title: Carcinogenic Liver Fluke Secretes Extracellular Vesicles That Promote Cholangiocytes to Adopt a Tumorigenic Phenotype.
abstract: BACKGROUND
  Throughout Asia, there is an unprecedented link between cholangiocarcinoma and infection with the liver fluke Opisthorchis viverrini. Multiple processes, including chronic inflammation and secretion of parasite proteins into the biliary epithelium, drive infection toward cancer. Until now, the mechanism and effects of parasite protein entry into cholangiocytes was unknown.
  
  
  METHODS
  Various microscopy techniques were used to identify O. viverrini extracellular vesicles (EVs) and their internalization by human cholangiocytes. Using mass spectrometry we characterized the EV proteome and associated changes in cholangiocytes after EV uptake, and we detected EV proteins in bile of infected hamsters and humans. Cholangiocyte proliferation and interleukin 6 (IL-6) secretion was measured to assess the impact of EV internalization.
  
  
  RESULTS
  EVs were identified in fluke culture medium and bile specimens from infected hosts. EVs internalized by cholangiocytes drove cell proliferation and IL-6 secretion and induced changes in protein expression associated with endocytosis, wound repair, and cancer. Antibodies to an O. viverrini tetraspanin blocked EV uptake and IL-6 secretion by cholangiocytes.
  
  
  CONCLUSIONS
  This is the first time that EVs from a multicellular pathogen have been identified in host tissues. Our findings imply a role for O. viverrini EVs in pathogenesis and highlight an approach to vaccine development for this infectious cancer.
authors.affiliation: Biomedical Sciences, Graduate School Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns.
authors.forename: Sujittra
authors.initials: S
authors.lastname: Chaiyadet
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns.
authors.forename: Javier
authors.initials: J
authors.lastname: Sotillo
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns.
authors.forename: Michael
authors.initials: M
authors.lastname: Smout
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns Department of Veterinary Medicine, University of Cambridge.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cantacessi
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane School of Veterinary Sciences, University of Queensland, Gatton.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Jones
authors.affiliation: iThree Institute, University of Technology Sydney, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Johnson
authors.affiliation: iThree Institute, University of Technology Sydney, Australia.
authors.forename: Lynne
authors.initials: L
authors.lastname: Turnbull
authors.affiliation: iThree Institute, University of Technology Sydney, Australia.
authors.forename: Cynthia B
authors.initials: CB
authors.lastname: Whitchurch
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Potriquet
authors.affiliation: Department of Pathology.
authors.forename: Marut
authors.initials: M
authors.lastname: Laohaviroj
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane.
authors.forename: Jason
authors.initials: J
authors.lastname: Mulvenna
authors.affiliation: Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, George Washington University, Washington D.C.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Brindley
authors.affiliation: Department of Microbiology, Immunology and Tropical Medicine, and Research Center for Neglected Diseases of Poverty, George Washington University, Washington D.C.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bethony
authors.affiliation: Department of Parasitology, Faculty of Medicine, Khon Kaen University, Thailand.
authors.forename: Thewarach
authors.initials: T
authors.lastname: Laha
authors.affiliation: Department of Pathology.
authors.forename: Banchob
authors.initials: B
authors.lastname: Sripa
authors.affiliation: Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns.
authors.forename: Alex
authors.initials: A
authors.lastname: Loukas
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D006224:Cricetinae; D004705:Endocytosis; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D000067128:Extracellular Vesicles / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D008853:Microscopy; D009889:Opisthorchiasis / Q000469:parasitology / Q000473:pathology; D009891:Opisthorchis / Q000378:metabolism*; D010641:Phenotype; D020543:Proteome / Q000032:analysis
chemical_list: D020543:Proteome
keywords: Opisthorchis viverrini; cancer; cholangiocarcinoma; extracellular vesicles; liver fluke