Abstract

Photodynamic therapy (PDT) is a palliative treatment option for unresectable hilar biliary tract cancer (BTC) showing a considerable benefit for survival and quality of life with few side effects. Currently, factors determining the cellular response of BTC cells towards PDT are unknown. Due to their multifaceted nature, microRNAs (miRs) are a promising analyte to investigate the cellular mechanisms following PDT. For two photosensitizers, Photofrin® and Foscan®, the phototoxicity was investigated in eight BTC cell lines. Each cell line (untreated) was profiled for expression of n = 754 miRs using TaqMan® Array Human MicroRNA Cards. Statistical analysis and bioinformatic tools were used to identify miRs associated with PDT efficiency and their putative targets, respectively. Twenty miRs correlated significantly with either high or low PDT efficiency. PDT was particularly effective in cells with high levels of clustered miRs 25-93*-106b and (in case of miR-106b) a phenotype characterized by high expression of the mesenchymal marker vimentin and high proliferation (cyclinD1 and Ki67 expression). Insensitivity towards PDT was associated with high miR-200 family expression and (for miR-cluster 200a/b-429) expression of differentiation markers Ck19 and Ck8/18. Predicted and validated downstream targets indicate plausible involvement of miRs 20a*, 25, 93*, 130a, 141, 200a, 200c and 203 in response mechanisms to PDT, suggesting that targeting these miRs could improve susceptibility to PDT in insensitive cell lines. Taken together, the miRNome pattern may provide a novel tool for predicting the efficiency of PDT and—following appropriate functional verification—may subsequently allow for optimization of the PDT protocol.

Highlights

  • Prognosis of patients with biliary tract cancer (BTC) is generally poor due to limited therapeutic options [1,2]

  • We demonstrated the phototoxicity of Photodynamic therapy (PDT) in different human BTC cell lines to be highly heterogeneous [12,13] and preferentially linked to low differentiation and proliferation of the cells

  • Phototoxic effects were significantly correlated to the uptake of PS, a discrepancy between PS uptake and final cytotoxicity could be observed with no actual explanation existing yet [13]. These results indicate that additional molecular factors determine the overall cytotoxic efficiency of PDT in BTC cells

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Summary

Introduction

Prognosis of patients with biliary tract cancer (BTC) is generally poor due to limited therapeutic options [1,2]. Photodynamic therapy (PDT) has been used in prospective clinical studies for palliative treatment of unresectable hilar BTC resulting in a median survival time between 12 and 21 months and better quality of life [4,5]. As summarized by Gao et al [7], PDT offers a considerable benefit for survival and quality of life with few side effects and should be offered to patients with unresectable hilar BTC. In this context, two main photosensitizers (PSs) have been successfully established for routine use in the clinic, i.e., hematoporphyrin derivative (porfimer sodium/Photofrin®) and meso-tetrahydroxyphenylchlorine (mTHPC/Foscan®) [7,8]

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