Polymeric Nanoparticle-Encapsulated Hedgehog Pathway Inhibitor HPI-1 (NanoHHI) Inhibits Systemic Metastases in an Orthotopic Model of Human Hepatocellular Carcinoma
Polymeric Nanoparticle-Encapsulated Hedgehog Pathway Inhibitor HPI-1 (NanoHHI) Inhibits Systemic Metastases in an Orthotopic Model of Human Hepatocellular Carcinoma
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聚合物纳米颗粒封装的 Hedgehog 通路抑制剂 HPI-1 (NanoHHI) 抑制人肝细胞癌原位模型中的全身转移
DOI：
10.1158/1078-0432.ccr-11-0950
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发表时间：
2012-03-01
影响因子：
11.5
通讯作者：
Anders, Robert A.
中科院分区：
文献类型：
--
作者：
Xu, Yang;Chenna, Venugopal;Anders, Robert A.
目的：为了说明刺猬（Hh）信号在肝细胞癌（HCC）患者的预后意义，并评估一种新的纳米颗粒封装的Hh转录因子抑制剂，Gli 1（NanoHHI）的疗效，使用在体外和在vivomodels的人类HCCs.Experimental设计：Patched 1（Ptch 1）的表达检测在2000年2月至2002年12月期间接受根治性手术切除的396例HCC患者的肿瘤组织微阵列。使用Kaplan-Meier生存估计和对数秩检验评估预后意义。研究了NanoHHI单独和与索拉非尼组合对HCC细胞系的作用。结果：Ptch 1在肝癌组织中的高表达与肝癌复发显著相关，且肝癌患者的复发时间较短; NanoHHI在体外可显著抑制肝癌细胞系的增殖和侵袭。NanoHHI在皮下和原位环境中有效抑制HCC异种移植物的体内肿瘤生长，并且与索拉非尼相反，导致原位环境中全身转移的显著衰减。此外，NanoHHI显着降低了表达CD 133的HCC细胞，这已牵连在肿瘤的发生和transferations.Conclusion：下游Hh信号传导在HCC患者的预后意义，因为它预测早期复发的人口。通过NanoHHI的Gli抑制在HCC模型中具有显著的肿瘤生长抑制和抗转移作用，这可以提供治疗HCC患者和预防术后复发的新策略。©2011 AACR。
Purpose:To illustrate the prognostic significance of hedgehog (Hh) signaling in patients with hepatocellular carcinoma (HCC) and to evaluate the efficacy of a novel nanoparticle-encapsulated inhibitor of the Hh transcription factor,Gli1(NanoHHI) usingin vitroandin vivomodels of human HCCs.Experimental Design:Patched1 (Ptch1) expression was detected in tumor tissue microarrays of 396 patients with HCC who underwent curative surgical resection during February 2000 to December 2002. Prognostic significance was assessed using Kaplan–Meier survival estimates and log-rank tests. The effects of NanoHHI alone and in combination with sorafenib were investigated on HCC cell lines. Primary HCC tumor growth and metastasis were examinedin vivousing subcutaneous and orthotopic HCC xenografts in nude mice.Results:Elevated expression ofPtch1in HCC tissues was significantly related to disease recurrence, as well as a shorter time to recurrence in patients with HCC.In vitro, NanoHHI significantly inhibited the proliferation and invasion of HCC cell lines. NanoHHI potently suppressedin vivotumor growth of HCC xenografts in both subcutaneous and orthotopic milieus, and in contrast to sorafenib, resulted in significant attenuation of systemic metastases in the orthotopic setting. Furthermore, NanoHHI significantly decreased the population of CD133-expressing HCC cells, which have been implicated in tumor initiation and metastases.Conclusion:Downstream Hh signaling has prognostic significance in patients with HCC as it predicts early recurrence. Gli inhibition through NanoHHI has profound tumor growth inhibition and antimetastatic effects in HCC models, which may provide a new strategy in the treatment of patients with HCC and prevention post-operative recurrence.Clin Cancer Res; 18(5); 1291–302. ©2011 AACR.