Adjuvant Gemcitabine Therapy Improves Survival in a Locally Induced, R0-Resectable Model of Metastatic Intrahepatic Cholangiocarcinoma
Adjuvant Gemcitabine Therapy Improves Survival in a Locally Induced, R0-Resectable Model of Metastatic Intrahepatic Cholangiocarcinoma
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DOI：
10.1002/hep.26468
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发表时间：
2013-09-01
期刊：
影响因子：
13.5
通讯作者：
Kuehnel, Florian
中科院分区：
文献类型：
--
作者：
Guerlevik, Engin;Fleischmann-Mundt, Bettina;Kuehnel, Florian
肝内胆管细胞癌（ICC）的根治性手术切除（R 0）是一种有效的治疗方法，但术后复发转移率高，预后差。辅助治疗可能会改善结果，但辅助方法的临床研究对于罕见肿瘤实体来说是困难和耗时的。因此，迫切需要反映临床情况的动物模型来研究新的辅助治疗。为了建立可切除的胆管癌的小鼠模型，包括人类ICC的最常见的遗传改变，我们电穿孔基于睡美人的致癌转座子质粒到小鼠的左肝叶。在肝细胞中KRas激活与p53敲除组合导致在3-5周内形成单个ICC结节。谱系追踪分析证实了ICC的发展是通过肝细胞的转分化。组织学检查表明，在原发性肿瘤进展过程中没有检测到肝外转移。然而，观察到靠近原发肿瘤的肿瘤卫星形成和血管浸润，表明早期浸润到邻近肿瘤的正常组织中。原发肿瘤R 0切除后，我们能够延长中位生存期，从而观察到肿瘤分期依赖性局部复发、腹膜癌转移和肺转移。R 0切除术后辅助吉西他滨化疗显著改善了治疗动物的中位生存期。结论：我们已经开发了一个小鼠模型，单一的，R 0-可切除的ICC的复发模式和切除后转移机制的研究具有良好的特点。该模型为临床前评价新的多模式或辅助治疗以预防R 0切除术后复发和转移提供了很大的希望。（肝病学2013;53：1031-1041）
Complete surgical tumor resection (R0) for treatment of intrahepatic cholangiocarcinoma (ICC) is potentially curative, but the prognosis remains dismal due to frequent tumor recurrence and metastasis after surgery. Adjuvant therapies may improve the outcome, but clinical studies for an adjuvant approach are difficult and time-consuming for rare tumor entities. Therefore, animal models reflecting the clinical situation are urgently needed to investigate novel adjuvant therapies. To establish a mouse model of resectable cholangiocarcinoma including the most frequent genetic alterations of human ICC, we electroporated Sleeping Beauty-based oncogenic transposon plasmids into the left liver lobe of mice. KRas-activation in combination with p53-knockout in hepatocytes resulted in formation of a single ICC nodule within 3-5 weeks. Lineage tracing analyses confirmed the development of ICC by transdifferentiation of hepatocytes. Histologic examination demonstrated that no extrahepatic metastases were detectable during primary tumor progression. However, formation of tumor satellites close to the primary tumor and vascular invasion were observed, indicating early invasion into normal tissue adjacent to the tumor. After R0-resection of the primary tumor, we were able to prolong median survival, thereby observing tumor stage-dependent local recurrence, peritoneal carcinomatosis, and lung metastasis. Adjuvant gemcitabine chemotherapy after R0-resection significantly improved median survival of treated animals. Conclusion: We have developed a murine model of single, R0-resectable ICC with favorable characteristics for the study of recurrence patterns and mechanisms of metastasis after resection. This model holds great promise for preclinical evaluation of novel multimodal or adjuvant therapies to prevent recurrence and metastasis after R0-resection. (Hepatology 2013;53:1031-1041)