bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2021‒03‒21
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Adv Exp Med Biol. 2021 ;1316 149-167
      T cells recognize "foreign" antigens and induce durable humoral and cellular immune responses, which are indispensable for defending pathogens, as well as maintaining the integrity and homeostasis of tissues and organs. T cells are the major immune cell population in the tumor microenvironment which play a critical role in the antitumor immune response and cancer immune surveillance. Defective immune response of tumor-infiltrating T cells is the main cause of cancer immune evasion. The antitumor response of T cells is affected by multiple factors in the tumor microenvironment, including immunosuppressive cells, immune inhibitory cytokines, tumor-derived suppressive signals like PD-L1, immnuogenicity of tumor cells, as well as metabolic factors like hypoxia and nutrient deprivation. Abundant studies in past decades have proved the metabolic regulations of the immune response of T cells and the tumor-infiltrating T cells. In this chapter, we will discuss the regulations of the antitumor response of tumor-infiltrating T cells by lipid metabolism, which is one of the main components of metabolic regulation.
    Keywords:  Fatty acid; Lipid; Metabolism; Tumor microenvironment; Tumor-infiltrating T cell
  2. Front Immunol. 2021 ;12 643144
      Glucose-dependent insulinotropic polypeptide (GIP) communicates information on energy availability from the gut to peripheral tissues. Disruption of its signaling in myeloid immune cells during high-fat diet (HFD)-induced obesity impairs energy homeostasis due to the unrestrained metabolically deleterious actions of S100A8/A9 alarmin. White adipose tissue (WAT) type 2 immune cell networks are important for maintaining metabolic and energy homeostasis and limiting obesity-induced inflammation. Nevertheless, the consequences of losing immune cell GIP receptor (GIPR) signaling on type 2 immunity in WAT remains unknown. Bone marrow (BM) chimerism was used to generate mice with GIPR (Gipr-/- BM) and GIPR/S100A8/A9 (Gipr-/- /S100a9-/- BM) deletion in immune cells. These mice were subjected to short (5 weeks) and progressive (14 weeks) HFD regimens. GIPR-deficiency was also targeted to myeloid cells by crossing Giprfl/fl mice and Lyz2cre/+ mice (LysMΔGipr ). Under both short and progressive HFD regimens, Gipr-/- BM mice exhibited altered expression of key type 2 immune cytokines in the epididymal visceral WAT (epiWAT), but not in subcutaneous inguinal WAT. This was further linked to declined representation of type 2 immune cells in epiWAT, such as group 2 innate lymphoid cells (ILC2), eosinophils, and FOXP3+ regulatory T cells (Tregs). Co-deletion of S100A8/A9 in Gipr-/- immune cells reversed the impairment of type 2 cytokine expression in epiWAT, suggesting a mechanistic role for this alarmin in type 2 immune suppression. LysMΔGipr mice on HFD also displayed altered expression of type 2 immune mediators, highlighting that GIPR-deficiency in myeloid immune cells is responsible for the impairment of type 2 immune networks. Finally, abrogated GIPR signaling in immune cells also affected adipocyte fraction cells, inducing their increased production of the beiging interfering cytokine IL-10 and stress- related type 2 cytokine IL-13. Collectively, these findings attribute an important role for GIPR in myeloid immune cells in supporting WAT type 2 immunity.
    Keywords:  S100A8/A9; glucose-dependent insulinotropic polypeptide receptor; obesity; type 2 immunity; white adipose tissue
  3. Biochem Biophys Rep. 2021 Jul;26 100967
      Obesity-induced endoplasmic reticulum (ER) stress contributes to low-grade chronic inflammation in adipose tissue and may cause metabolic disorders such as diabetes mellitus and dyslipidemia. Identification of high serpina A1 (alpha-1 antitrypsin, A1AT) expression in mouse adipose tissue and adipocytes prompted us to explore the role of A1AT in the inflammatory response of adipocytes under ER stress. We aimed to determine the role of A1AT expression in adipocytes with ER stress during regulation of adipocyte homeostasis and inflammation. To this end, we chemically induced ER stress in A1AT small interfering RNA-transfected differentiating adipocytes using thapsigargin. Induction of CCAAT-enhancer-binding protein homologous protein (CHOP), an ER stress marker, by thapsigargin was lower in A1AT-deficient SW872 adipocytes. Thapsigargin or the proinflammatory cytokine tumor necrosis factor (TNF)α increased basal expression of cytokines such as interleukin (IL)-1β and IL-8 in both SW872 and primary omental adipocytes. This thapsigargin- or TNFα-induced expression of proinflammatory genes was increased by A1AT deficiency. These findings indicate that adipose A1AT may suppress the ER stress response to block excessive expression of proinflammatory factors, which suggests that A1AT protects against adipose tissue dysfunction associated with ER stress activation.
    Keywords:  Adipocyte; Alpha-1 antitrypsin; Endoplasmic reticulum stress; Proinflammatory factor
  4. Cell Biosci. 2021 Mar 16. 11(1): 53
      BACKGROUND: The availability of a reliable tumor target for advanced colorectal cancer (CRC) therapeutic approaches is critical since current treatments are limited. Epidermal growth factor-like domain 6 (EGFL6) has been reported to be associated with cancer development. Here, we focused on the role of EGFL6 in CRC progression and its clinical relevance. In addition, an anti-EGFL6 antibody was generated by phage display technology to investigate its potential therapeutic efficacy in CRC.RESULTS: EGFL6 expression significantly increased in the colon tissues from CRC patients and mice showing spontaneous tumorigenesis, but not in normal tissue. Under hypoxic condition, EGFL6 expression was enhanced at both protein and transcript levels. Moreover, EGFL6 could promote cancer cell migration invasion, and proliferation of CRC cells via up-regulation of the ERK/ AKT pathway. EGFL6 also regulated cell migration, invasion, proliferation, and self-renewal through EGFR/αvβ3 integrin receptors. Treatment with the anti-EGFL6 antibody EGFL6-E5-IgG showed tumor-inhibition and anti-metastasis abilities in the xenograft and syngeneic mouse models, respectively. Moreover, EGFL6-E5-IgG treatment had no adverse effect on angiogenesis and wound healing CONCLUSIONS: We demonstrated that EGFL6 plays a role in CRC tumorigenesis and tumor progression, indicating that EGFL6 is a potential therapeutic target worth further investigation.
    Keywords:  Colorectal cancer; EGFL6; EGFR/αvβ3; Therapeutic antibody; Tumor progression
  5. iScience. 2021 Mar 19. 24(3): 102181
      Perturbation of mitochondrial proteostasis provokes cell autonomous and cell non-autonomous responses that contribute to homeostatic adaptation. Here, we demonstrate distinct metabolic effects of hepatic metabokines as cell non-autonomous factors in mice with mitochondrial OxPhos dysfunction. Liver-specific mitochondrial stress induced by a loss-of-function mutation in Crif1 (LKO) leads to aberrant oxidative phosphorylation and promotes the mitochondrial unfolded protein response. LKO mice are highly insulin sensitive and resistant to diet-induced obesity. The hepatocytes of LKO mice secrete large quantities of metabokines, including GDF15 and FGF21, which confer metabolic benefits. We evaluated the metabolic phenotypes of LKO mice with global deficiency of GDF15 or FGF21 and show that GDF15 regulates body and fat mass and prevents diet-induced hepatic steatosis, whereas FGF21 upregulates insulin sensitivity, energy expenditure, and thermogenesis in white adipose tissue. This study reveals that the mitochondrial integrated stress response (ISRmt) in liver mediates metabolic adaptation through hepatic metabokines.
    Keywords:  Cell Biology; Physiology; Systems Biology
  6. Eur J Pharmacol. 2021 Mar 16. pii: S0014-2999(21)00174-6. [Epub ahead of print] 174021
      Angiogenesis is the process of formation of new blood vessels from existing ones. Vessels serve the purpose of providing oxygen, nutrients and removal of waste from the cells. The physiological angiogenesis is a normal process and is required in the embryonic development, wound healing, menstrual cycle. For homeostasis, balance of pro angiogenic factors and anti angiogenic factors like is important. Their imbalance causes a process known as "angiogenic switch" which leads to various pathological conditions like inflammation, tumor and restenosis. Like normal cells, tumor cells also require oxygen and nutrients to grow which is provided by tumor angiogenesis. Hence angiogenic process can be inhibited to prevent tumor growth. This gives rise to study of anti angiogenic drugs. Currently approved anti angiogenic drugs are mostly VEGF inhibitors, but VEGF inhibitors have certain limitations like toxicity, low progression free survival (PFS), and resistance to anti VEGF therapy. This article focuses on angiopoietins as alternative and potential targets for anti angiogenic therapy. Angiopoietins are ligands of Tie receptor and play a crucial role in angiogenesis, their inhibition can prevent many tumor growths even on later stages of development. We present current clinical and preclinical stages of angiopoietin inhibitors. Drugs studied in the article are selective as well as non-selective inhibitors of angiopoietin 2 like Trebananib (AMG 386), AMG 780, REGN 910, CVX 060, MEDI 3617 and dual inhibitors of angiopoietin 2 and VEGF like Vanucizumab and RG7716. The angiopoietin inhibitors show promising results alone and in combination with VEGF inhibitors in various malignancies.
    Keywords:  Angiopoietin inhibitors; Angiopoietins; Pathophysiology of tumor angiogenesis; Tumor angiogenesis
  7. Eur J Pharmacol. 2021 Mar 12. pii: S0014-2999(21)00172-2. [Epub ahead of print] 174019
      The drug resistance of cancer cells has become one of the biggest obstacles of effective anticancer treatments. Adipocytes produce plenty of cytokines (also known as adipokines), which remarkably affect the drug resistance exhibited by cancer cells. Different adipokines (leptin, visfatin, resistin, adiponectin, Interleukin 6, and tumor necrosis factor α) can induce drug resistance in different cancer cells by various functional mechanisms. This phenomenon is of great interest in pharmacological anti-cancer studies since it indicates that in the cancers with adipocyte-rich microenvironment, all adipokines join together to assist cancer cells to survive by facilitating drug resistance. Studies on adipokines contribute to the development of novel pharmacological strategies for cancer therapy if their roles and molecular targets are better understood. The review will elucidate the roles and the underlying mechanisms of adipokines in drug resistance, which may be of great significance for revealing new strategies for cancer treatment.
    Keywords:  adipokine; cancer; drug resistance