Carcinogenic liver fluke secretes extracellular vesicles that promote cholangiocytes to adopt a tumorigenic phenotype

Chaiyadet, Sujittra, Sotillo, Javier, Smout, Michael, Cantacessi, Cinzia, Jones, Malcolm K., Johnson, Michael S., Turnbull, Lynne, Whitchurch, Cynthia B., Potriquet, Jeremy, Laohaviroj, Marut, Mulvenna, Jason, Brindley, Paul J., Bethony, Jeffrey M., Laha, Thewarach, Sripa, Banchob, and Loukas, Alex (2015) Carcinogenic liver fluke secretes extracellular vesicles that promote cholangiocytes to adopt a tumorigenic phenotype. Journal of Infectious Diseases, 212 (10). pp. 1636-1645.

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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.

Item ID: 39028
Item Type: Article (Research - C1)
ISSN: 1537-6613
Keywords: extracellular vesicles; Opisthorchis viverrini; cholangiocarcinoma; liver fluke; cancer
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© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (, which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact

Funders: National Health and Medical Research Council of Australia (NHMRC), Thailand Research Fund (TRF)
Projects and Grants: NHMRC Project Grant APP1085309, TRF Royal Golden Jubilee
Date Deposited: 04 Nov 2015 03:17
FoR Codes: 06 BIOLOGICAL SCIENCES > 0603 Evolutionary Biology > 060307 Host-Parasite Interactions @ 20%
11 MEDICAL AND HEALTH SCIENCES > 1108 Medical Microbiology > 110803 Medical Parasitology @ 10%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060109 Proteomics and Intermolecular Interactions (excl Medical Proteomics) @ 70%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 50%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 50%
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