Evidence map›Paper›PMID 36443822›Full record

ArticleJournal of experimental & clinical cancer research : CR2022

Crenigacestat blocking notch pathway reduces liver fibrosis in the surrounding ecosystem of intrahepatic CCA viaTGF-β inhibition.

Serena Mancarella, Isabella Gigante, Grazia Serino, Elena Pizzuto, Francesco Dituri, Maria F Valentini, Jingxiao Wang, Xin Chen, Raffaele Armentano, Diego F Calvisi and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed, 2 pooled it
3.5field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

22 citing papers in PubMed, 2 syntheses or guidelines pooled it, 20 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 4 institutions in 3 countries.

Serena Mancarella *National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, Italy.
Isabella Gigante *National Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, Italy.
Grazia SerinoNational Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, Italy.
Elena PizzutoNational Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, Italy.
Francesco DituriNational Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, Italy.
Maria F ValentiniDepartment of Emergency and Organ Transplant, University of Bari Medical School, Bari, Italy.
Jingxiao WangDepartment of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, 94143, USA.
Xin ChenDepartment of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, 94143, USA.
Raffaele ArmentanoNational Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, Italy.
Diego F CalvisiInstitute of Pathology, University of Regensburg, 93053, Regensburg, Germany.
Gianluigi GiannelliNational Institute of Gastroenterology S. De Bellis, IRCCS Research Hospital, Via Turi 27, 70013, Castellana Grotte, Italy. gianluigi.giannelli@irccsdebellis.it.ORCID http://orcid.org/0000-0002-5140-8060
Gastroenterology Hospital "Saverio de Bellis" · ITUniversity of California, San Francisco · USUniversity of Bari Aldo Moro · ITUniversity of Regensburg · DE

Funding

Associazione Italiana per la Ricerca sul Cancro IG 2020 ID 24815Ministero della Salute Ricerca Corrente 2022
6 · The paper itself

Abstract

backgroundIntrahepatic 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)-β1 and expressing high levels of α-smooth muscle actin (α-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.

methodsWe investigated Crenigacestat's effectiveness in a PDX model of iCCA and human primary culture of CAFs isolated from patients with iCCA.

resultsIn 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-β1 pathway as a master regulator gene showing a robust connection between TGF-β1 and Notch pathways. Consistently, drug treatment significantly (p < 0.05) reduced TGF-β1 mRNA and protein levels in tumoral tissue. In PDX tissues, Crenigacestat remarkably inhibited TGF-β signaling and extracellular matrix protein gene expression and reduced α-SMA expression. Furthermore, Crenigacestat synergistically increased Gemcitabine effectiveness in the iCCA PDX model. In 31 iCCA patients, TGF-β1 and α-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-β1 secretion, and Smad-2 activation. Consequently, Crenigacestat also inactivated CAFs reducing (p < 0.001) α-SMA expression. Finally, CAFs treated with Crenigacestat produced less (p < 005) ECM components such as fibronectin, collagen 1A1, and collagen 1A2.

conclusionsNotch signaling inhibition reduces the peritumoral desmoplastic reaction in iCCA, blocking the TGF-β1 canonical pathway.

Indexed as

Bile Duct NeoplasmsCholangiocarcinomaBenzazepinesBile Ducts, IntrahepaticEcosystemFibrosisHumansLiverTransforming Growth Factor beta1Tumor MicroenvironmentBenzazepinescrenigacestatTransforming Growth Factor beta1CrenigacestatLiver fibrosisSmad2Tissue microenvironmentTumor stroma crosstalk

Identifiers

PMID36443822
PMCPMC9703776
OpenAlexW4310235081

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.