bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2021–11–14
eleven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. SIRT1-mediated deacetylation of FOXO3a transcription factor supports pro-angiogenic activity of IFN-deficient tumor-associated neutrophils.
  2. Metabolism in tumor microenvironment: Implications for cancer immunotherapy.
  3. The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment.
  4. Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-β/Smad2/3 pathway.
  5. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment.
  6. The integrated stress response in ischemic diseases.
  7. IL-6/STAT3 Induced Neuron Apoptosis in Hypoxia by Downregulating ATF6 Expression.
  8. Aspartate Metabolism Facilitates IL-1β Production in Inflammatory Macrophages.
  9. Activation of SGLT3a in endometrial epithelial cells induces paracrine stromal cell decidualization.
  10. Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment.
  11. Leptin Augments Antitumor Immunity in Obesity by Repolarizing Tumor-Associated Macrophages.
  1. Int J Cancer. 2021 Nov 09.
    SIRT1-mediated deacetylation of FOXO3a transcription factor supports pro-angiogenic activity of IFN-deficient tumor-associated neutrophils.
    Sharareh Bordbari, Britta Mörchen, Ekaterina Pylaeva, Elena Siakaeva, Ilona Spyra, Maksim Domnich, Freya Droege, Oliver Kanaan, Karl Sebastian Lang, Dirk Schadendorf, Stephan Lang, Iris Helfrich, Jadwiga Jablonska.
      Angiogenesis plays an important role during tumor growth and metastasis. We could previously show that type I IFN-deficient tumor-associated neutrophils show strong pro-angiogenic activity, and stimulate tumor angiogenesis and growth. However, the exact mechanism responsible for their pro-angiogenic shift is not clear. Here, we set out to delineate the molecular mechanism and factors regulating pro-angiogenic properties of neutrophils in the context of type I IFN availability. We demonstrate that neutrophils from IFN-deficient (Ifnar1-/- ) mice efficiently release pro-angiogenic factors, such as VEGF, MMP9 or BV8, and thus significantly support the vascular normalization of tumors by increasing the maturation of perivascular cells. Mechanistically, we could show here that the expression of pro-angiogenic factors in neutrophils is controlled by the transcription factor FOXO3a, which activity depends on its posttranslational modifications, such as deacetylation or phosphorylation. In TANs isolated from Ifnar1-/- mice we observe significantly elevated SIRT1, resulting in SIRT1-mediated deacetylation of FOXO3a, its nuclear retention and activation. Activated FOXO3a supports in turn the transcription of pro-angiogenic genes in TANs. In the absence of SIRT1, or after its inhibition in neutrophils, elevated kinase MEK/ERK and PI3K/AKT activity is observed, leading to FOXO3a phosphorylation, cytoplasmic transfer and inactivation. In summary, we have found that FOXO3a is a key transcription factor controlling the angiogenic switch of neutrophils. Posttranslational FOXO3a modifications regulate its transcriptional activity and, as a result, the expression of pro-angiogenic factors supporting development of vascular network in growing tumors. Therefore, targeting FOXO3a activity could provide a novel strategy of anti-angiogenic targeted therapy for cancer.
    Keywords:  FOXO3a; SIRT1; Tumor-associated neutrophils; deacetylation; melanoma; pro-angiogenic neutrophils; tumor angiogenesis; type I IFN; vascular normalization
    DOI:  https://doi.org/10.1002/ijc.33871
  2. MedComm (Beijing). 2020 Jun;1(1): 47-68
    Metabolism in tumor microenvironment: Implications for cancer immunotherapy.
    Rongchen Shi, Yi-Quan Tang, Hongming Miao.
      Tumor microenvironment is a special environment for tumor survival, which is characterized by hypoxia, acidity, nutrient deficiency, and immunosuppression. The environment consists of the vasculature, immune cells, extracellular matrix, and proteins or metabolic molecules. A large number of recent studies have shown that not only tumor cells but also the immune cells in the tumor microenvironment have undergone metabolic reprogramming, which is closely related to tumor drug resistance and malignant progression. Tumor immunotherapy based on T cells gives patients new hope, but faces the dilemma of low response rate. New strategies sensitizing cancer immunotherapy are urgently needed. Metabolic reprogramming can directly affect the biological activity of tumor cells and also regulate the differentiation and activation of immune cells. The authors aim to review the characteristics of tumor microenvironment, the metabolic changes of tumor-associated immune cells, and the regulatory role of metabolic reprogramming in cancer immunotherapy.
    Keywords:  cancer therapy; immunity; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.6
  3. Cancers (Basel). 2021 Oct 29. pii: 5447. [Epub ahead of print]13(21):
    The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment.
    Maria Iorio, Nikkitha Umesh Ganesh, Monica De Luise, Anna Maria Porcelli, Giuseppe Gasparre, Ivana Kurelac.
      Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which cancer cells coexist and interact with several types of microenvironment populations, including endothelial cells, fibroblasts and immune cells. We are just starting to understand how such populations are affected by the metabolic changes occurring in a transformed cell and little is known about the impact of metabolism-targeting drugs on the non-malignant tumor components. Here we provide a general overview of the links between cancer cell metabolism and tumor microenvironment (TME), particularly focusing on the emerging literature reporting TME-specific effects of metabolic therapies.
    Keywords:  cancer metabolism; cancer-associated fibroblasts; metabolic reprogramming; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/cancers13215447
  4. Cell Death Dis. 2021 Nov 09. 12(11): 1068
    Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-β/Smad2/3 pathway.
    Lin Zhang, Wei Wei, Xiaoyu Ai, Ertugrul Kilic, Dirk M Hermann, Vivek Venkataramani, Mathias Bähr, Thorsten R Doeppner.
      Systemic transplantation of oxygen-glucose deprivation (OGD)-preconditioned primary microglia enhances neurological recovery in rodent stroke models, albeit the underlying mechanisms have not been sufficiently addressed. Herein, we analyzed whether or not extracellular vesicles (EVs) derived from such microglia are the biological mediators of these observations and which signaling pathways are involved in the process. Exposing bEnd.3 endothelial cells (ECs) and primary cortical neurons to OGD, the impact of EVs from OGD-preconditioned microglia on angiogenesis and neuronal apoptosis by the tube formation assay and TUNEL staining was assessed. Under these conditions, EV treatment stimulated both angiogenesis and tube formation in ECs and repressed neuronal cell injury. Characterizing microglia EVs by means of Western blot analysis and other techniques revealed these EVs to be rich in TGF-β1. The latter turned out to be a key compound for the therapeutic potential of microglia EVs, affecting the Smad2/3 pathway in both ECs and neurons. EV infusion in stroke mice confirmed the aforementioned in vitro results, demonstrating an activation of the TGF-β/Smad2/3 signaling pathway within the ischemic brain. Furthermore, enriched TGF-β1 in EVs secreted from OGD-preconditioned microglia stimulated M2 polarization of residing microglia within the ischemic cerebral environment, which may contribute to a regulation of an early inflammatory response in postischemic hemispheres. These observations are not only interesting from the mechanistic point of view but have an immediate therapeutic implication as well, since stroke mice treated with such EVs displayed a better functional recovery in the behavioral test analyses. Hence, the present findings suggest a new way of action of EVs derived from OGD-preconditioned microglia by regulating the TGF-β/Smad2/3 pathway in order to promote tissue regeneration and neurological recovery in stroke mice.
    DOI:  https://doi.org/10.1038/s41419-021-04363-7
  5. J Hematol Oncol. 2021 Nov 06. 14(1): 187
    Contradictory roles of lipid metabolism in immune response within the tumor microenvironment.
    Weina Yu, Qingyang Lei, Li Yang, Guohui Qin, Shasha Liu, Dan Wang, Yu Ping, Yi Zhang.
      Complex interactions between the immune system and tumor cells exist throughout the initiation and development of cancer. Although the immune system eliminates malignantly transformed cells in the early stage, surviving tumor cells evade host immune defense through various methods and even reprogram the anti-tumor immune response to a pro-tumor phenotype to obtain unlimited growth and metastasis. The high proliferation rate of tumor cells increases the demand for local nutrients and oxygen. Poorly organized vessels can barely satisfy this requirement, which results in an acidic, hypoxic, and glucose-deficient tumor microenvironment. As a result, lipids in the tumor microenvironment are activated and utilized as a primary source of energy and critical regulators in both tumor cells and related immune cells. However, the exact role of lipid metabolism reprogramming in tumor immune response remains unclear. A comprehensive understanding of lipid metabolism dysfunction in the tumor microenvironment and its dual effects on the immune response is critical for mapping the detailed landscape of tumor immunology and developing specific treatments for cancer patients. In this review, we have focused on the dysregulation of lipid metabolism in the tumor microenvironment and have discussed its contradictory roles in the tumor immune response. In addition, we have summarized the current therapeutic strategies targeting lipid metabolism in tumor immunotherapy. This review provides a comprehensive summary of lipid metabolism in the tumor immune response.
    Keywords:  Immune response; Immunotherapy; Lipid metabolism; Malignant tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13045-021-01200-4
  6. Cell Death Differ. 2021 Nov 06.
    The integrated stress response in ischemic diseases.
    Guangyu Zhang, Xiaoding Wang, Beverly A Rothermel, Sergio Lavandero, Zhao V Wang.
      Ischemic disease is among the deadliest and most disabling illnesses. Prominent examples include myocardial infarction and stroke. Most, if not all, underlying pathological changes, including oxidative stress, inflammation, and nutrient deprivation, are potent inducers of the integrated stress response (ISR). Four upstream kinases are involved in ISR signaling that sense a myriad of input stress signals and converge on the phosphorylation of serine 51 of eukaryotic translation initiation factor 2α (eIF2α). As a result, translation initiation is halted, creating a window of opportunity for the cell to repair itself and restore homeostasis. A growing number of studies show strong induction of the ISR in ischemic disease. Genetic and pharmacological evidence suggests that the ISR plays critical roles in disease initiation and progression. Here, we review the basic regulation of the ISR, particularly in response to ischemia, and summarize recent findings relevant to the actions of the ISR in ischemic disease. We then discuss therapeutic opportunities by modulating the ISR to treat ischemic heart disease, brain ischemia, ischemic liver disease, and ischemic kidney disease. Finally, we propose that the ISR represents a promising therapeutic target for alleviating symptoms of ischemic disease and improving clinical outcomes.
    DOI:  https://doi.org/10.1038/s41418-021-00889-7
  7. Front Physiol. 2021 ;12 729925
    IL-6/STAT3 Induced Neuron Apoptosis in Hypoxia by Downregulating ATF6 Expression.
    Simin Zhou, Zhifeng Zhong, Pei Huang, Bin Xiang, Xiaoxu Li, Huaping Dong, Gang Zhang, Yu Wu, Peng Li.
      Background: Neuron apoptosis, regulated by endoplasmic reticulum (ER) stress in the hippocampus, is an essential factor influencing the cognitive impairment induced by hypobaric hypoxia. Hypoxia mainly changes the activating transcription factor (ATF6) pathway of ER stress. However, the role of ATF6 in neuron survival, apoptosis, and upstream regulation is still controversial. Methods: We established a hypobaric hypoxia-induced C57BL/6 murine model and cell lines exposed to 1% hypoxia, including PC12 and HT22. First, we tested the expressions of interleukin 6 (IL-6), IL-1β, and IL-10 in C57BL/6 mice's hippocampus under hypoxia using enzyme-linked immunosorbent assay (ELISA). We determined the signal transducer and activator of transcription 3 (STAT3) phosphorylation at tyrosine (Tyr)705 by western blot and the expression of ATF6, 78-kDa glucose-regulated protein (GRP78), and C/-EBP homologous protein (CHOP) related to ER stress by immunofluorescence (IF), western blot, and qRT-PCR; they were then verified on the cell model. Additionally, IL-6 (40 ng/mL) and STAT3 siRNA were used to treat the PC12 cells for 48 and 4 h to activate or silence STAT3, respectively. Subsequently, the cells of siRNA group were exposed to 1% hypoxia for 48 h. Furthermore, the ATF6 and CHOP expressions were detected with western blot and qRT-PCR. Finally, we examined the binding of STAT3 to the ATF6 promoter by chromatin immunoprecipitation (ChIP)-seq. Results: The results showed that IL-6 increased, IL-10 decreased in the hypoxia group, and IL-1β showed no difference between the hypoxia and the normoxia groups. Neuron apoptosis was significantly elevated by exposure to hypoxia for 48h in PC12 cells. The hypobaric hypoxia-induced ER stress proteins, ATF6, GRP78, and CHOP, and the p-STAT3 (Tyr705) expressions increased both in in vivo and in vitro. Besides, STAT3 silencing significantly promoted the ATF6 expression and inhibited CHOP, while STAT3 activation downregulated the expression of ATF6 and upregulated CHOP in PC12 cells. The ChIP-seq assay demonstrated that p-STAT3 (Tyr705) protein could bind to the ATF6 promoter region in HT22 cells. Conclusion: Phosphorylation of STAT3 at the Tyr705 site contributes to hypoxia-induced neuron apoptosis by downregulating ATF6, which might explain the inflammatory reaction and apoptosis of the hippocampal neurons induced by ER stress.
    Keywords:  ATF6; ER stress; STAT3; cognitive impairment; hypoxia
    DOI:  https://doi.org/10.3389/fphys.2021.729925
  8. Front Immunol. 2021 ;12 753092
    Aspartate Metabolism Facilitates IL-1β Production in Inflammatory Macrophages.
    Hao Wang, Xueyue Zheng, Bingnan Liu, Yaoyao Xia, Zhongquan Xin, Baichuan Deng, Liuqin He, Jinping Deng, Wenkai Ren.
      Increasing evidence support that cellular amino acid metabolism shapes the fate of immune cells; however, whether aspartate metabolism dictates macrophage function is still enigmatic. Here, we found that the metabolites in aspartate metabolism are depleted in lipopolysaccharide (LPS) plus interferon gamma (IFN-γ)-stimulated macrophages. Aspartate promotes interleukin-1β (IL-1β) secretion in M1 macrophages. Mechanistically, aspartate boosts the activation of hypoxia-inducible factor-1α (HIF-1α) and inflammasome and increases the levels of metabolites in aspartate metabolism, such as asparagine. Interestingly, asparagine also accelerates the activation of cellular signaling pathways and promotes the production of inflammatory cytokines from macrophages. Moreover, aspartate supplementation augments the macrophage-mediated inflammatory responses in mice and piglets. These results uncover a previously uncharacterized role for aspartate metabolism in directing M1 macrophage polarization.
    Keywords:  HIF-1α; asparagine; aspartate; inflammasome; macrophage
    DOI:  https://doi.org/10.3389/fimmu.2021.753092
  9. J Cell Physiol. 2021 Nov 10.
    Activation of SGLT3a in endometrial epithelial cells induces paracrine stromal cell decidualization.
    Min Liu, Yicheng Wang, Yongdan Ma, Xueqin Zhang, Lixue Zhang, Li Nie, Wenjing Guo, Dan Zhao, Jinhu Zhang, Dongzhi Yuan, Limin Yue.
      Endometrial epithelial cells (EECs) and stromal cells (ESCs) have a close functional association. During the peri-implantation period, EECs with enhanced functional activities secrete a variety of paracrine factors to promote the decidualization of ESCs. However, little is known about the specific process by which EECs secrete paracrine factors to induce the decidualization of ESCs. Some evidence suggests that the activation of sodium-glucose cotransporter 3a (SGLT3a) induces the depolarization of ESCs to affect their function. Therefore, SGLT3a acts as a sensor molecule in certain cell types. In this study, the expression of SGLT3a was investigated in EECs to determine whether its levels increased during the peri-implantation period in female mice. The activation of SGLT3a in mouse EECs induced Na+ -dependent depolarization of the cell membrane and an influx of extracellular Ca2+ , which further promoted the expression and release of the paracrine factors prostaglandin E2 (PGE2) and F2-alpha (PGF2α) by upregulating the expression of cyclooxygenase-2. In turn, PGE2 and PGF2α induced the decidualization of ESCs. Importantly, we identified SGLT3a as a key molecule involved in the cross-talk between EECs and ESCs during the process of uterine decidualization.
    Keywords:  decidualization; endometrial epithelial cells; endometrial stromal cells; paracrine; sodium-glucose cotransporter 3
    DOI:  https://doi.org/10.1002/jcp.30629
  10. Nat Metab. 2021 Nov 11.
    Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment.
    Simon Schwörer, Natalya N Pavlova, Francesco V Cimino, Bryan King, Xin Cai, Gina M Sizemore, Craig B Thompson.
      The aberrant production of collagen by fibroblasts is a hallmark of many solid tumours and can influence cancer progression. How the mesenchymal cells in the tumour microenvironment maintain their production of extracellular matrix proteins as the vascular delivery of glutamine and glucose becomes compromised remains unclear. Here we show that pyruvate carboxylase (PC)-mediated anaplerosis in tumour-associated fibroblasts contributes to tumour fibrosis and growth. Using cultured mesenchymal and cancer cells, as well as mouse allograft models, we provide evidence that extracellular lactate can be utilized by fibroblasts to maintain tricarboxylic acid (TCA) cycle anaplerosis and non-essential amino acid biosynthesis through PC activity. Furthermore, we show that fibroblast PC is required for collagen production in the tumour microenvironment. These results establish TCA cycle anaplerosis as a determinant of extracellular matrix collagen production, and identify PC as a potential target to inhibit tumour desmoplasia.
    DOI:  https://doi.org/10.1038/s42255-021-00480-x
  11. J Immunol. 2021 Nov 12. pii: ji2001152. [Epub ahead of print]
    Leptin Augments Antitumor Immunity in Obesity by Repolarizing Tumor-Associated Macrophages.
    Stephanie O Dudzinski, Jackie E Bader, Kathryn E Beckermann, Kirsten L Young, Rachel Hongo, Matthew Z Madden, Abin Abraham, Bradley E Reinfeld, Xiang Ye, Nancie J MacIver, Todd D Giorgio, Jeffrey C Rathmell.
      Although obesity can promote cancer, it may also increase immunotherapy efficacy in what has been termed the obesity-immunotherapy paradox. Mechanisms of this effect are unclear, although obesity alters key inflammatory cytokines and can promote an inflammatory state that may modify tumor-infiltrating lymphocytes and tumor-associated macrophage populations. To identify mechanisms by which obesity affects antitumor immunity, we examined changes in cell populations and the role of the proinflammatory adipokine leptin in immunotherapy. Single-cell RNAseq demonstrated that obesity decreased tumor-infiltrating lymphocyte frequencies, and flow cytometry confirmed altered macrophage phenotypes with lower expression of inducible NO synthase and MHC class II in tumors of obese animals. When treated with anti-programmed cell death protein 1 (PD-1) Abs, however, obese mice had a greater absolute decrease in tumor burden than lean mice and a repolarization of the macrophages to inflammatory M1-like phenotypes. Mechanistically, leptin is a proinflammatory adipokine that is induced in obesity and may mediate enhanced antitumor immunity in obesity. To directly test the effect of leptin on tumor growth and antitumor immunity, we treated lean mice with leptin and observed tumors over time. Treatment with leptin, acute or chronic, was sufficient to enhance antitumor efficacy similar to anti-PD-1 checkpoint therapy. Further, leptin and anti-PD-1 cotreatment may enhance antitumor effects consistent with an increase in M1-like tumor-associated macrophage frequency compared with non-leptin-treated mice. These data demonstrate that obesity has dual effects in cancer through promotion of tumor growth while simultaneously enhancing antitumor immunity through leptin-mediated macrophage reprogramming.
    DOI:  https://doi.org/10.4049/jimmunol.2001152
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