1. Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2016.51
Figure 4 Intracellular pathways involved in CCA proliferation and apoptosis
Figure 4 | Intracellular pathways involved in CCA proliferation and apoptosis. a | Multiple factors and molecular pathways modulate the proliferative capacity of cholangiocarcinoma (CCA) cells. Reactive and neoplastic cholangiocytes actively secrete a number of neuroendocrine factors that either stimulate or inhibit cellular proliferation in an autocrine or paracrine fashion. Bile acids are able to influence a number of intracellular oncogenic pathways, either by direct binding to bile acid receptors (e.g. S1PR2), transactivation of growth factor receptors or intracellular entry. Inflammatory cytokines can induce DNA damage via induction of inducible nitric oxide synthase (iNOS) and regulate the expression of survival signalling cascades. Lately, pathways involved in biliary embryological development such as Notch and Hedgehog have also been shown to modulate the neoplastic proliferation of CCA cells. Many of these pathways are actively investigated as potential therapeutic targets. b | Escape from apoptosis is equally essential for CCA cell survival. Bile acids, inflammatory cytokines and developmental pathways play crucial roles in apoptosis resistance, mainly via the overexpression of MCL1 and the blockage of caspase activation. A number of neuroendocrine factors have also been shown to induce apoptosis and might prove useful as therapeutic tools. 2-AG, 2-arachidonylglycerol; COX-2, cyclooxygenase 2; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ER, estrogen receptor; GABA, γ-aminobutyric acid; IL-6R, IL-6 receptor; NO, nitric oxide; OR, opioid receptor; TGF, transforming growth factor.
Banales, J. M. et al. (2016) Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)
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