**6. Mechanism of carcinogenesis in the biliary tract**

Cholangiocytes are considered the potential cells of origin for biliary tract cancers, including gallbladder cancer [78]. Any insult to the cholangiocytes leads to the release of pro-inflammatory mediators like IL-6 and IL-1β which results in the differentiation of T helper cells (Th-17 cells). The cholangiocytes interact with Th-17 cells leading to their activation and proliferation, in order to compensate for the cell loss [79]. Moreover, the bacteria and their products are recognized by the cholangiocytes through the Pathogen Associated Molecular Patterns (PAMPs) present in the bile, which interacts with the pattern recognition receptors, that are, the Toll-like receptors (TLRs) and the NOD-like receptors (NLRs), leading to their activation [80]. This results in collagen deposition and fibrosis. The resultant cholangiopathy may lead to ductopenia, dysplasia, and malignant transformation [81]. Chronic inflammation leads to the release of mediators like IL-17, TNF-α, and TGF-β which cause genetic alterations in the tumor suppressor genes and the proto-oncogenes resulting in cell transformation [82]. These mediators are among the few which have been implicated in the causation of carcinogenesis [83–85].
