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

肝内胆管癌(CC)和胆道树的其他癌症，包括胆囊癌，通常与胆道树的非肿瘤性炎症性疾病有关，如硬化性胆管炎、华支睾吸虫病和肝胆管结石。这些疾病还涉及修复性的、非肿瘤性的胆管上皮细胞(BEC)增殖。不幸的是，虽然相当数量的胆道癌是在可预见的条件下发生的，但它们的预后很差，因为在肿瘤达到无法治愈的阶段之前，很难确定诊断。早期诊断和尝试根治疗法需要更好地了解控制修复性和癌性BEC生长的分子机制，以及在这两个过程之间过渡所涉及的步骤。在非肿瘤性BEC修复过程中，就像梗阻性胆管疾病一样，有丝分裂和有丝分裂抑制相互竞争地影响对BEC的作用，主要是旁分泌方式，是一种…。更多伴有导管周围肌成纤维细胞的激活和纤维化。例如，胆道梗阻后最初几天到几周的特点是BEC的爆炸性增殖。这与肝细胞生长因子(HGF)和白介素6(IL-6)在胆管周围基质细胞和血淋巴细胞中的上调有关，这些介质在体外刺激了非肿瘤性BEC DNA的合成。然而，如果梗阻持续存在，BEC的增殖恢复到接近子宫内膜的水平，继而发生进行性纤维化。这与有丝分裂抑制因子和纤维化生长因子的诱导同时发生，如成纤维细胞生长因子和有丝分裂抑制细胞因子家族，包括转化生长因子-β1和激活素A。在反应的连续阶段，这些有丝分裂原或有丝分裂抑制物的受体分别在BEC表面上调。从反应性BEC向CC的转变伴随着有利于持续生长的改变，而不是有丝分裂抑制和凋亡。因此，恶性肿瘤可以绕过抑制生长或诱导细胞凋亡的介质的S效应，或者获得合成和分泌自己的生长因子的能力(S)，用自分泌途径取代正常的旁路信号。较少

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