bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2021‒05‒16
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Cancer Res. 2021 May 14. pii: canres.CAN-20-2562-A.2020. [Epub ahead of print]
      In pancreatic cancer, the robust fibroinflammatory stroma contributes to immune suppression and renders tumors hypoxic, altering intra-tumoral metabolic pathways and leading to poor survival. One metabolic enzyme activated during hypoxia is lactate dehydrogenase A (LDHA). As a result of its promiscuous activity under hypoxia, LDHA produces L-2 hydroxyglutarate, an epigenetic modifier, that regulates the tumor transcriptome. However, the role of L-2HG in remodeling the pancreatic tumor microenvironment is not known. Here we used mass spectrometry to detect L-2HG in serum samples from pancreatic cancer patients, comprising tumor cells as well as stromal cells. Both hypoxic pancreatic tumors as well as serum from pancreatic cancer patients accumulated L-2HG as a result of promiscuous activity of LDHA. This abnormally accumulated L-2HG led to H3 hypermethylation and altered gene expression, which regulated a critical balance between stemness and differentiation in pancreatic tumors. Secreted L-2HG inhibited T cell proliferation and migration, suppressing anti-tumor immunity. In a syngeneic orthotopic model of pancreatic cancer, inhibition of LDHA with GSK2837808A decreased L-2HG, induced tumor regression, and sensitized tumors to anti-PD1 therapy. In conclusion, hypoxia-mediated promiscuous activity of LDHA produces L-2HG in pancreatic tumor cells, regulating the stemness-differentiation balance and contributing to immune evasion. Targeting LDHA can be developed as a potential therapy to sensitize pancreatic tumors to checkpoint inhibitor therapy.
  2. Trends Cancer. 2021 May 07. pii: S2405-8033(21)00082-0. [Epub ahead of print]
      Mechanisms that control translation play important roles in tumor progression and metastasis. Emerging evidence has revealed that dysregulated translation also impacts immune evasion in response to cellular or oncogenic stress. Here, we summarize current knowledge regarding the translational control of immune checkpoints and implications for cancer immunotherapies.
    Keywords:  PD-1/PD-L1; alternative translation initiation factors; immune checkpoints; integrated stress response (ISR) pathway; translation regulation
  3. Front Cell Dev Biol. 2021 ;9 654337
      Cancer cells reprogram glucose metabolism to meet their malignant proliferation needs and survival under a variety of stress conditions. The prominent metabolic reprogram is aerobic glycolysis, which can help cells accumulate precursors for biosynthesis of macromolecules. In addition to glycolysis, recent studies show that gluconeogenesis and TCA cycle play important roles in tumorigenesis. Here, we provide a comprehensive review about the role of glycolysis, gluconeogenesis, and TCA cycle in tumorigenesis with an emphasis on revealing the novel functions of the relevant enzymes and metabolites. These functions include regulation of cell metabolism, gene expression, cell apoptosis and autophagy. We also summarize the effect of glucose metabolism on chromatin modifications and how this relationship leads to cancer development. Understanding the link between cancer cell metabolism and chromatin modifications will help develop more effective cancer treatments.
    Keywords:  epigenetic modifications; gene transcription; histone modifications; metabolism; tumorigenesis
  4. Mol Metab. 2021 May 05. pii: S2212-8778(21)00091-0. [Epub ahead of print] 101246
      OBJECTIVE: Stress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality including multiple organ failure. Stress-induced hyperglycemia is often attributed to insulin resistance as controlling glucose levels via exogenous insulin improves outcomes, but mechanisms are unclear. Forkhead box O (FOXO) transcription factors are direct targets of insulin signaling in the liver that regulate glucose homeostasis via direct and indirect pathways. Loss of hepatic FOXO transcription factors reduces hyperglycemia in chronic insulin-resistance; however, the role of FOXOs in stress-induced hyperglycemia is unknown.METHODS: We subjected mice lacking FOXO transcription factors in liver to a model of injury known to cause stress-induced hyperglycemia. Glucose, insulin, glycerol, fatty acids, cytokines, and adipokines were assessed before and after injury. Liver and adipose tissue were analyzed for changes in glycogen, FOXO target gene expression, and insulin signaling.
    RESULTS: Stress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO1, 3, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia. Mechanistically, loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. Reductions were associated with decreased IL-6, TNF-α, and follistatin and increased FGF21, suggesting that cytokines and FOXO-regulated hepatokines contribute to the stress-induced hyperglycemia response.
    CONCLUSIONS: This work implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross talk between liver and adipose, highlighting a novel mechanism underlying acute hyperglycemia and insulin resistance in stress.
    Keywords:  AKT; FOXO; Insulin resistance; Lipolysis; Stress-induced hyperglycemia
  5. Cell Rep. 2021 May 11. pii: S2211-1247(21)00435-6. [Epub ahead of print]35(6): 109101
      Depleting the microenvironment of important nutrients such as arginine is a key strategy for immune evasion by cancer cells. Many tumors overexpress arginase, but it is unclear how these cancers, but not T cells, tolerate arginine depletion. In this study, we show that tumor cells synthesize arginine from citrulline by upregulating argininosuccinate synthetase 1 (ASS1). Under arginine starvation, ASS1 transcription is induced by ATF4 and CEBPβ binding to an enhancer within ASS1. T cells cannot induce ASS1, despite the presence of active ATF4 and CEBPβ, as the gene is repressed. Arginine starvation drives global chromatin compaction and repressive histone methylation, which disrupts ATF4/CEBPβ binding and target gene transcription. We find that T cell activation is impaired in arginine-depleted conditions, with significant metabolic perturbation linked to incomplete chromatin remodeling and misregulation of key genes. Our results highlight a T cell behavior mediated by nutritional stress, exploited by cancer cells to enable pathological immune evasion.
    Keywords:  ASS1; ATF4; H3K27me3; T cell chromatin; arginine; cancer metabolism; immunometabolism; immunosuppression; metabolic regulation; nutritional stress
  6. FEBS Open Bio. 2021 May 12.
      Endothelial cell function and metabolism are closely linked to differential use of energy substrate sources and combustion. While endothelial cell migration is promoted by 2-phosphofructokinase-6/fructose-2,6-bisphosphatase (PFKFB3)-driven glycolysis, proliferation also depends on fatty acid oxidation for dNTP synthesis. We show that inflammatory activation of human umbilical vein endothelial cells (HUVECs) by interleukin-1β (IL-1β), despite inhibiting proliferation, promotes a shift toward more metabolically active phenotype. This was reflected in increased cellular glucose uptake and consumption, which was preceded by an increase in PFKFB3 mRNA and protein expression. However, despite a modest increase in extracellular acidification rates, the increase in glycolysis did not correlate with extracellular lactate accumulation. Accordingly, IL-1β stimulation also increased oxygen consumption rate, but without a concomitant rise in fatty acid oxidation. Together, this suggests that the IL-1β-stimulated energy shift is driven by shunting of glucose-derived pyruvate into mitochondria to maintain elevated oxygen consumption in HUVECs. We also revealed a marked donor-dependent variation in the amplitude of the metabolic response to IL-1β and postulate that the donor-specific response should be taken into account when considering targeting dysregulated endothelial cell metabolism.
    Keywords:  IL-1β; endothelial cells; glycolysis; inflammation; metabolism
  7. Front Cell Neurosci. 2021 ;15 652647
      Stroke is the leading cause of disability and mortality in the world, but the pathogenesis of ischemic stroke (IS) is not completely clear and treatments are limited. Mounting evidence indicate that neovascularization is a critical defensive reaction to hypoxia that modulates the process of long-term neurologic recovery after IS. Angiogenesis is a complex process in which the original endothelial cells in blood vessels are differentiated, proliferated, migrated, and finally remolded into new blood vessels. Many immune cells and cytokines, as well as growth factors, are directly or indirectly involved in the regulation of angiogenesis. Inflammatory cells can affect endothelial cell proliferation, migration, and activation by secreting a variety of cytokines via various inflammation-relative signaling pathways and thus participate in the process of angiogenesis. However, the mechanism of inflammation-mediated angiogenesis has not been fully elucidated. Hence, this review aimed to discuss the mechanism of inflammation-mediated angiogenesis in IS and to provide new ideas for clinical treatment of IS.
    Keywords:  angiogenesis; immune cells; inflammation; inflammatory cytokine; stroke