Visualization of exosome-mediated miR-210 transfer from hypoxic tumor cells

Cancer cells actively release exosomes carrying specific cellular components, such as proteins, mRNA, and miRNA, to communicate with various cells in the tumor microenvironment. We visualized exosome-mediated transfer of miR-210 from hypoxic breast cancer cells to neighboring cells using a miR-210 specific reporter system. By in vitro and in vivo visualization, we found that exosomes with miR-210 were transferred to cells in the tumor microenvironment and that miR-210 was involved in expression of vascular remodeling related genes, such as Ephrin A3 and PTP1B, to promote angiogenesis. These results indicate that cellular components, such as miRNAs from hypoxic cancer cells, spread to adjacent cancer cells in the tumor microenvironment via exosomes and influence tumor progression.

[1]  W. Ding,et al.  Intercellular Communication by Exosome-Derived microRNAs in Cancer , 2013, International journal of molecular sciences.

[2]  Kyvan Dang,et al.  The Role of Hypoxia-Induced miR-210 in Cancer Progression , 2015, International journal of molecular sciences.

[3]  C. Croce,et al.  MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review , 2012, EMBO molecular medicine.

[4]  Sabita Roy,et al.  Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-α isoforms and promotes angiogenesis. , 2010, The Journal of clinical investigation.

[5]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

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

[7]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[8]  D. Quail,et al.  Microenvironmental regulation of tumor progression and metastasis , 2014 .

[9]  Quynh-Thu Le,et al.  Circulating miR-210 as a Novel Hypoxia Marker in Pancreatic Cancer. , 2010, Translational oncology.

[10]  Payam Shahi,et al.  microRNA-mediated regulation of the tumor microenvironment , 2013, Cell cycle.

[11]  M. Todaro,et al.  Tumor and its microenvironment: a synergistic interplay. , 2013, Seminars in cancer biology.

[12]  P. Vaupel,et al.  Hypoxia in cancer: significance and impact on clinical outcome , 2007, Cancer and Metastasis Reviews.

[13]  K. O'Byrne,et al.  Functions and Therapeutic Roles of Exosomes in Cancer , 2014, Front. Oncol..

[14]  Graça Raposo,et al.  Extracellular vesicles: Exosomes, microvesicles, and friends , 2013, The Journal of cell biology.

[15]  Cecilia Lässer Exosomal RNA as biomarkers and the therapeutic potential of exosome vectors , 2012, Expert opinion on biological therapy.

[16]  M. Dewhirst,et al.  Molecular Imaging of Hypoxia , 2011, The Journal of Nuclear Medicine.

[17]  W. Wilson,et al.  Targeting hypoxia in cancer therapy , 2011, Nature Reviews Cancer.

[18]  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.

[19]  M. Kuroda,et al.  Leukemia cell to endothelial cell communication via exosomal miRNAs , 2013, Oncogene.

[20]  Christophe Van de Wiele,et al.  Molecular imaging of hypoxia with radiolabelled agents , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[21]  J. Lötvall,et al.  Exosome as a novel shuttle for innovation. Preface. , 2013, Advanced drug delivery reviews.

[22]  A. Seifalian,et al.  Exosomes as nano-theranostic delivery platforms for gene therapy. , 2013, Advanced drug delivery reviews.

[23]  H. Jäck,et al.  Serum microRNAs as powerful cancer biomarkers. , 2010, Biochimica et biophysica acta.

[24]  G. Calin,et al.  HypoxamiRs and cancer: from biology to targeted therapy. , 2014, Antioxidants & redox signaling.

[25]  G. Song,et al.  Role of hypoxia in the hallmarks of human cancer , 2009, Journal of cellular biochemistry.

[26]  M. Michael,et al.  Hypoxic enhancement of exosome release by breast cancer cells , 2012, BMC Cancer.

[27]  M. Simon,et al.  mir-210: a sensor for hypoxic stress during tumorigenesis. , 2009, Molecular cell.

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

[29]  Laurence Zitvogel,et al.  Exosomes: composition, biogenesis and function , 2002, Nature Reviews Immunology.

[30]  Sanne Kuijper,et al.  Regulation of angiogenesis by Eph-ephrin interactions. , 2007, Trends in cardiovascular medicine.

[31]  S. Chiou,et al.  miR-31 ablates expression of the HIF regulatory factor FIH to activate the HIF pathway in head and neck carcinoma. , 2010, Cancer research.

[32]  M. Record,et al.  Exosomes as intercellular signalosomes and pharmacological effectors. , 2011, Biochemical pharmacology.