Sulfatase-2 from Cancer Associated Fibroblasts: An Environmental Target for Hepatocellular Carcinoma?

IF 11.6 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Liver Cancer Pub Date : 2022-07-13 eCollection Date: 2022-12-01 DOI:10.1159/000525375
Marco Y W Zaki, Sari F Alhasan, Ruchi Shukla, Misti McCain, Maja Laszczewska, Daniel Geh, Gillian L Patman, Despina Televantou, Anna Whitehead, João P Maurício, Ben Barksby, Lucy M Gee, Hannah L Paish, Jack Leslie, Ramy Younes, Alastair D Burt, Lee A Borthwick, Huw Thomas, Gary S Beale, Olivier Govaere, Daniela Sia, Quentin M Anstee, Dina Tiniakos, Fiona Oakley, Helen L Reeves
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引用次数: 0

Abstract

Introduction: 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.

Methods: 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.

Results: 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, p = 0.003). Stromal SULF2 modulated glypican-3/β-catenin signalling in vitro, although in vivo associations suggested additional mechanisms underlying the CAF-SULF2 impact on prognosis. Stromal SULF2 was released by CAFS isolated from human HCC. It was induced by TGFβ1, promoted HCC proliferation and sorafenib resistance, with CAF-SULF2 linked to TGFβ1 and immune exhaustion in TGCA HCC patients. Autocrine activation of PDGFRβ/STAT3 signalling was evident in stromal cells, with the release of the potent monocyte/macrophage chemoattractant CCL2 in vitro. In human PBMCs, SULF2 preferentially induced the migration of macrophage precursors (monocytes), inducing a phenotypic change consistent with immune exhaustion. In human HCC tissues, CAF-SULF2 was associated with increased macrophage recruitment, with tumouroid studies showing stromal-derived SULF2-induced paracrine activation of the IKKβ/NF-κB pathway, tumour cell proliferation, invasion, and sorafenib resistance.

Conclusion: 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.

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来自癌症相关成纤维细胞的硫酸酯酶-2:肝细胞癌的环境靶标?
简介肝脏肿瘤微环境(TME)中的肝素硫酸盐蛋白聚糖是细胞信号的关键调节因子,受硫酸酯酶-2(SULF2)调节。SULF2在肝细胞癌(HCC)中出现过表达。我们的目的是确定 SULF2 在 HCC TME 中的性质和影响:方法:在60名HCC患者的肝活检组织中,分析SULF2的表达和定位与临床参数和预后的关系。通过免疫组织化学(IHC)、利用癌症基因组图谱(TGCA)对原发性分离癌活化成纤维细胞、单培养物、三维球体以及转诊接受索拉非尼治疗的20名患者的独立队列进行了功能和机理影响评估。IHC靶标包括αSMA、glypican-3、β-catenin、RelA-P-ser536、CD4、CD8、CD66b、CD45、CD68和CD163。通过迁移试验评估了SULF2对外周血单核细胞的影响,并利用荧光激活细胞分选技术确定了免疫细胞的表型:我们报告说,在15%(9/60)的病例中,SULF2在肿瘤细胞中表达,这与肿瘤晚期和2型糖尿病有关,而SULF2在癌症相关成纤维细胞(CAFs)中表达更为常见(52%),并且与生存期缩短(7.2个月对29.2个月,p = 0.003)独立相关。基质SULF2在体外调节glypican-3/β-catenin信号,但体内相关性表明CAF-SULF2对预后的影响还存在其他机制。从人类 HCC 中分离出的 CAFS 释放了基质 SULF2。它由TGFβ1诱导,促进HCC增殖和索拉非尼耐药,CAF-SULF2与TGFβ1和TGCA HCC患者的免疫衰竭有关。在基质细胞中,PDGFRβ/STAT3 信号的自分泌激活非常明显,并在体外释放出强效的单核细胞/巨噬细胞趋化吸引剂 CCL2。在人PBMCs中,SULF2优先诱导巨噬细胞前体(单核细胞)迁移,诱导与免疫衰竭一致的表型变化。在人类HCC组织中,CAF-SULF2与巨噬细胞募集增加有关,肿瘤研究显示基质衍生的SULF2诱导了IKKβ/NF-κB通路的旁分泌激活、肿瘤细胞增殖、侵袭和索拉非尼抗性:结论:来自CAFs的SULF2不仅能调节glypican-3/β-catenin信号,还能调节HCC免疫TME,通过激活TAK1/IKKβ/NF-κB通路,与肿瘤进展和耐药性相关。它是对 HCC 患者进行联合治疗的一个有吸引力的靶点。
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来源期刊
Liver Cancer
Liver Cancer Medicine-Oncology
CiteScore
20.80
自引率
7.20%
发文量
53
审稿时长
16 weeks
期刊介绍: Liver Cancer is a journal that serves the international community of researchers and clinicians by providing a platform for research results related to the causes, mechanisms, and therapy of liver cancer. It focuses on molecular carcinogenesis, prevention, surveillance, diagnosis, and treatment, including molecular targeted therapy. The journal publishes clinical and translational research in the field of liver cancer in both humans and experimental models. It publishes original and review articles and has an Impact Factor of 13.8. The journal is indexed and abstracted in various platforms including PubMed, PubMed Central, Web of Science, Science Citation Index, Science Citation Index Expanded, Google Scholar, DOAJ, Chemical Abstracts Service, Scopus, Embase, Pathway Studio, and WorldCat.
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