title: Extracellular vesicles carry microRNA-195 to intrahepatic cholangiocarcinoma and improve survival in a rat model.
abstract: The cancer microenvironment plays a central role in cancer development, growth, and homeostasis. This paradigm suggests that cancer fibroblasts support cancers, probably in response to stimuli received from the cancer cells. We aimed at investigating whether extracellular vesicles (EVs) can shuttle microRNA (miR) species between cancer-associated fibroblasts (CAFs) and cancer cells. To this end, we extracted EVs according to published protocols. EVs were studied for their miR content by quantitative reverse-transcription polymerase chain reaction. EVs were transfected with select miR species and utilized in vitro as well as in vivo in a rat model of cholangiocarcinoma (CCA). We found that miR-195 is down-regulated in CCA cells, as well as in adjoining fibroblasts. Furthermore, we report that EVs shuttle miR-195 from fibroblasts to cancer cells. Last, we show that fibroblast-derived EVs, loaded with miR-195, can be administered in a rat model of CCA, concentrate within the tumor, decrease the size of cancers, and improve survival of treated rats.
  
  
  
  EVs play a salient role in trafficking miR species between cancer cells and CAFs in human CCA. Understanding of these mechanisms may allow devising of novel therapeutics. (Hepatology 2017;65:501-514).
authors.affiliation: Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, MD.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, MD.
authors.forename: Klaus
authors.initials: K
authors.lastname: Piontek
authors.affiliation: Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, MD.|Department of Surgery, Tohoku University, Sendai, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Ishida
authors.affiliation: Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Michel
authors.initials: M
authors.lastname: Fausther
authors.affiliation: Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Dranoff
authors.affiliation: Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, MD.
authors.forename: Rongdang
authors.initials: R
authors.lastname: Fu
authors.affiliation: Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, MD.
authors.forename: Esteban
authors.initials: E
authors.lastname: Mezey
authors.affiliation: Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gould
authors.affiliation: Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Francis K
authors.initials: FK
authors.lastname: Fordjour
authors.affiliation: Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, MD.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Meltzer
authors.affiliation: Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA.
authors.forename: Alphonse E
authors.initials: AE
authors.lastname: Sirica
authors.affiliation: Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, MD.|Sidney Kimmel Cancer Center, The Johns Hopkins University, Baltimore, MD.|The Institute for Nanobiotechnology, The Johns Hopkins University, Baltimore, MD.
authors.forename: Florin M
authors.initials: FM
authors.lastname: Selaru
mesh_terms: D000818:Animals; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D018281:Cholangiocarcinoma / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D000067128:Extracellular Vesicles / Q000235:genetics*; D005347:Fibroblasts / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D015996:Survival Rate; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D035683:MicroRNAs