bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2020–01–05
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Fumarate and oxidative stress synergize to promote stability of C/EBP homologous protein in the adipocyte.
  2. HIF-2-induced long non-coding RNA RAB11B-AS1 promotes hypoxia-mediated angiogenesis and breast cancer metastasis.
  3. Fatal Alliance of Hypoxia-/HIF-1α-Driven Microenvironmental Traits Promoting Cancer Progression.
  4. Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage.
  5. Hypoxia Compromises Anti-Cancer Immune Responses.
  6. Mast Cells Localize in Hypoxic Zones of Tumors and Secrete CCL-2 under Hypoxia through Activation of L-Type Calcium Channels.
  7. Mitochondrial TCA cycle metabolites control physiology and disease.
  8. Tumor-derived CCL20 affects B16 melanoma growth in mice.
  9. Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy.
  1. Free Radic Biol Med. 2019 Dec 26. pii: S0891-5849(19)31525-4. [Epub ahead of print]
    Fumarate and oxidative stress synergize to promote stability of C/EBP homologous protein in the adipocyte.
    Allison M Manuel, Michael D Walla, Margaret Dorn, Ross M Tanis, Gerardo G Piroli, Norma Frizzell.
      C/EBP homologous protein (CHOP) is a transcription factor that is elevated in adipose tissue across many models of diabetes and metabolic stress. Although increased CHOP levels are associated with the terminal response to endoplasmic reticulum stress and apoptosis, there is no evidence for CHOP mediated apoptosis in the adipose tissue during diabetes. CHOP protein levels increase in parallel with protein succination, a fumarate derived cysteine modification, in the adipocyte during metabolic stress. We investigated the factors contributing to sustained CHOP proteins levels in the adipocyte, with an emphasis on the regulation of CHOP protein turnover by metabolite-driven modification of Keap1 cysteines. CHOP protein stability was investigated in conditions of nutrient stress due to high glucose or elevated fumarate (fumarase knockdown model); where cysteine succination is specifically elevated. CHOP protein turnover is significantly reduced in models of elevated glucose and fumarate with a ∼30% increase in CHOP stability (p > 0.01), in part due to decreased CHOP phosphorylation. Sustained CHOP levels occur in parallel with elevated heme-oxygenase-1, a production of increased Nrf2 transcriptional activity and Keap1 modification. While Keap1 is directly succinated in the presence of excess fumarate derived from genetic knockdown of fumarase (fumarate levels are elevated >20-fold), it is the oxidative modification of Keap1 that predominates in adipocytes matured in high glucose (fumarate increases 4-5 fold). Elevated fumarate indirectly regulates CHOP stability through the induction of oxidative stress. The antioxidant N-acetylcysteine (NAC) reduces fumarate levels, protein succination and CHOP levels in adipocytes matured in high glucose. Elevated CHOP does not contribute elevated apoptosis in adipocytes, but plays a redox-dependent role in decreasing the adipocyte secretion of interleukin-13, an anti-inflammatory chemokine. NAC treatment restores adipocyte IL-13 secretion, confirming the redox-dependent regulation of a potent anti-inflammatory eotaxin. This study demonstrates that physiological increases in the metabolite fumarate during high glucose exposure contributes to the presence of oxidative stress and sustained CHOP levels in the adipocyte during diabetes. The results reveal a novel metabolic link between mitochondrial metabolic stress and reduced anti-inflammatory adipocyte signaling as a consequence of reduced CHOP protein turnover.
    Keywords:  Adipocytes; Adipose; ER stress; Glucotoxicity; Metabolism; Oxidative stress; Protein modification
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.12.037
  2. Cancer Res. 2020 Jan 03. pii: canres.1532.2019. [Epub ahead of print]
    HIF-2-induced long non-coding RNA RAB11B-AS1 promotes hypoxia-mediated angiogenesis and breast cancer metastasis.
    Yanling Niu, Lei Bao, Yan Chen, Chenliang Wang, Maowu Luo, Bo Zhang, Mi Zhou, Jennifer E Wang, Yisheng V Fang, Ashwani Kumar, Chao Xing, Yingfei Wang, Weibo Luo.
      Hypoxia induces a vast array of long non-coding RNAs (lncRNAs) in breast cancer cells, but their biological functions remain largely unknown. Here we identified a hitherto uncharacterized hypoxia-induced lncRNA RAB11B-AS1 in breast cancer cells. RAB11B-AS1 is a natural lncRNA upregulated in human breast cancer and its expression is induced by hypoxia-inducible factor 2 (HIF-2), but not HIF-1, in response to hypoxia. RAB11B-AS1 enhanced the expression of angiogenic factors including VEGFA and ANGPTL4 in hypoxic breast cancer cells by increasing recruitment of RNA polymerase II. In line with increased angiogenic factors, conditioned media from RAB11B-AS1-overexpressing breast cancer cells promoted tube formation of human umbilical vein endothelial cells in vitro. Gain- and loss-of-function studies revealed that RAB11B-AS1 increased breast cancer cell migration and invasion in vitro and promoted tumor angiogenesis and breast cancer distant metastasis without affecting primary tumor growth in mice. Taken together, these findings uncover a fundamental mechanism of hypoxia-induced tumor angiogenesis and breast cancer metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-19-1532
  3. Adv Exp Med Biol. 2020 ;1232 169-176
    Fatal Alliance of Hypoxia-/HIF-1α-Driven Microenvironmental Traits Promoting Cancer Progression.
    Peter Vaupel, Gabriele Multhoff.
      Inhospitable conditions within the tumor microenvironment (TME) are a characteristic feature ('hallmark') of most solid malignancies. Regional tumor hypoxia is a primary deficiency since it plays a key role in malignant progression. Severe hypoxia is often associated with other detrimental conditions in the TME as a consequence of hypoxia-/HIF-1α-induced (with/without oncogene-direction and/or reciprocal interaction of cancer cells with TME cells) metabolic re-programming, exorbitant extracellular adenosine (ADO) generation and VEGF overexpression/VEGF-R activation. Re-programming of the tumor metabolism inter alia includes a 'selfish' upregulation of aerobic glycolysis/glycolytic flux ('Warburg effect'), a strongly enhanced glutaminolysis in tumor cells, ketogenesis in cancer-associated fibroblasts, and an acceleration of the tryptophan uptake/intensified catabolism yielding kynurenine, which can support the malignant phenotype. Aerobic glycolysis and glutaminolysis result in lactate accumulation (up to 40 mM), and together with the enhanced ketogenesis and CO2/carbonic acid production lead to extracellular acidosis (pHe < 6.8). These traits of the TME individually or collectively operate towards cancer progression via e.g. promotion of genetic instability and mutation, resistance to apoptosis, clonal selection, limitless cell survival and sustained proliferation, continuous angiogenesis and tumor growth, local invasion and distant metastasis, anti-tumor immunosuppression and resistance to therapy.
    Keywords:  Adenosine; Aerobic glycolysis; Glutaminolysis; HIF-1α; Lactate; Metabolic re-programming; Tumor acidosis; Tumor hypoxia; Tumor progression; VEGF; Warburg effect
    DOI:  https://doi.org/10.1007/978-3-030-34461-0_21
  4. Nat Commun. 2020 Jan 02. 11(1): 42
    Tissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage.
    Evi Goulielmaki, Anna Ioannidou, Maria Tsekrekou, Kalliopi Stratigi, Ioanna K Poutakidou, Katerina Gkirtzimanaki, Michalis Aivaliotis, Konstantinos Evangelou, Pantelis Topalis, Janine Altmüller, Vassilis G Gorgoulis, Georgia Chatzinikolaou, George A Garinis.
      DNA damage and metabolic disorders are intimately linked with premature disease onset but the underlying mechanisms remain poorly understood. Here, we show that persistent DNA damage accumulation in tissue-infiltrating macrophages carrying an ERCC1-XPF DNA repair defect (Er1F/-) triggers Golgi dispersal, dilation of endoplasmic reticulum, autophagy and exosome biogenesis leading to the secretion of extracellular vesicles (EVs) in vivo and ex vivo. Macrophage-derived EVs accumulate in Er1F/- animal sera and are secreted in macrophage media after DNA damage. The Er1F/- EV cargo is taken up by recipient cells leading to an increase in insulin-independent glucose transporter levels, enhanced cellular glucose uptake, higher cellular oxygen consumption rate and greater tolerance to glucose challenge in mice. We find that high glucose in EV-targeted cells triggers pro-inflammatory stimuli via mTOR activation. This, in turn, establishes chronic inflammation and tissue pathology in mice with important ramifications for DNA repair-deficient, progeroid syndromes and aging.
    DOI:  https://doi.org/10.1038/s41467-019-13894-9
  5. Adv Exp Med Biol. 2020 ;1232 131-143
    Hypoxia Compromises Anti-Cancer Immune Responses.
    Gabriele Multhoff, Peter Vaupel.
      Hypoxia, one of the hallmarks of cancer, is caused by an insufficient oxygen supply, mostly due to a chaotic, deficient tumor microcirculation. Apart from a hypoxia-mediated resistance to standard therapies, modulated gene and protein expression, genetic instability and malignant progression, hypoxia also plays a pivotal role in anti-cancer immune responses by (a) reducing survival, cytolytic and migratory activity of effector cells such as CD4+ cells, CD8+ cytotoxic T cells, natural killer-like T cells and natural killer cells, (b) reducing the production and release of effector cytokines, (c) supporting immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and M2 macrophages, (d) increasing the production and release of immunosuppressive cytokines, and (e) inducing the expression of immune checkpoint inhibitors. In this minireview, immunosuppressive effects of hypoxia- and HIF-1a-driven traits in cancers are described.
    Keywords:  Anti-cancer immunity; Hypoxia; Immunosuppression; Immunosuppressive cells hypoxia; Immunosuppressive factors; Tumor hypoxia; Tumor microenvironment HIF-1 alpha hypoxia
    DOI:  https://doi.org/10.1007/978-3-030-34461-0_18
  6. J Immunol. 2020 Jan 03. pii: ji1801430. [Epub ahead of print]
    Mast Cells Localize in Hypoxic Zones of Tumors and Secrete CCL-2 under Hypoxia through Activation of L-Type Calcium Channels.
    Itzel G Ramírez-Moreno, Alfredo Ibarra-Sánchez, Jorge Ivan Castillo-Arellano, Ulrich Blank, Claudia González-Espinosa.
      Hypoxia is a condition that together with low pH, high amounts of reactive oxygen species (ROS), and increased adenosine levels characterize tumor microenvironment. Mast cells (MCs) are part of tumor microenvironment, but the effect of hypoxia on the production of MC-derived cytokines has not been fully described. Using the hypoxia marker pimonidazole in vivo, we found that MCs were largely located in the low-oxygen areas within B16-F1 mice melanoma tumors. In vitro, hypoxia promoted ROS production, a ROS-dependent increase of intracellular calcium, and the production of MCP 1 (CCL-2) in murine bone marrow-derived MCs. Hypoxia-induced CCL-2 production was sensitive to the antioxidant trolox and to nifedipine, a blocker of L-type voltage-dependent Ca2+ channels (LVDCCs). Simultaneously with CCL-2 production, hypoxia caused the ROS-dependent glutathionylation and membrane translocation of the α1c subunit of Cav1.2 LVDCCs. Relationship between ROS production, calcium rise, and CCL-2 synthesis was also observed when cells were treated with H2O2 In vivo, high CCL-2 production was detected on hypoxic zones of melanoma tumors (where tryptase-positive MCs were also found). Pimonidazole and CCL-2 positive staining diminished when B16-F1 cell-inoculated animals were treated with trolox, nifedipine, or the adenosine receptor 2A antagonist KW6002. Our results show that MCs are located preferentially in hypoxic zones of melanoma tumors, hypoxia-induced CCL-2 production in MCs requires calcium rise mediated by glutathionylation and membrane translocation of LVDCCs, and this mechanism of CCL-2 synthesis seems to operate in other cells inside melanoma tumors, with the participation of the adenosine receptor 2A.
    DOI:  https://doi.org/10.4049/jimmunol.1801430
  7. Nat Commun. 2020 Jan 03. 11(1): 102
    Mitochondrial TCA cycle metabolites control physiology and disease.
    Inmaculada Martínez-Reyes, Navdeep S Chandel.
      Mitochondria are signaling organelles that regulate a wide variety of cellular functions and can dictate cell fate. Multiple mechanisms contribute to communicate mitochondrial fitness to the rest of the cell. Recent evidence confers a new role for TCA cycle intermediates, generally thought to be important for biosynthetic purposes, as signaling molecules with functions controlling chromatin modifications, DNA methylation, the hypoxic response, and immunity. This review summarizes the mechanisms by which the abundance of different TCA cycle metabolites controls cellular function and fate in different contexts. We will focus on how these metabolites mediated signaling can affect physiology and disease.
    DOI:  https://doi.org/10.1038/s41467-019-13668-3
  8. J Dermatol Sci. 2019 Dec 13. pii: S0923-1811(19)30388-3. [Epub ahead of print]
    Tumor-derived CCL20 affects B16 melanoma growth in mice.
    Diego Martin-Garcia, Cinthia Silva-Vilches, Rainer Will, Alexander H Enk, Anke S Lonsdorf.
       BACKGROUND: Chemokine ligand-20 (CCL20) expressed in the epidermis is a potent impetus for the recruitment of CC-chemokine receptor 6 (CCR6)-expressing subsets of DCs, B-cells and memory T-cells into the skin. CCL20 and CCR6+ immune cells have been detected in chronic inflammatory skin diseases and several malignancies, including melanoma. Yet, the functional contribution of the CCR6/CCL20 axis for melanoma progression remains controversial.
    OBJECTIVE: The functional contribution of CCR6-expressing immune cell subsets and local CCL20 in the tumor microenvironment for the immune control of melanoma was studied.
    METHODS: Homeostatic and inducible CCL20 secretion of murine (B16, Ret) and human (A375, C32) melanoma cells was analyzed by ELISA. To assess the functional relevance of CCR6/CCL20 interactions on local tumor progression, prestimulated or retrovirally transduced B16/F1 melanoma cells overexpressing CCL20 (B16-CCL20) were injected subcutaneously into C57BL/6 Wt mice and congenic CCR6-deficient (CCR6-/-) mice. Infiltrating leucocytes were examined by flow cytometry in tumors and draining lymph nodes (DLNs).
    RESULTS: Melanoma cell lines up-regulate CCL20 secretion upon stimulation with pro-inflammatory cytokines in vitro. While only moderate changes in phenotype and composition of leucocytes were detected in advanced tumors and DLNs, mice injected with CCR6+ B16-CCL20 cells developed smaller tumors compared to B16-Control injected littermates, with CCR6-/- mice displaying the most pronounced reduction in tumor growth and incidence.
    CONCLUSION: Our results suggest that CCR6/CCL20 interactions and individual independent effects of CCL20 and CCR6 in the microenvironment may be essential for melanoma progression and suggest a decisive role of this chemokine axis for melanoma pathogenesis beyond chemoattraction.
    Keywords:  CCL20; CCR6; Chemokines; Melanoma; Tumor infiltrating leucocytes
    DOI:  https://doi.org/10.1016/j.jdermsci.2019.12.005
  9. Proc Natl Acad Sci U S A. 2019 Dec 30. pii: 201902145. [Epub ahead of print]
    Optimized antiangiogenic reprogramming of the tumor microenvironment potentiates CD40 immunotherapy.
    Abhishek S Kashyap, Martina Schmittnaegel, Nicolò Rigamonti, Daniela Pais-Ferreira, Philipp Mueller, Melanie Buchi, Chia-Huey Ooi, Matthias Kreuzaler, Petra Hirschmann, Alan Guichard, Natascha Rieder, Ruben Bill, Frank Herting, Yvonne Kienast, Stefan Dirnhofer, Christian Klein, Sabine Hoves, Carola H Ries, Emily Corse, Michele De Palma, Alfred Zippelius.
      Cancer immunotherapies are increasingly combined with targeted therapies to improve therapeutic outcomes. We show that combination of agonistic anti-CD40 with antiangiogenic antibodies targeting 2 proangiogenic factors, vascular endothelial growth factor A (VEGFA) and angiopoietin 2 (Ang2/ANGPT2), induces pleiotropic immune mechanisms that facilitate tumor rejection in several tumor models. On the one hand, VEGFA/Ang2 blockade induced regression of the tumor microvasculature while decreasing the proportion of nonperfused vessels and reducing leakiness of the remaining vessels. On the other hand, both anti-VEGFA/Ang2 and anti-CD40 independently promoted proinflammatory macrophage skewing and increased dendritic cell activation in the tumor microenvironment, which were further amplified upon combination of the 2 treatments. Finally, combined therapy provoked brisk infiltration and intratumoral redistribution of cytotoxic CD8+ T cells in the tumors, which was mainly driven by Ang2 blockade. Overall, these nonredundant synergistic mechanisms endowed T cells with improved effector functions that were conducive to more efficient tumor control, underscoring the therapeutic potential of antiangiogenic immunotherapy in cancer.
    Keywords:  CD40; VEGFA; angiogenesis; angiopoetin; immunotherapy
    DOI:  https://doi.org/10.1073/pnas.1902145116
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