Regulation of pancreatic stellate cell activation by Notch3

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Abstract

Background

Activated pancreatic stellate cells (PaSCs) are the key cellular source of cancer-associated fibroblasts in the pancreatic stroma of patients with pancreatic ductal adenocarcinoma (PDAC), however, the activation mechanism of PaSCs is not yet known. The Notch signaling pathway, components of which are expressed in stromal cells, is involved in the fibrosis of several organs, including the lung and liver. In the current study, we investigated whether Notch signal transduction is involved in PaSC activation in PDAC.

Methods

The expression of Notch signaling pathway components in human PDAC was examined via immunohistochemical staining and assessed in mouse PaSCs using RT-qPCR and western blotting. Notch3 expression in both PDAC stromal cells and activated mouse PaSCs was evaluated using immunofluorescence, RT-qPCR and western blotting. The impact of siRNA-mediated Notch3 knockdown on PaSC activation was detected with RT-qPCR and western blotting, and the impact on PaSC proliferation and migration was detected using CCK-8 assays and scratch experiments. The effect of conditioned medium from PaSCs activated with Notch3 siRNA on pancreatic cancer (LTPA) cells was also detected with CCK-8 assays and scratch experiments. The data were analyzed for statistical significance using Student’s t-test.

Results

Notch3 was overexpressed in both human PDAC stromal cells and activated mouse PaSCs, and Notch3 knockdown with Notch3 siRNA decreased the proliferation and migration of mouse PaSCs. The levels of markers related to PaSC activation, such as α-smooth muscle actin (α-SMA), collagen I and fibronectin, decreased in response to Notch3 knockdown, indicating that Notch3 plays an important role in PaSC activation. Furthermore, we confirmed that inhibition of PaSC activation via Notch3 siRNA reduced the proliferation and migration of PaSC-induced mouse pancreatic cancer (LTPA) cells.

Conclusions

Notch3 inhibition in PaSCs can inhibit the activation, proliferation and migration of PaSCs and reduce the PaSC-induced pro-tumorigenic effect. Therefore, Notch3 silencing in PaSCs is a potential novel therapeutic option for patients with PDAC.

Electronic supplementary material

The online version of this article (10.1186/s12885-017-3957-2) contains supplementary material, which is available to authorized users.

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Most cited references 40

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Notch signalling in solid tumours: a little bit of everything but not all the time.

Prathibha Ranganathan, Kelly L Weaver, Anthony J. Capobianco (2011)

The discovery of Notch in Drosophila melanogaster nearly a century ago opened the door to an ever-widening understanding of cellular processes that are controlled or influenced by Notch signalling. As would be expected with such a pleiotropic pathway, the deregulation of Notch signalling leads to several pathological conditions, including cancer. A role for Notch is well established in haematological malignancies, and more recent studies have provided evidence for the importance of Notch activity in solid tumours. As it is thought to act as an oncogene in some cancers but as a tumour suppressor in others, the role of Notch in solid tumours seems to be highly context dependent.

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Stromal biology and therapy in pancreatic cancer.

Albrecht Neesse, Patrick Michl, Kristopher K Frese … (2011)

Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease. One explanation for the devastating prognosis is the failure of many chemotherapies, including the current standard of care therapy gemcitabine. Although our knowledge of the molecular events underlying multistep carcinogenesis in PDA has steadily increased, translation into more effective therapeutic approaches has been inefficient over the last several decades. Evidence for this innate resistance to systemic therapies was recently provided in an accurate mouse model of PDA by the demonstration that chemotherapies are poorly delivered to PDA tissues because of a deficient vasculature. This vascular deficiency correlated with the presence of a dense stromal matrix that is a prominent histological hallmark of PDA tumours. Therapeutic targeting of stromal cells decreased the stroma from pancreatic tumours, resulting in increased intratumoral perfusion and therapeutic delivery of gemcitabine. Stromal cells contained within the PDA tumour microenvironment therefore represent an additional constituent to neoplastic cells that should be critically evaluated for optimal therapeutic development in preclinical models and early clinical trials.

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Identification, culture, and characterization of pancreatic stellate cells in rats and humans.

Max Bachem, Erik Schneider, Hans Groß … (1998)

Until now, the basic matrix-producing cell type responsible for pancreas fibrosis has not been identified. In this report, retinoid-containing pancreatic stellate cells (PSCs) in rat and human pancreas are described, and morphological and biochemical similarities to hepatic stellate cells are shown. Electron and immunofluorescence microscopy (collagen types I and III, fibronectin, laminin, alpha-actin, and desmin) was performed using pancreatic tissue and cultured PSCs. Extracellular matrix synthesis was shown using quantitative immunoassay and Northern blot analysis. PSCs are located in interlobular areas and in interacinar regions. Early primary cultured PSCs contain retinol and fatty acid retinyl-esters. Addition of retinol to passaged cells resulted in retinol uptake and esterification. During primary culture, the cells changed from a quiescent fat-storing phenotype to a highly synthetic myofibroblast-like cell expressing iso-alpha-smooth muscle actin (>90%) and desmin (20%-40%) and showing strong positive staining with antibodies to collagen types I and III, fibronectin, and laminin. As determined on protein and messenger RNA level, serum growth factors stimulated the synthesis of collagen type I and fibronectin. The identification of PSCs, particularly in fibrotic areas, and the similarities of these cells to hepatic stellate cells suggest that PSCs participate in the development of pancreas fibrosis.

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Author and article information

Contributors

Haiyan Song: (86-010) 83950121 , shy80825@163.com

Yuxiang Zhang:

ORCID: http://orcid.org/0000-0002-4075-3950

(86-010) 83950122 , yxzhang@ccmu.edu.cn

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 5 January 2018

Publication date PMC-release: 5 January 2018

Publication date Collection: 2018

Volume: 18

Electronic Location Identifier: 36

Affiliations

ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Biochemistry and Molecular Biology, Cancer Institute, Beijing Key Laboratory for Cancer Invasion and Metastasis Research, , Capital Medical University, ; No. 10 Xitoutiao, You An Men, Fengtai District, Beijing, 100069 People’s Republic of China

Author information

Yuxiang Zhang http://orcid.org/0000-0002-4075-3950

Article

Publisher ID: 3957

DOI: 10.1186/s12885-017-3957-2

PMC ID: 5756326

PubMed ID: 29304760

SO-VID: 45dbdcde-acb6-4f33-a240-67a038201ef4

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 23 March 2017

Date accepted : 21 December 2017

Funding

Funded by: the National Natural Science Foundation of China

Award ID: 81372156

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: pancreatic ductal adenocarcinoma,pancreatic stellate cells,notch3,activation

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: pancreatic ductal adenocarcinoma, pancreatic stellate cells, notch3, activation

Regulation of pancreatic stellate cell activation by Notch3

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Cancer Immunotherapy

Most cited references 40

Notch signalling in solid tumours: a little bit of everything but not all the time.

Stromal biology and therapy in pancreatic cancer.

Identification, culture, and characterization of pancreatic stellate cells in rats and humans.

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