Hypothesized pathways of pathogenesis of liver fluke-induced cholangiocarcinoma (CCA). Opisthorchis viverrini damages bile-duct epithelia via three pathways: (1)
mechanical damage by feeding parasites; (2) immunopathology, particularly due to reactive oxygen intermediates (ROI) and nitric oxide (NO); (3) direct effects of fluke secreted
proteins including induction of cell proliferation and inhibiting cancer prevention pathways (DNA repair/apoptosis). These pathways converge, resulting in genetic lesions that
become fixed after successive replications, eventually leading to malignant transformation of cholangiocytes into CCA. Adapted from [121]. Abbreviation: ES, excretory/secretory.