Mancarella, Serena and Gigante, Isabella and Serino, Grazia and Pizzuto, Elena and Dituri, Francesco and Valentini, Maria F. and Wang, Jingxiao and Chen, Xin and Armentano, Raffaele and Calvisi, Diego F. and Giannelli, Gianluigi (2022) Crenigacestat blocking notch pathway reduces liver fibrosis in the surrounding ecosystem of intrahepatic CCA viaTGF-beta inhibition. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, 41 (1): 331. ISSN , 1756-9966
Full text not available from this repository. (Request a copy)Abstract
Background Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant tumor characterized by an intensive desmoplastic reaction due to the exaggerated presence of the extracellular (ECM) matrix components. Liver fibroblasts close to the tumor, activated by transforming growth factor (TGF)-beta 1 and expressing high levels of alpha-smooth muscle actin (alpha-SMA), become cancer-associated fibroblasts (CAFs). CAFs are deputed to produce and secrete ECM components and crosstalk with cancer cells favoring tumor progression and resistance to therapy. Overexpression of Notch signaling is implicated in CCA development and growth. The study aimed to determine the effectiveness of the Notch inhibitor, Crenigacestat, on the surrounding microenvironment of iCCA. Methods We investigated Crenigacestat's effectiveness in a PDX model of iCCA and human primary culture of CAFs isolated from patients with iCCA. Results In silico analysis of transcriptomic profiling from PDX iCCA tissues treated with Crenigacestat highlighted "liver fibrosis" as one of the most modulated pathways. In the iCCA PDX model, Crenigacestat treatment significantly (p < 0.001) reduced peritumoral liver fibrosis. Similar results were obtained in a hydrodynamic model of iCCA. Bioinformatic prediction of the upstream regulators related to liver fibrosis in the iCCA PDX treated with Crenigacestat revealed the involvement of the TGF-beta 1 pathway as a master regulator gene showing a robust connection between TGF-beta 1 and Notch pathways. Consistently, drug treatment significantly (p < 0.05) reduced TGF-beta 1 mRNA and protein levels in tumoral tissue. In PDX tissues, Crenigacestat remarkably inhibited TGF-beta signaling and extracellular matrix protein gene expression and reduced alpha-SMA expression. Furthermore, Crenigacestat synergistically increased Gemcitabine effectiveness in the iCCA PDX model. In 31 iCCA patients, TGF-beta 1 and alpha-SMA were upregulated in the tumoral compared with peritumoral tissues. In freshly isolated CAFs from patients with iCCA, Crenigacestat significantly (p < 0.001) inhibited Notch signaling, TGF-beta 1 secretion, and Smad-2 activation. Consequently, Crenigacestat also inactivated CAFs reducing (p < 0.001) alpha-SMA expression. Finally, CAFs treated with Crenigacestat produced less (p < 005) ECM components such as fibronectin, collagen 1A1, and collagen 1A2. Conclusions Notch signaling inhibition reduces the peritumoral desmoplastic reaction in iCCA, blocking the TGF-beta 1 canonical pathway.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEPATIC STELLATE CELLS; SIGNALING PATHWAYS; HEPATOCELLULAR-CARCINOMA; TGF-BETA/SMAD; PROGRESSION; CHOLANGIOCARCINOMA; DIFFERENTIATION; FIBROBLASTS; PROMOTE; CHEMORESISTANCE; Tissue microenvironment; Liver fibrosis; Tumor stroma crosstalk; Crenigacestat; Smad2 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Feb 2024 09:53 |
| Last Modified: | 27 Feb 2024 09:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58109 |
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