bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒02‒23
five papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Future Oncol. 2020 Feb 18.
    Ou X, Lv W.
      It is universally acknowledged that a large number of immune cells, as well as inflammatory factors, regulatory factors and metabolites, accumulate in the tumor microenvironment to jointly promote tumor escape, development and metastasis. Hypoxia is one of the characteristics in tumor microenvironment and is a common phenomenon in all solid tumors. In tumor hypoxia response, there is a key regulator called HIF-1a, which is a key transcriptional regulatory protein that regulates many critical genes. In this paper, the effects of hypoxia on glucose metabolism of tumor cells, myeloid-derived suppressor cells and T cells in tumor microenvironment were reviewed, and the interaction among the three was also described.
    Keywords:  HIF-1a; MDSC; T cells; glycolysis; hypoxia; tumor microenvironment
  2. Biomed Res Int. 2020 ;2020 5958272
    Zheng H, Wu Y, Guo T, Liu F, Xu Y, Cai S.
      Hypoxia plays an essential role in orchestrating Epithelial-mesenchymal transition and promoting metastasis of colorectal cancer. However, the underlying mechanisms are still not well elucidated. Here, we present that hypoxic exposure causes endoplasmic reticulum stress and activates the unfolded protein response pathways, which drives GDF15 expression in colorectal cancer cells. Mechanistically, upregulated CHOP led by activated PERK-eIF2α signaling promotes GDF15 transcription via directly binding to its promoter. Further study implicates that hypoxia-induced GDF15 is required for the EMT and invasion of colorectal cancer cells; enforced expression of GDF15 promotes the mitochondrial oxidation of fatty acids in colorectal cancer cells. Moreover, the abrogation of GDF15 results in smaller xenograft tumors in size and impaired metastasis. GDF15 is expressed much more in tumor tissues of CRC patients and displays positive correlations with CHOP and HIF1α in mRNA levels. Our study demonstrates a novel molecular mechanism underlying hypoxia-promoted metastasis of CRC and provides PERK signaling-regulated GDF15 as a new and promising therapeutic target for clinical treatment and drug discovery.
  3. Nat Immunol. 2020 Feb 17.
    Wang H, Franco F, Tsui YC, Xie X, Trefny MP, Zappasodi R, Mohmood SR, Fernández-García J, Tsai CH, Schulze I, Picard F, Meylan E, Silverstein R, Goldberg I, Fendt SM, Wolchok JD, Merghoub T, Jandus C, Zippelius A, Ho PC.
      Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.
  4. Int J Mol Sci. 2020 Feb 14. pii: E1283. [Epub ahead of print]21(4):
    Alonso-Alconada D, Álvarez FJ, Goñi-de-Cerio F, Hilario E, Álvarez A.
      In the process of neonatal encephalopathy, oxidative stress and neuroinflammation have a prominent role after perinatal asphyxia. With the exception of therapeutic hypothermia, no therapeutic interventions are available in the clinical setting to target either the oxidative stress or inflammation, despite the high prevalence of neurological sequelae of this devastating condition. The endocannabinoid system (ECS), recently recognized as a widespread neuromodulatory system, plays an important role in the development of the central nervous system (CNS). This study aims to evaluate the potential effect of the cannabinoid (CB) agonist WIN 55,212-2 (WIN) on reactive oxygen species (ROS) and early inflammatory cytokine production after hypoxia-ischemia (HI) in fetal lambs. Hypoxic-ischemic animals were subjected to 60 min of HI by partial occlusion of the umbilical cord. A group of lambs received a single dose of 0.01 μg/kg WIN, whereas non-asphyctic animals served as controls. WIN reduced the widespread and notorious increase in inflammatory markers tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6 induced by HI, a modulatory effect not observed for oxidative stress. Our study suggests that treatment with a low dose of WIN can alter the profile of pro-inflammatory cytokines 3 h after HI.
    Keywords:  Cannabinoid; agonist WIN 55,212-2; fetal lambs; hypoxia ischemia; inflammation; oxidative stress
  5. Biomolecules. 2020 Feb 17. pii: E314. [Epub ahead of print]10(2):
    Ryu KY, Jeon EJ, Leem J, Park JH, Cho H.
      Adpsin is an adipokine that stimulates insulin secretion from β-cells and improves glucose tolerance. Its expression has been found to be markedly reduced in obese animals. However, it remains unclear what factors lead to downregulation of adipsin in the context of obesity. Endoplasmic reticulum (ER) stress response is activated in various tissues under obesity-related conditions and can induce transcriptional reprogramming. Therefore, we aimed to investigate the relationship between adipsin expression and ER stress in adipose tissues during obesity. We observed that obese mice exhibited decreased levels of adipsin in adipose tissues and serum and increased ER stress markers in adipose tissues compared to lean mice. We also found that ER stress suppressed adipsin expression via adipocytes-intrinsic mechanisms. Moreover, the ER stress-mediated downregulation of adipsin was at least partially attributed to decreased expression of peroxisome proliferator-activated receptor γ (PPARγ), a key transcription factor in the regulation of adipocyte function. Finally, treatment with chemical chaperones recovered the ER stress-mediated downregulation of adipsin and PPARγ in vivo and in vitro. Our findings suggest that activated ER stress in adipose tissues is an important cause of the suppression of adipsin expression in the context of obesity.
    Keywords:  adipocytes; adipsin; diabetes mellitus; endoplasmic reticulum stress; obesity