Autocrine and Paracrine Mechanisms Promoting Chemoresistance in Cholangiocarcinoma

Abstract

Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in the tumor microenvironment. Here, recent evidence regarding molecular mechanisms of chemoresistance is reviewed, as well as associations between well-developed chemoresistance and activation of the cancer stem cell compartment. It is concluded that improved understanding of the complex interplay between apoptosis signaling and the promotion of cell survival represent potentially productive areas for active investigation, with the ultimate aim of encouraging future studies to unveil new, effective strategies able to overcome current limitations on treatment.

Keywords: apoptosis; cancer stem cells; liver cancer; morphogens; tumor reactive stroma.

Figure 1

Molecular mechanisms of chemoresistance in CCA induced by autocrine and paracrine signals: IL-6/LIF, PDGF-BB/-DD, Hh, Wnt/β-catenin and Notch, released in the tumor microenvironment. Different effects on escape from apoptosis, modulation of transporter expression, induction of EMT properties and expansion of CSC compartment are illustrated. See the text for details. Abbreviations: ABCB1, ATP binding cassette subfamily B member 1; ADAM10, A disintegrin and metalloproteinase domain 10; CSC, cancer stem cells; DR4, death receptor 4; Dvl, disheveled; EMT, epithelial-mesenchymal transition; Frz, frizzled; gp130, glycoprotein 130; IL, interleukin; LIF, leukemia inhibitory factor; MAPK, mitogen-activated protein kinase; Mcl-1, myeloid cell leukemia 1; miR, micro-RNA; MRP1, multidrug resistance associated protein 1, NICD, intracellular domain of the notch protein; PDGF, platelet-derived growth factor; PI3K, phosphoinositide 3-kinase; PLK2, polo-like kinase 2; Ptc, patched; SHH, sonic hedgehog; Smo, smoothened; TACE, tumor necrosis factor, α, converting enzyme; YAP, yes associated protein 1. Red boxes and arrows: up-regulated proteins; blue boxes and arrows: down-regulated proteins.