Sulfatase-2 from Cancer Associated Fibroblasts: An Environmental Target for Hepatocellular Carcinoma?
Biomarkers
Glypican-3
Hepatocellular carcinoma
Inflammation
Metabolic disease
Molecular targets
NASH
Spheroids
Sulfatase-2
Tumour microenvironment
Journal
Liver cancer
ISSN: 2235-1795
Titre abrégé: Liver Cancer
Pays: Switzerland
ID NLM: 101597993
Informations de publication
Date de publication:
Dec 2022
Dec 2022
Historique:
received:
11
08
2021
accepted:
12
05
2022
entrez:
2
1
2023
pubmed:
3
1
2023
medline:
3
1
2023
Statut:
epublish
Résumé
Heparin sulphate proteoglycans in the liver tumour microenvironment (TME) are key regulators of cell signalling, modulated by sulfatase-2 (SULF2). SULF2 overexpression occurs in hepatocellular carcinoma (HCC). Our aims were to define the nature and impact of SULF2 in the HCC TME. In liver biopsies from 60 patients with HCC, expression and localization of SULF2 were analysed associated with clinical parameters and outcome. Functional and mechanistic impacts were assessed with immunohistochemistry (IHC), in silico using The Cancer Genome Atlas (TGCA), in primary isolated cancer activated fibroblasts, in monocultures, in 3D spheroids, and in an independent cohort of 20 patients referred for sorafenib. IHC targets included αSMA, glypican-3, β-catenin, RelA-P-ser536, CD4, CD8, CD66b, CD45, CD68, and CD163. SULF2 impact of peripheral blood mononuclear cells was assessed by migration assays, with characterization of immune cell phenotype using fluorescent activated cell sorting. We report that while SULF2 was expressed in tumour cells in 15% (9/60) of cases, associated with advanced tumour stage and type 2 diabetes, SULF2 was more commonly expressed in cancer-associated fibroblasts (CAFs) (52%) and independently associated with shorter survival (7.2 vs. 29.2 months, SULF2 derived from CAFs modulates glypican-3/β-catenin signalling but also the HCC immune TME, associated with tumour progression and therapy resistance via activation of the TAK1/IKKβ/NF-κB pathway. It is an attractive target for combination therapies for patients with HCC.
Identifiants
pubmed: 36589727
doi: 10.1159/000525375
pii: lic-0011-0540
pmc: PMC9801184
doi:
Types de publication
Journal Article
Langues
eng
Pagination
540-557Subventions
Organisme : Cancer Research UK
ID : 26813
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0900535
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K001949/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R023026/1
Pays : United Kingdom
Informations de copyright
Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.
Déclaration de conflit d'intérêts
F.O. is a director and shareholder in Fibrofind Ltd. J.L. is a shareholder in Fibrofind Ltd, all other authors declare no competing interests.
Références
JAMA Oncol. 2021 Jan 01;7(1):113-123
pubmed: 33090190
Glycobiology. 2013 Jun;23(6):709-19
pubmed: 23418199
Sci Rep. 2017 Feb 24;7:43378
pubmed: 28233816
Dig Dis Sci. 2016 May;61(5):1234-45
pubmed: 26921078
Neuron. 2018 Oct 10;100(1):183-200.e8
pubmed: 30269986
Mol Med Rep. 2017 Dec;16(6):7879-7889
pubmed: 28983598
Nat Commun. 2017 Oct 24;8(1):1130
pubmed: 29066712
N Engl J Med. 2008 Nov 6;359(19):1995-2004
pubmed: 18923165
Nat Rev Immunol. 2018 May;18(5):309-324
pubmed: 29379212
J Hepatol. 2006 Sep;45(3):419-28
pubmed: 16842882
Oncogene. 2015 Jul;34(28):3700-10
pubmed: 25220414
N Engl J Med. 2008 Jul 24;359(4):378-90
pubmed: 18650514
Gastroenterology. 2003 Jul;125(1):89-97
pubmed: 12851874
Gastroenterology. 2018 Jan;154(1):195-210
pubmed: 28918914
J Biol Chem. 2014 Jul 18;289(29):20295-306
pubmed: 24878958
J Biol Chem. 2002 Dec 20;277(51):49175-85
pubmed: 12368295
Oncogene. 2012 Sep 13;31(37):4107-16
pubmed: 22158045
Front Immunol. 2019 May 22;10:1147
pubmed: 31191529
Lancet. 2018 Mar 31;391(10127):1301-1314
pubmed: 29307467
PLoS One. 2015 May 20;10(5):e0127028
pubmed: 25992611
Oncogene. 2018 Aug;37(32):4443-4454
pubmed: 29720727
Cell Death Dis. 2019 Mar 20;10(4):273
pubmed: 30894509
Cancer. 1954 May;7(3):462-503
pubmed: 13160935
Hepatology. 2010 Nov;52(5):1680-9
pubmed: 20725905
Cancer Sci. 2009 Apr;100(4):646-53
pubmed: 19175606
Lab Invest. 2000 May;80(5):697-707
pubmed: 10830780
J Hepatol. 2012 Apr;56(4):908-43
pubmed: 22424438
Neoplasia. 2013 Feb;15(2):204-17
pubmed: 23441134
BMC Biotechnol. 2011 Nov 07;11:102
pubmed: 22059503
Gastroenterology. 2017 Sep;153(3):812-826
pubmed: 28624577
Cancer Cell. 2012 Nov 13;22(5):571-84
pubmed: 23153532
Cancer Res. 2013 May 15;73(10):3007-18
pubmed: 23514705
Nucleic Acids Res. 2019 Apr 23;47(7):3365-3382
pubmed: 30698737
Cell Res. 2011 Jan;21(1):159-68
pubmed: 21187858
Jpn J Cancer Res. 2000 Dec;91(12):1285-95
pubmed: 11123428
J Cell Sci. 2017 Feb 1;130(3):577-589
pubmed: 27980069
Gut. 2017 Jan;66(1):157-167
pubmed: 26452628
Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
pubmed: 9254694
Hepatology. 2008 Apr;47(4):1211-22
pubmed: 18318435
FEBS Open Bio. 2013 Dec 30;4:96-104
pubmed: 24490130
FASEB J. 2010 Jun;24(6):2040-55
pubmed: 20154269
Hepatology. 2011 Mar;53(3):1020-2
pubmed: 21374666
CA Cancer J Clin. 2018 Nov;68(6):394-424
pubmed: 30207593
Clin Cancer Res. 2012 Sep 15;18(18):4997-5007
pubmed: 22811581
Gastric Cancer. 2020 Nov;23(6):988-1002
pubmed: 32617693
Cancer Immunol Immunother. 2004 Nov;53(11):1049-50
pubmed: 15449044
Cell Commun Signal. 2013 Dec 20;11:97
pubmed: 24359404
Stroke. 2020 Oct;51(10):3095-3106
pubmed: 32933419
Oncotarget. 2016 Mar 29;7(13):16090-103
pubmed: 26895473
J Immunol. 2008 May 1;180(9):6421-9
pubmed: 18424766