bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2021–10–17
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation: A Review of the Molecular Mechanisms.
  2. mTOR-dependent immunometabolism as Achilles' heel of anticancer therapy.
  3. Normalization of the tumor microvasculature based on targeting and modulation of the tumor microenvironment.
  4. Metabolic Messengers: tumour necrosis factor.
  5. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives.
  6. Neutrophils correlate with hypoxia microenvironment and promote progression of non-small-cell lung cancer.
  7. Hyperthermia alters interleukin-6 production in response to lipopolysaccharide via endoplasmic reticulum stress in bovine endometrial cells.
  1. Int J Mol Sci. 2021 Oct 02. pii: 10701. [Epub ahead of print]22(19):
    Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation: A Review of the Molecular Mechanisms.
    Jan Korbecki, Donata Simińska, Magdalena Gąssowska-Dobrowolska, Joanna Listos, Izabela Gutowska, Dariusz Chlubek, Irena Baranowska-Bosiacka.
      Chronic (continuous, non-interrupted) hypoxia and cycling (intermittent, transient) hypoxia are two types of hypoxia occurring in malignant tumors. They are both associated with the activation of hypoxia-inducible factor-1 (HIF-1) and nuclear factor κB (NF-κB), which induce changes in gene expression. This paper discusses in detail the mechanisms of activation of these two transcription factors in chronic and cycling hypoxia and the crosstalk between both signaling pathways. In particular, it focuses on the importance of reactive oxygen species (ROS), reactive nitrogen species (RNS) together with nitric oxide synthase, acetylation of HIF-1, and the action of MAPK cascades. The paper also discusses the importance of hypoxia in the formation of chronic low-grade inflammation in cancerous tumors. Finally, we discuss the effects of cycling hypoxia on the tumor microenvironment, in particular on the expression of VEGF-A, CCL2/MCP-1, CXCL1/GRO-α, CXCL8/IL-8, and COX-2 together with PGE2. These factors induce angiogenesis and recruit various cells into the tumor niche, including neutrophils and monocytes which, in the tumor, are transformed into tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) that participate in tumorigenesis.
    Keywords:  HIF-1α; HIF-1β; NF-κB; cancer; cycling hypoxia; hypoxia-inducible factor; low-grade inflammation; tumor
    DOI:  https://doi.org/10.3390/ijms221910701
  2. Eur J Immunol. 2021 Oct 14.
    mTOR-dependent immunometabolism as Achilles' heel of anticancer therapy.
    Clarissa Braun, Thomas Weichhart.
      Immune cells are important constituents of the tumor microenvironment and essential in eradicating tumor cells during conventional therapies or novel immunotherapies. The mechanistic target of rapamycin (mTOR) signaling pathway senses the intra- and extracellular nutrient status, growth factor supply and cell stress-related changes to coordinate cellular metabolism and activation dictating effector and memory functions in mainly all hematopoietic immune cells. In addition, the mTOR complex 1 (mTORC1) and mTORC2 are frequently deregulated and become activated in cancer cells to drive cell transformation, survival, neovascularization, and invasion. In this review we provide an overview of the influence of mTOR complexes on immune and cancer cell function and metabolism. We discuss how mTOR inhibitors aiming to target cancer cells will influence immunometabolic cell functions participating either in anti-tumor responses or favoring tumor cell progression in individual immune cells. We suggest immunometabolism as the weak spot of anticancer therapy and propose to evaluate patients according to their predominant immune cell subtype in the cancer tissue. Advances in metabolic drug development that hold promise for more effective treatments in different types of cancer will have to consider their effects on the immune system. This article is protected by copyright. All rights reserved.
    Keywords:  Immunometabolism; cancer treatment; immunotherapy; mTORC1; tumor microenvironment
    DOI:  https://doi.org/10.1002/eji.202149270
  3. Nanoscale. 2021 Oct 15.
    Normalization of the tumor microvasculature based on targeting and modulation of the tumor microenvironment.
    Zhipeng Li, Fang Ning, Changduo Wang, Hongli Yu, Qingming Ma, Yong Sun.
      Angiogenesis is an essential process for tumor development. Owing to the imbalance between pro- and anti-angiogenic factors, the tumor vasculature possesses the characteristics of tortuous, hyperpermeable vessels and compressive force, resulting in a reduction in the effect of traditional chemotherapy and radiotherapy. Anti-angiogenesis has emerged as a promising strategy for cancer treatment. Tumor angiogenesis, however, has been proved to be a complex process in which the tumor microenvironment (TME) plays a vital role in the initiation and development of the tumor microvasculature. The host stromal cells in the TME, such as cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs) and Treg cells, contribute to angiogenesis. Furthermore, the abnormal metabolic environment, such as hypoxia and acidosis, leads to the up-regulated expression of angiogenic factors. Indeed, normalization of the tumor microvasculature via targeting and modulating the TME has become a promising strategy for anti-angiogenesis and anti-tumor therapy. In this review, we summarize the abnormalities of the tumor microvasculature, tumor angiogenesis induced by an abnormal metabolic environment and host stromal cells, as well as drug delivery therapies to restore the balance between pro- and anti-angiogenic factors by targeting and normalizing the tumor vasculature in the TME.
    DOI:  https://doi.org/10.1039/d1nr03387e
  4. Nat Metab. 2021 Oct 14.
    Metabolic Messengers: tumour necrosis factor.
    Jaswinder K Sethi, Gökhan S Hotamisligil.
      Tumour necrosis factor (TNF) is a classical, pleiotropic pro-inflammatory cytokine. It is also the first 'adipokine' described to be produced from adipose tissue, regulated in obesity and proposed to contribute to obesity-associated metabolic disease. In this review, we provide an overview of TNF in the context of metabolic inflammation or metaflammation, its discovery as a metabolic messenger, its sites and mechanisms of action and some critical considerations for future research. Although we focus on TNF and the studies that elucidated its immunometabolic actions, we highlight a conceptual framework, generated by these studies, that is equally applicable to the complex network of pro-inflammatory signals, their biological activity and their integration with metabolic regulation, and to the field of immunometabolism more broadly.
    DOI:  https://doi.org/10.1038/s42255-021-00470-z
  5. Mol Cancer. 2021 Oct 11. 20(1): 131
    Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives.
    Xiaoqi Mao, Jin Xu, Wei Wang, Chen Liang, Jie Hua, Jiang Liu, Bo Zhang, Qingcai Meng, Xianjun Yu, Si Shi.
      Cancer-associated fibroblasts (CAFs), a stromal cell population with cell-of-origin, phenotypic and functional heterogeneity, are the most essential components of the tumor microenvironment (TME). Through multiple pathways, activated CAFs can promote tumor growth, angiogenesis, invasion and metastasis, along with extracellular matrix (ECM) remodeling and even chemoresistance. Numerous previous studies have confirmed the critical role of the interaction between CAFs and tumor cells in tumorigenesis and development. However, recently, the mutual effects of CAFs and the tumor immune microenvironment (TIME) have been identified as another key factor in promoting tumor progression. The TIME mainly consists of distinct immune cell populations in tumor islets and is highly associated with the antitumor immunological state in the TME. CAFs interact with tumor-infiltrating immune cells as well as other immune components within the TIME via the secretion of various cytokines, growth factors, chemokines, exosomes and other effector molecules, consequently shaping an immunosuppressive TME that enables cancer cells to evade surveillance of the immune system. In-depth studies of CAFs and immune microenvironment interactions, particularly the complicated mechanisms connecting CAFs with immune cells, might provide novel strategies for subsequent targeted immunotherapies. Herein, we shed light on recent advances regarding the direct and indirect crosstalk between CAFs and infiltrating immune cells and further summarize the possible immunoinhibitory mechanisms induced by CAFs in the TME. In addition, we present current related CAF-targeting immunotherapies and briefly describe some future perspectives on CAF research in the end.
    Keywords:  CAF-targeted therapy; Cancer; Cancer-associated fibroblasts; Cell–cell interaction; Immune suppression; Tumor immune microenvironment; Tumor microenvironment; Tumor-infiltrating immune cells
    DOI:  https://doi.org/10.1186/s12943-021-01428-1
  6. Bioengineered. 2021 Oct 12.
    Neutrophils correlate with hypoxia microenvironment and promote progression of non-small-cell lung cancer.
    Chunyan Zhang, Bingxiang Tang, Jianping Hu, Xiang Fang, Hongzhi Bian, Junlei Han, Congxia Hou, Fang Sun.
      Hypoxia, a strong and selective pressure, has been involved in invasion, metastasis, and angiogenesis of tumor cells. Our study performed the transcriptome profiles of 666 non-small-cell lung cancer (NSCLC) patients. Various bioinformatic approaches were combined to evaluate the immune cell infiltration in the high hypoxia risk patients. In addition, in vitro experiments were performed to assess the effects of tumor-associated neutrophils (TANs) on NSCLC cells proliferation, migration and invasion and to reveal the underlying mechanisms. We divided NSCLC into two groups (Cluster1/2) based on the expression profiles of hypoxia-associated genes. Compared with the Cluster1 subgroup, the Cluster2 had a worse prognosis. Significant enrichment analysis revealed that PI3K/AKT/mTOR signaling pathway and TANs were highly related to hypoxia microenvironment. Eleven hypoxia-related genes (FBP1, NDST2, ADM, LDHA, DDIT4, EXT1, BCAN, IGFBP1, PDGFB, AKAP12, and CDKN3) were scored by LASSO COX regression to yield risk scores, and we revealed a significant difference in overall survival (OS) between the low- and high-risk groups. Mechanistically, CXCL6 in hypoxic cancer cells promoted the migration of TANs in vitro, and in turn promote NSCLC cells proliferation, migration and invasion. In summary, this study revealed a 11-hypoxia gene signature that predicted OS of NSCLC patients, and improved our understanding of the role of TANs in hypoxia microenvironment.
    Keywords:  CXCL6; gene signature; hypoxia; non-small-cell lung cancer; progression; tumor-associated neutrophils
    DOI:  https://doi.org/10.1080/21655979.2021.1987820
  7. J Cell Physiol. 2021 Oct 14.
    Hyperthermia alters interleukin-6 production in response to lipopolysaccharide via endoplasmic reticulum stress in bovine endometrial cells.
    Shunsuke Sakai, Yuki Inoue, Keisuke Tanaka, Yuki Yamamoto, Hisataka Iwata, Koji Kimura.
      In the postpartum period, cows experience the uterine bacterial infection and develop the endometritis. To eliminate bacteria and recover from endometritis, endometrial epithelial and stromal cells secrete the cytokine and chemokine, such as interleukin 6 (IL-6), IL-8, and monocyte chemotactic protein 1 (MCP1), to recruit immune cells. Moreover, the symptom of endometritis is prolonged in summer and we have recently indicated that hyperthermia suppresses and enhances the IL-6 production in response to lipopolysaccharide (LPS) challenge in endometrial epithelial and stromal cells, respectively. However, the mechanisms for the opposite reaction of IL-6 secretion in response to LPS challenge in both types of endometrial cells under hyperthermia conditions were still unclear. To reveal these mechanisms, both types of endometrial cells were cultured with LPS under the control (38.5°C) or hyperthermia (40.5°C) conditions and comprehensively analyzed differential gene expressions of them by RNA-seq. In addition, based on these results, we examined the effect of endoplasmic reticulum (ER) stress on the IL-6 production in both types of endometrial cells cultured with LPS under hyperthermia conditions. In comprehensive analysis, hyperthermia induced the ER stress in the endometrial stromal cells but not in the endometrial epithelial cells. Actually, we confirmed that hyperthermia increased the gene expression of BiP, ATF4, and sXBP1 and protein expression of BiP and phosphorylated inositol requiring 1, ER stress marker, in the endometrial stromal cells but not in the endometrial epithelial cells. Moreover, in the endometrial stromal cells exposed to LPS, activation and inhibition of ER stress enhanced the IL-6 production under control conditions and suppressed it under hyperthermia conditions, respectively. In this study, we could uncover the one of causes for the disruption of IL-6 production in response to LPS challenge in the endometrial cells under hyperthermia conditions. This finding might be a clue for the improvement of the symptom of endometritis in cows during summer.
    Keywords:  IL-6; cattle; endometrial cells; endoplasmic reticulum stress; heat stress; hyperthermia
    DOI:  https://doi.org/10.1002/jcp.30604
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