the roles of hypoxic tumor-derived exosomes (H-TDEs) and miR-4508 in the lung metastasis of liver cancer, H22 tumor cells were injected through the tail vein of mice. Blood plasma-derived exosomes from patients with HCC who underwent transarterial chemoembolization (TACE) were applied to determine clinical correlations. Results: We demonstrated that H-TDEs activated lung fibroblasts and facilitated PMN formation, thereby promoting lung metastasis in mice. Screening for upregulated exosomal miRNAs revealed that miR-4508 and its target, regulatory factor X1 (RFX1), were involved in H-TDE-induced lung PMN formation. Moreover, miR-4508 was significantly upregulated in plasma exosomes derived from patients with HCC after TACE. We confirmed that the p38 MAPK-NF-κB signaling pathway is involved in RFX1 knockdown-induced fibroblast activation and PMN formation. In addition, IL17A, a downstream target of RFX1, was identified as a link between RFX1 knockdown and p38 MAPK activation in fibroblasts. Conclusion: Hypoxia enhances the release of TDEs enriched with miR-4508, thereby promoting lung PMN formation by targeting the RFX1-IL17A-p38 MAPK-NF-κB pathway. These findings highlight a novel mechanism underlying hypoxia-induced pulmonary metastasis of HCC.
    Keywords:  Hypoxia; MicroRNA; Pre-metastatic niche; Tumor-derived exosomes
    DOI:  https://doi.org/10.7150/ijbs.86767
  3. Am J Physiol Endocrinol Metab. 2023 Oct 04.
    GCN2 is required to maintain core body temperature in mice during acute cold.
    Jordan L Levy, Emily T Mirek, Esther M Rodriguez, Brian Zalma, Jeffrey Burns, William O Jonsson, Harini Sampath, Kirk A Staschke, Ronald C Wek, Tracy G Anthony.
      Nonshivering thermogenesis in rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. In this study, we examined the role of the nutrient sensing kinase, general control nonderepressible 2 (GCN2) in directing adaptive thermogenesis during acute cold exposure in mice. We hypothesized that GCN2 is required for adaptation to acute cold stress via activation of the integrated stress response (ISR) resulting in liver production of FGF21 and increased amino acid transport to support nonshivering thermogenesis. In alignment with our hypothesis, female and male mice lacking GCN2 failed to adequately increase energy expenditure and veered into torpor. Mice administered a small molecule inhibitor of GCN2 were also profoundly intolerant to acute cold stress. GCN2 deletion also impeded liver-derived FGF21 but in males only. Within the brown adipose (BAT), acute cold exposure increased ISR activation and its transcriptional execution in males and females. RNA sequencing in BAT identified transcripts that encode actomyosin mechanics and transmembrane transport as requiring GCN2 during cold exposure. These transcripts included class II myosin heavy chain and amino acid transporters, critical for maximal thermogenesis during cold stress. Importantly, GCN2 deletion corresponded with higher circulating amino acids and lower intracellular amino acids in the BAT during cold stress. In conclusion, we identify a sex-independent role for GCN2 activation to support adaptive thermogenesis via uptake of amino acids into brown adipose.
    Keywords:  Activating Transcription Factor 4 (ATF4); Energy expenditure; Eukaryotic initiation factor 2 (eIF2); Hypothermia; Mechanistic target of rapamycin complex 1 (mTORC1)
    DOI:  https://doi.org/10.1152/ajpendo.00181.2023
  4. Front Oncol. 2023 ;13 1254694
    The role of angiogenic growth factors in the immune microenvironment of glioma.
    Zhengmao Ge, Qi Zhang, Wei Lin, Xiaofan Jiang, Yanyu Zhang.
      Angiogenic growth factors (AGFs) are a class of secreted cytokines related to angiogenesis that mainly include vascular endothelial growth factors (VEGFs), stromal-derived factor-1 (SDF-1), platelet-derived growth factors (PDGFs), fibroblast growth factors (FGFs), transforming growth factor-beta (TGF-β) and angiopoietins (ANGs). Accumulating evidence indicates that the role of AGFs is not only limited to tumor angiogenesis but also participating in tumor progression by other mechanisms that go beyond their angiogenic role. AGFs were shown to be upregulated in the glioma microenvironment characterized by extensive angiogenesis and high immunosuppression. AGFs produced by tumor and stromal cells can exert an immunomodulatory role in the glioma microenvironment by interacting with immune cells. This review aims to sum up the interactions among AGFs, immune cells and cancer cells with a particular emphasis on glioma and tries to provide new perspectives for understanding the glioma immune microenvironment and in-depth explorations for anti-glioma therapy.
    Keywords:  angiogenic growth factor; glioma; immune cell; immune modulation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2023.1254694
  5. J Leukoc Biol. 2023 Sep 30. pii: qiad118. [Epub ahead of print]
    The effect of leptin on trained innate immunity and on systemic inflammation in subjects with obesity.
    Daniela Flores Gomez, Siroon Bekkering, Rob Ter Horst, Benjamin Cossins, Inge C L van den Munckhof, Joost H W Rutten, Leo A B Joosten, Mihai G Netea, Niels P Riksen.
      Leptin is associated with cardiometabolic complications of obesity, such as metabolic syndrome and atherosclerosis. In obese men, the presence of metabolic syndrome is associated with higher circulating leptin and interleukin-6 concentrations, and increased monocyte cytokine production capacity. Here we investigated the effects of leptin on monocyte function and systemic inflammatory markers in obese individuals. We specifically explored whether leptin can induce long-term changes in innate immune function by inducing innate immune memory (also called trained immunity). We exposed human primary monocytes for 24 hours to relevant leptin concentrations in vitro and measured cytokine production. In addition, after removing leptin, we incubated monocytes for 5 days in culture medium, and we restimulated them on day 6 to assess cytokine production capacity, phagocytosis and foam cell formation. Direct stimulation with leptin did not induce cytokine production, but exposure to 50 ng/ml leptin augmented LPS- and R848-induced tumor necrosis factor (TNF-α) production after 1 week. In a separate in vivo study in a cohort of 302 obese subjects (BMI>27, 55-81 years), we measured circulating leptin, inflammatory markers, and cytokine production upon ex-vivo stimulation of isolated peripheral blood mononuclear cells. Circulating leptin concentrations positively correlated with circulating IL-1β and IL-6, which was more pronounced in men than in women. Four single nucleotide polymorphisms in the leptin gene influenced circulating IL-6 concentrations in men, suggesting a direct effect of leptin on IL-6. In conclusion, in vitro, leptin does not directly stimulate monocytes to produce cytokines, yet induces long-term monocyte hyperresponsiveness, i.e. trained immunity. In obese subjects, leptin is associated with circulating IL-6 in a sex-dependent manner. The underlying mechanisms of the sex-specific effect of leptin on innate immune cells remain to be further investigated.
    Keywords:  Adipokines; atherosclerosis; cytokines; metabolic syndrome
    DOI:  https://doi.org/10.1093/jleuko/qiad118
  6. Curr Stem Cell Res Ther. 2023 Sep 27.
    Adipose Mesenchymal Stem Cell-derived Exosomes Enhanced Glycolysis through the SIX1/HBO1 Pathway against Oxygen and Glucose Deprivation Injury in Human Umbilical Vein Endothelial Cells.
    Xiangyu Zhang, Xin Zhang, Lu Chen, Jiaqi Zhao, Ashok Raj, Yanping Wang, Shulin Li, Chi Zhang, Jing Yang, Dong Sun.
       BACKGROUND: Angiogenesis and energy metabolism mediated by adipose mesenchymal stem cell-derived exosomes (AMSC-exos) are promising therapeutics for vascular diseases.
    OBJECTIVES: The current study aimed to explore whether AMSC-exos have therapeutic effects on oxygen and glucose deprivation (OGD) human umbilical vein endothelial cells (HUVECs) injury by modulating the SIX1/HBO1 signaling pathway to upregulate endothelial cells (E.C.s) glycolysis and angiogenesis.
    METHODS: AMSC-exos were isolated and characterized following standard protocols. AMSC-exos cytoprotective effects were evaluated in the HUVECs-OGD model. The proliferation, migration, and tube formation abilities of HUVECs were assessed. The glycolysis level was evaluated by detecting lactate production and ATP synthesis. The expressions of HK2, PKM2, VEGF, HIF-1α, SIX1, and HBO1 were determined by western blotting, and finally, the SIX1 overexpression vector or small interfering RNA (siRNA) was transfected into HUVECs to assess the change in HBO1 expression.
    RESULTS: Our study revealed that AMSC-exos promotes E.C.s survival after OGD, reducing E.C.s apoptosis while strengthening E.C.'s angiogenic ability. AMSC-exos enhanced glycolysis and reduced OGD-induced ECs injury by modulation of the SIX1/HBO1 signaling pathway, which is a novel anti-endothelial cell injury role of AMSC-exos that regulates glycolysis via activating the SIX1/HBO1 signaling pathway.
    CONCLUSION: The current study findings demonstrate a useful angiogenic therapeutic strategy for AMSC-exos treatment in vascular injury, thus providing new therapeutic ideas for treating ischaemic diseases.
    Keywords:  Adipose mesenchymal stem cell; Endothelial cells; Exosome; Glycolysis; Oxygen; glucose
    DOI:  https://doi.org/10.2174/011574888X265623230921045240
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