肿瘤起始细胞和IGF/FGF信号传导促成肝细胞癌对索拉非尼的耐药性。
Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma.
作者信息
Tovar Victoria, Cornella Helena, Moeini Agrin, Vidal Samuel, Hoshida Yujin, Sia Daniela, Peix Judit, Cabellos Laia, Alsinet Clara, Torrecilla Sara, Martinez-Quetglas Iris, Lozano Juan José, Desbois-Mouthon Christèle, Solé Manel, Domingo-Domenech Josep, Villanueva Augusto, Llovet Josep M
机构信息
Liver Cancer Translational Research Laboratory, Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit and Pathology Department, IDIBAPS, Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain.
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, USA.
出版信息
Gut. 2017 Mar;66(3):530-540. doi: 10.1136/gutjnl-2015-309501. Epub 2015 Dec 11.
OBJECTIVE
Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance.
DESIGN
HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts.
RESULTS
Sorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC).
CONCLUSIONS
Acquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.
目的
索拉非尼对肝细胞癌（HCC）有效，但患者最终会出现疾病进展。获得性耐药的分子机制仍不清楚。在此，我们阐述肿瘤起始细胞（T-ICs）的作用以及参与索拉非尼耐药的信号通路。
设计
对用索拉非尼治疗的HCC异种移植小鼠（n = 22）进行反应性（n = 5）和获得性耐药（n = 17）研究。通过以下方法评估获得性耐药机制：（1）使用NOD/SCID小鼠，通过体外成球和体内肿瘤发生试验研究T-ICs的作用；（2）替代信号通路的激活；（3）抗FGF和抗IGF药物在实验模型中的疗效。进行基因表达（微阵列、定量实时PCR（qRT-PCR））和蛋白质分析（免疫组织化学、蛋白质印迹）。生成一种新的索拉非尼耐药基因特征，并在两个独立队列中进行测试。
结果
与索拉非尼敏感肿瘤（13400个细胞）和未治疗肿瘤（1292个细胞）相比，索拉非尼获得性耐药肿瘤显示T-ICs显著富集（形成肿瘤所需164个细胞），p<0.001。具有索拉非尼获得性耐药的肿瘤富含胰岛素样生长因子（IGF）和成纤维细胞生长因子（FGF）信号级联（错误发现率（FDR）<0.05）。在体外，源自索拉非尼获得性耐药肿瘤的细胞和两种索拉非尼耐药HCC细胞系对IGF或FGF抑制有反应。在体内，FGF阻断可延迟索拉非尼耐药肿瘤的生长并提高生存率。一种索拉非尼耐药175基因特征表现为祖细胞特征富集、侵袭性肿瘤性状，并在两个队列（n = 442例HCC患者）中预测生存率低。
结论
索拉非尼获得性耐药由T-ICs驱动，伴有祖细胞标志物富集以及IGF和FGF信号激活。抑制这些通路将使索拉非尼进展后的一部分患者受益。
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