The Tumor Microenvironment Drives Intrahepatic Cholangiocarcinoma Progression

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Apr 23

PMID 35457006

Authors

Serena Mancarella

Grazia Serino

Sergio Coletta

Raffaele Armentano

Francesco Dituri

Francesco Ardito

Andrea Ruzzenente

Isabel Fabregat

Gianluigi Giannelli

Affiliations

Soon will be listed here.

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with limited therapeutic options and short overall survival. iCCA is characterized by a strong desmoplastic reaction in the surrounding ecosystem that likely affects tumoral progression. Overexpression of the Notch pathway is implicated in iCCA development and progression. Our aim was to investigate the effectiveness of Crenigacestat, a selective inhibitor of NOTCH1 signaling, against the cross-talk between cancer cells and the surrounding ecosystem in an in vivo HuCCT1-xenograft model. In the present study, a transcriptomic analysis approach, validated by Western blotting and qRT-PCR on iCCA tumor masses treated with Crenigacestat, was used to study the molecular pathways responsive to drug treatment. Our results indicate that Crenigacestat significantly inhibited NOTCH1 and HES1, whereas tumor progression was not affected. In addition, the drug triggered a strong immune response and blocked neovascularization in the tumor ecosystem of the HuCCT1-xenograft model without affecting the occurrence of fibrotic reactions. Therefore, although these data need further investigation, our observations confirm that Crenigacestat selectively targets NOTCH1 and that the desmoplastic response in iCCA likely plays a key role in both drug effectiveness and tumor progression.

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