miR-210 and hypoxic microvesicles: Two critical components of hypoxia involved in the regulation of killer cells function.

It has become clear that tumor stroma components are engaged in an active and complex molecular cross-talk that has serious implications for immunological recognition of tumor cells in shaping the microenvironment. Hypoxia which is a major component of tumor microenvironment influences the characteristics of neoplasia by favoring heterogeneity, invasiveness, metastatic potency and tumor progression. In this regard, an important mode of communication between carcinoma cells and immune cells may involve tumor-derived microvesicles, which are able to carry lipids, proteins, mRNAs and miRNAs. This review covers new evidence indicating that the efficacy of the cell-mediated cytotoxicity (CTLs and NK) may be dependent on hypoxia induced miRNA and microvesicles in the tumor microenvironment by inhibiting the efficacy of natural host anti-tumor immune response and improving the ability of tumors to avoid immunosurveillance. This emphasizes that hypoxic tumors actively develop additional mechanisms to suppress the sensing of the immunologic danger signals in order to survive and propagate without inciting anti-tumor immunity.

[1]  G. Ruvkun,et al.  Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans , 1993, Cell.

[2]  T. Whiteside,et al.  Blast-derived microvesicles in sera from patients with acute myeloid leukemia suppress natural killer cell function via membrane-associated transforming growth factor-β1 , 2011, Haematologica.

[3]  Carme Camps,et al.  hsa-miR-210 Is Induced by Hypoxia and Is an Independent Prognostic Factor in Breast Cancer , 2008, Clinical Cancer Research.

[4]  P. Dessen,et al.  PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation , 2014, The Journal of experimental medicine.

[5]  S. Chouaib,et al.  Targeting hypoxia at the forefront of anticancer immune responses , 2014, Oncoimmunology.

[6]  G. Semenza.  Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. , 2012, Trends in pharmacological sciences.

[7]  William E. Grizzle,et al.  Murine Mammary Carcinoma Exosomes Promote Tumor Growth by Suppression of NK Cell Function1 , 2006, The Journal of Immunology.

[8]  Katrin J. Svensson,et al.  Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity , 2013, Proceedings of the National Academy of Sciences.

[9]  Joan Pérez Roca,et al.  Hypoxia-inducible factors : , 2015 .

[10]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

[11]  Laurence Zitvogel,et al.  Dendritic Cell-Derived Exosomes Promote Natural Killer Cell Activation and Proliferation: A Role for NKG2D Ligands and IL-15Rα , 2009, PloS one.

[12]  Fabio Martelli,et al.  MicroRNA-210 Modulates Endothelial Cell Response to Hypoxia and Inhibits the Receptor Tyrosine Kinase Ligand Ephrin-A3* , 2008, Journal of Biological Chemistry.

[13]  Laurence Zitvogel,et al.  Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming , 2001, Nature Medicine.

[14]  U. A. Ørom,et al.  MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation. , 2008, Molecular cell.

[15]  M. Belting,et al.  Emerging roles of extracellular vesicles in the adaptive response of tumour cells to microenvironmental stress , 2013, Journal of extracellular vesicles.

[16]  M. Peterson,et al.  miR-210 promotes IPF fibroblast proliferation in response to hypoxia. , 2014, American journal of physiology. Lung cellular and molecular physiology.

[17]  Brian Keith,et al.  Hypoxia-Inducible Factors, Stem Cells, and Cancer , 2007, Cell.

[18]  M. Johansson,et al.  Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2–mediated heparin-binding EGF signaling in endothelial cells , 2011, Proceedings of the National Academy of Sciences.

[19]  Lai Wei,et al.  Negative Regulation of Hif1a Expression and TH17 Differentiation by Hypoxia Regulated miR-210 , 2014, Nature Immunology.

[20]  M. Martínez-Lorenzo,et al.  The human melanoma cell line MelJuSo secretes bioactive FasL and APO2L/TRAIL on the surface of microvesicles. Possible contribution to tumor counterattack. , 2004, Experimental cell research.

[21]  L. Zitvogel,et al.  Exosomes as Potent Cell-Free Peptide-Based Vaccine. I. Dendritic Cell-Derived Exosomes Transfer Functional MHC Class I/Peptide Complexes to Dendritic Cells 1 , 2004, The Journal of Immunology.

[22]  S. Pomeroy,et al.  Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. , 2011, Nature communications.

[23]  A. Engert,et al.  Dendritic Cells Release HLA-B-Associated Transcript-3 Positive Exosomes to Regulate Natural Killer Function , 2008, PloS one.

[24]  Adrian L. Harris,et al.  Hypoxia — a key regulatory factor in tumour growth , 2002, Nature Reviews Cancer.

[25]  B. Janji,et al.  Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumor progression and antitumor response. , 2011, Critical reviews in immunology.

[26]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[27]  Ricky T. Tong,et al.  Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. , 2009, Molecular cell.

[28]  Jianni Qi,et al.  microRNA‐210 negatively regulates LPS‐induced production of proinflammatory cytokines by targeting NF‐κB1 in murine macrophages , 2012, FEBS letters.

[29]  L. Mincheva-Nilsson,et al.  Thermal- and Oxidative Stress Causes Enhanced Release of NKG2D Ligand-Bearing Immunosuppressive Exosomes in Leukemia/Lymphoma T and B Cells , 2011, PloS one.

[30]  A. Burny,et al.  MicroRNA Profile of Circulating CD4-positive Regulatory T Cells in Human Adults and Impact of Differentially Expressed MicroRNAs on Expression of Two Genes Essential to Their Function* , 2012, The Journal of Biological Chemistry.

[31]  C. Théry,et al.  Membrane vesicles as conveyors of immune responses , 2009, Nature Reviews Immunology.

[32]  K. Ohyashiki,et al.  Exosomal miR-135b shed from hypoxic multiple myeloma cells enhances angiogenesis by targeting factor-inhibiting HIF-1. , 2014, Blood.

[33]  G. Semenza,et al.  Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis , 2014, Proceedings of the National Academy of Sciences.

[34]  A. Clayton,et al.  Exosomes and the MICA-NKG2D system in cancer. , 2005, Blood cells, molecules & diseases.

[35]  R. Agarwal,et al.  Exosomes secreted under hypoxia enhance invasiveness and stemness of prostate cancer cells by targeting adherens junction molecules , 2015, Molecular carcinogenesis.

[36]  Lin Zhang,et al.  Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells , 2011, Nature.

[37]  G. Berchem,et al.  Hypoxic tumor-derived microvesicles negatively regulate NK cell function by a mechanism involving TGF-β and miR23a transfer , 2015, Oncoimmunology.

[38]  M. Record,et al.  Exosomes as new vesicular lipid transporters involved in cell-cell communication and various pathophysiologies. , 2014, Biochimica et biophysica acta.

[39]  Riitta Lahesmaa,et al.  Exosomes with Immune Modulatory Features Are Present in Human Breast Milk1 , 2007, The Journal of Immunology.

[40]  M. Mason,et al.  Human Tumor-Derived Exosomes Down-Modulate NKG2D Expression1 , 2008, The Journal of Immunology.

[41]  S. Chouaib,et al.  Hypoxia Promotes Tumor Growth in Linking Angiogenesis to Immune Escape , 2012, Front. Immun..

[42]  R V Davuluri,et al.  A microRNA component of the hypoxic response , 2008, Cell Death and Differentiation.

[43]  David A. Simpson,et al.  MicroRNA-155 Promotes Resolution of Hypoxia-Inducible Factor 1α Activity during Prolonged Hypoxia , 2011, Molecular and Cellular Biology.

[44]  J. Loscalzo.  The cellular response to hypoxia: tuning the system with microRNAs. , 2010, The Journal of clinical investigation.

[45]  G. Semenza,et al.  Hypoxia-Inducible Factors in Physiology and Medicine , 2012, Cell.

[46]  Aled Clayton,et al.  Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. , 2007, Cancer research.

[47]  S. Kondo,et al.  Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes , 2014, Oncogene.

[48]  Li-hong Lv,et al.  Anticancer Drugs Cause Release of Exosomes with Heat Shock Proteins from Human Hepatocellular Carcinoma Cells That Elicit Effective Natural Killer Cell Antitumor Responses in Vitro* , 2012, The Journal of Biological Chemistry.

[49]  E. Miska,et al.  MicroRNA functions in animal development and human disease , 2005, Development.

[50]  P. Romero,et al.  Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells. , 2012, Cancer research.

[51]  J. Steitz,et al.  Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation , 2007, Science.

[52]  A. Guha,et al.  Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells , 2008, Nature Cell Biology.

[53]  R. Jain.  Normalization of Tumor Vasculature: An Emerging Concept in Antiangiogenic Therapy , 2005, Science.

[54]  A. Molinari,et al.  Immune Surveillance Properties of Human NK Cell-Derived Exosomes , 2012, The Journal of Immunology.

[55]  R. Place,et al.  MicroRNA-373 induces expression of genes with complementary promoter sequences , 2008, Proceedings of the National Academy of Sciences.

[56]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[57]  Michael Hallek,et al.  Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. , 2007, Immunity.

[58]  Gwendoline Gros,et al.  Cutting Edge: Hypoxia-Induced Nanog Favors the Intratumoral Infiltration of Regulatory T Cells and Macrophages via Direct Regulation of TGF-β1 , 2013, The Journal of Immunology.

[59]  Gema Moreno-Bueno,et al.  Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET , 2012, Nature Medicine.

[60]  M. Büchler,et al.  Tumor-exosomes and leukocyte activation: an ambivalent crosstalk , 2012, Cell Communication and Signaling.

[61]  William J. Buchser,et al.  Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands , 2012, Oncoimmunology.

[62]  M. Ringnér,et al.  Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development , 2013, Proceedings of the National Academy of Sciences.

[63]  Julia Christina Gross,et al.  Active Wnt proteins are secreted on exosomes , 2012, Nature Cell Biology.

[64]  George A. Calin,et al.  A MicroRNA Signature of Hypoxia , 2006, Molecular and Cellular Biology.

[65]  J. Skepper,et al.  Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes. , 2010, Cancer research.

[66]  M. Ivan,et al.  miR‐210: More than a silent player in hypoxia , 2011, IUBMB life.

[67]  T. Fehniger,et al.  MicroRNA regulation of natural killer cells , 2013, Front. Immunol..

[68]  Xin Huang,et al.  MiR-210--micromanager of the hypoxia pathway. , 2010, Trends in molecular medicine.