The role of IL-6, HGF and TGFβ_1 in biliary epithelial cells carcinogenesis

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Intraheptatic chollagiocarcinoma (CC) and other cancers of the biliary tree, including the gallbladder, are often associated with non-neoplastic inflammatory diseases of the biliary tree, such as sclerosing cholangitis, clonorchiasis, and hepatolithiasis. These diseases also involve reparative, non-neoplastic biliary epithelial cell (BEC) proliferation. Unfortunately, although a significant number of biliary tract cancers arise under predictable conditions, they carry a poor prognosis because of difficulties in establishing the diagnosis before the tumors reach a noncurative stage. Earlier diagnosis and attempts at curative therapy will require a better understanding of the molecular mechanisms controlling reparative and cancerous BEC growth and the steps involved in a transition between the 2 processes. During non-neoplastic BEC repair like that seen with obstructive cholangiopathy, competing mitogenic and mitoinhibitory influences action on BECs, largely in a paracrine fashion, are a … More ccompanied by activation of periductal myofibroblasts and fibrogenesis. For example, the first several days to weeks afte biliary obstraction are characterized by explosive BEC proliferation. This is associated with up-regulation of hepatocyte growth factor (HGF) and interleukin 6 (IL-6) in the peribiliary stromal and hematolymphoid cells, and these same mediators stimulate non-neoplastic BEC DNA synthesis, in vitro. However, if the obstruction persists, BEC proliferation returns to near beseline levels and progressive fibrogenesis ensues. This occurs coincidently with tht induction of mitoinhibitory and fibrogenic growth factors, such as fibroblast growth factor and the TGF-b family of mitoinhibitory cytokines, including TGF-b1 and activin A. Receptros for these mitogens or mitoinhibitors, respectivily, are upregulated on the sruface of the BEC during successive stages of the response. The transition from reactive BEC to CC is accompanied by alterations that favor continued growth over mitoinhibition and apoptosis. Thus, malignancies can circumvent the effect s of mediators that inhibit growth or induce apoptosis, or acquire the ability to synthesize and secrete their own growth factor(s), superseding the normal paractine signaling with autocrine pathways. Less