bims-stacyt Biomed news
on Paracrine crosstalk between cancer and the organism
Issue of 2018‒11‒18
three papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge


  1. Int J Mol Sci. 2018 Nov 09. pii: E3523. [Epub ahead of print]19(11):
    Hiraga T.
      Hypoxia is a common feature of solid tumors and is associated with an increased risk of metastasis and a poor prognosis. Recent imaging techniques revealed that bone marrow contains a quite hypoxic microenvironment. Low oxygen levels activate hypoxia signaling pathways such as hypoxia-inducible factors, which play critical roles in the key stages of metastatic dissemination including angiogenesis, epithelial-mesenchymal transition, invasion, maintenance of cancer stem cells, tumor cell dormancy, release of extracellular vesicles, and generation of pre-metastatic niches. Hypoxia also affects bone cells, such as osteoblasts and osteoclasts, and immune cells, which also act to support the development and progression of bone metastases. Paradoxically, hypoxia and related signaling molecules are recognized as high-priority therapeutic targets and many candidate drugs are currently under preclinical and clinical investigation. The present review focuses on our current knowledge of the potential roles of hypoxia in cancer metastasis to bone by considering the interaction between metastatic cancer cells and the bone microenvironment. Current therapeutic approaches targeting hypoxia are also described.
    Keywords:  bone metastasis; hypoxia; hypoxia-inducible factors
    DOI:  https://doi.org/10.3390/ijms19113523
  2. Cytokine. 2018 Nov 13. pii: S1043-4666(18)30406-X. [Epub ahead of print]
    Duvigneau JC, Luís A, Gorman AM, Samali A, Kaltenecker D, Moriggl R, Kozlov AV.
      An excessive inflammatory response is frequently associated with cellular dysfunction and cell death. The latter may cause single and multiple organ failure. The most susceptible organs are liver, lung, kidney, heart and intestine. This review will focus on the liver as a target organ for an excessive inflammatory response. It is commonly accepted that organ failure is caused by the action of inflammatory cytokines released in excess during the inflammatory response. It has been suggested that inflammation mediated liver failure is not due to an increased death rate of parenchymal cells, but due to an intracellular metabolic disorder. This metabolic disorder is associated with mitochondrial and endoplasmic reticulum (ER) dysfunction during the acute phase response elicited by systemic inflammation. An overproduction of acute phase proteins in the liver as well as elevated reactive oxygen species (ROS) generation induce ER stress, triggering the unfolded protein response (UPR), which may initiate or aggravate inflammation. It is known that certain inflammatory mediators, such as the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α induce ER stress. These findings suggest that ER stress and the subsequent UPR on the one hand, and the inflammatory response on the other create a kind of feed forward loop, which can be either beneficial (e.g., elimination of the pathogen and restoration of tissue homeostasis) or deleterious (e.g., excessive cell dysfunction and cell death). This review aims to unfurl the different pathways contributing to this loop and to highlight the relevance of UPR signaling (IRE1α, ATF6, and PERK) and mediators of the inflammatory response (NF-κB, STAT3, IL-1β, IL-6, TLR) which have a particular role as pathophysiological triggers in the liver.
    Keywords:  Endoplasmic reticulum stress; IL-1β; Inflammatory response; Interleukin-6; Liver diseases; TNF-α; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.cyto.2018.10.018
  3. Purinergic Signal. 2018 Nov 10.
    Doktor F, Prager P, Wiedemann P, Kohen L, Bringmann A, Hollborn M.
      Retinal hypoxia is a major condition of the chronic inflammatory disease age-related macular degeneration. Extracellular ATP is a danger signal which is known to activate the NLRP3 inflammasome in various cell systems. We investigated in cultured human retinal pigment epithelial (RPE) cells whether hypoxia alters the expression of inflammasome-associated genes and whether purinergic receptor signaling contributes to the hypoxic expression of key inflammatory (NLRP3) and angiogenic factor (VEGF) genes. Hypoxia and chemical hypoxia were induced by a 0.2%-O2 atmosphere and addition of CoCl2, respectively. Gene expression was determined with real-time RT-PCR. Cytosolic NLRP3 and (pro-) IL-1β levels, and the extracellular VEGF level, were evaluated with Western blot and ELISA analyses. Cell culture in 0.2% O2 induced expression of NLRP3 and pro-IL-1β genes but not of the pro-IL-18 gene. Hypoxia also increased the cytosolic levels of NLRP3 and (pro-) IL-1β proteins. Inflammasome activation by lysosomal destabilization decreased the cell viability under hypoxic, but not control conditions. In addition to activation of IL-1 receptors, purinergic receptor signaling mediated by a pannexin-dependent release of ATP and a release of adenosine, and activation of P2Y2 and adenosine A1 receptors, was required for the full hypoxic expression of the NLRP3 gene. P2Y2 (but not A1) receptor signaling also contributed to the hypoxic expression and secretion of VEGF. The data indicate that hypoxia induces priming and activation of the NLRP3 inflammasome in cultured RPE cells. The hypoxic NLRP3 and VEGF gene expression and the secretion of VEGF are in part mediated by P2Y2 receptor signaling.
    Keywords:  Hypoxia; Inflammasome; NLRP3; P2Y2; Retinal pigment epithelium; VEGF
    DOI:  https://doi.org/10.1007/s11302-018-9631-6