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Laminin-332 sustains chemoresistance and quiescence as part of the human hepatic cancer stem cell niche

Lookup NU author(s): Dr Olivier Govaere

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 2015 European Association for the Study of the Liver.Background & Aims Cancer stem cells (CSCs) are thought to be persistent in tumours due to their chemoresistance and to cause relapse and metastasis. Hepatic carcinomas displaying hepatic progenitor cell (HPC) features have been associated with a poor prognosis, though it remains unclear how CSCs relate to these different histological subtypes. Methods Candidate CSCs were isolated using the side population (SP) technique from primary tissue samples diagnosed as keratin(K)19-negative or -positive hepatocellular carcinoma (HCC) or as combined hepatocellular/cholangiocarcinoma and analysed for gene and protein expression. The effect of laminin-332 was analysed in vitro by using HCC cell lines and in vivo using a xenograft mouse model. Results The size of the SP correlated with the degree of HPC features found in human hepatic cancer, and also showed an elevated mRNA expression of biliary/HPC markers and the extracellular matrix marker LAMC2, the gene encoding the laminin γ2-chain. Immunopositivity for the γ2-chain of laminin-332 was seen in the extracellular matrix surrounding small HPC-like tumour cells with a low proliferation rate. In vitro, laminin-332 increased K19 expression, phosphorylated mTOR and decreased phospho-histone H3 expression, indicating reduced cell mitosis. The effect of laminin-332 was enhanced upon mTORC1 inhibition and diminished when inhibiting mTORC1+C2. Resistance to doxorubicin and sorafenib treatment, and the SP fraction increased in the coated condition. In vivo, laminin-332 reduced tumour growth and sustained K19 expression. Conclusions In this study we identified a prominent role for laminin-332 as part of the specialised CSC niche in maintaining and supporting cell 'stemness', which leads to chemoresistance and quiescence.


Publication metadata

Author(s): Govaere O, Wouters J, Petz M, Vandewynckel Y-P, Van Den Eynde K, Van Den Broeck A, Verhulst S, Dolle L, Gremeaux L, Ceulemans A, Nevens F, Van Grunsven LA, Topal B, Vankelecom H, Giannelli G, Van Vlierberghe H, Mikulits W, Komuta M, Roskams T

Publication type: Article

Publication status: Published

Journal: Journal of Hepatology

Year: 2016

Volume: 64

Issue: 3

Pages: 609-617

Print publication date: 01/03/2016

Online publication date: 17/11/2015

Acceptance date: 10/11/2015

Date deposited: 08/12/2017

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier B.V.

URL: https://doi.org/10.1016/j.jhep.2015.11.011

DOI: 10.1016/j.jhep.2015.11.011

PubMed id: 26592953


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