Acquired Resistance to Antiangiogenic Therapies in Hepatocellular Carcinoma Is Mediated by Yes-Associated Protein 1 Activation and Transient Expansion of Stem-Like Cancer Cells.
Acquired Resistance to Antiangiogenic Therapies in Hepatocellular Carcinoma Is Mediated by Yes-Associated Protein 1 Activation and Transient Expansion of Stem-Like Cancer Cells.
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DOI：
10.1002/hep4.1869
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发表时间：
2022-05
影响因子：
5.1
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中科院分区：
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诱导新生血管生成是肝细胞癌（HCC）疾病进展过程中的标志性特征。抗血管生成化合物代表了治疗方法的支柱;然而，在大多数患者中观察到化学抗性的发展。最近的研究结果表明，肿瘤起始细胞（TIC）可能在获得耐药性中发挥关键作用，但HCC在此过程中的确切相关性仍有待确定。将原代和已建立的肝癌细胞系暴露于长期索拉非尼处理以模拟耐药性的获得。通过体外成球能力、体内致瘤性和流式细胞术评估对TIC的治疗效果。通过全转录组分析评估适应性分子变化。抗性的补偿机制被鉴定并直接评价。在6个HCC细胞系中的3个中观察到索拉非尼治疗后的持续抗增殖作用，随后快速再生长，从而模拟在患者中观察到的反应。耐药细胞显示出体外球体形成诱导和体内肿瘤引发能力，以及侧群和上皮细胞粘附分子阳性细胞数量增加。相反，敏感细胞系显示TIC特性的一致降低。鉴定了与耐药和不良预后相关的基因集，包括Hippo/yes相关蛋白（雅普）。Western blot和免疫组化证实雅普水平升高。索拉非尼和特异性雅普抑制剂的联合治疗在耐药细胞系中一致地显示出协同抗癌作用。结论：对抗血管生成治疗的耐药可能是由TIC的短暂扩张和代偿性原癌信号通路（包括雅普）的激活驱动的。特异性靶向TIC可能是克服HCC耐药的有效治疗策略。
Induction of neoangiogenesis is a hallmark feature during disease progression of hepatocellular carcinoma (HCC). Antiangiogenetic compounds represent a mainstay of therapeutic approaches; however, development of chemoresistance is observed in the majority of patients. Recent findings suggest that tumor‐initiating cells (TICs) may play a key role in acquisition of resistance, but the exact relevance for HCC in this process remains to be defined. Primary and established hepatoma cell lines were exposed to long‐term sorafenib treatment to model acquisition of resistance. Treatment effects on TICs were estimated by sphere‐forming capacity in vitro, tumorigenicity in vivo, and flow cytometry. Adaptive molecular changes were assessed by whole transcriptome analyses. Compensatory mechanisms of resistance were identified and directly evaluated. Sustained antiproliferative effect following sorafenib treatment was observed in three of six HCC cell lines and was followed by rapid regrowth, thereby mimicking responses observed in patients. Resistant cells showed induction in sphere forming in vitro and tumor‐initiating capacity in vivo as well as increased number of side population and epithelial cell adhesion molecule‐positive cells. Conversely, sensitive cell lines showed consistent reduction of TIC properties. Gene sets associated with resistance and poor prognosis, including Hippo/yes‐associated protein (YAP), were identified. Western blot and immunohistochemistry confirmed increased levels of YAP. Combined treatment of sorafenib and specific YAP inhibitor consistently revealed synergistic antioncogenic effects in resistant cell lines. Conclusion: Resistance to antiangiogenic therapy might be driven by transient expansion of TICs and activation of compensatory pro‐oncogenic signaling pathways, including YAP. Specific targeting of TICs might be an effective therapeutic strategy to overcome resistance in HCC.