Epithelial-to-mesenchymal transition and acquired resistance to sunitinib in a patient with hepatocellular carcinoma
Epithelial-to-mesenchymal transition and acquired resistance to sunitinib in a patient with hepatocellular carcinoma
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DOI：
10.1016/j.jhep.2010.11.011
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发表时间：
2011-05-01
影响因子：
25.7
通讯作者：
Faivre, Sandrine
中科院分区：
文献类型：
--
作者：
Marijon, Helene;Dokmak, Safi;Faivre, Sandrine
背景与目的：基于索拉非尼的成功，目前对几种抗血管生成疗法在晚期肝细胞癌中进行了评估。目前从患者那里获得的生物学数据很少，这可能有助于了解这些药物获得性耐药的机制。在这里，我们报告了一例对舒尼替尼产生获得性耐药性的患者的治疗后手术标本的翻译数据。方法：收集治疗前、治疗中和肿瘤进展时的临床、放射和病理数据。结果：在这例非酒精性脂肪性肝炎患者中，在治疗后6个月内，对舒尼替尼的初步反应和肿瘤的进展，要求挽救手术切除。令人惊讶的是，治疗后标本的病理检查显示，存在两个并列的组织成分，其中要么含有肉瘤样间充质细胞，要么含有分化良好至中等的肝细胞癌细胞。癌细胞在这两种成分中都保持高甲胎蛋白表达。然而，免疫染色显示，来自癌细胞的细胞表达E-钙粘蛋白，而不表达波形蛋白，而来自间充质成分的癌细胞高表达波形蛋白，丢失E-钙粘蛋白的蛋白表达。HMGA2和Ki67在间充质中的表达水平也高于癌细胞。结论：本病例报告提示，在对舒尼替尼产生耐药的肝细胞癌的离散区域中，发生了上皮向间充质的转变。(C)2011年由Elsevier B.V.代表欧洲肝脏研究协会出版。
Background & Aims: Based on the success of sorafenib, several anti-angiogenic therapies are currently evaluated in advanced hepatocellular carcinomas. Few biological data are currently available from patients that may help understanding mechanisms of acquired resistance to these drugs. Herein, we report translational data from a post-treatment surgical specimen in a patient who experienced acquired resistance to sunitinib.Methods: Clinical, radiological, and pathological data were collected before treatment, under treatment, and at the time of tumor progression. In addition, a biomolecular analysis was performed at the time of progression.Results: In this patient with non-alcoholic steatohepatitis, initial response to sunitinib was followed by tumor progression within 6 months of treatment, requesting salvage surgical resection. Surprisingly, pathological examination on post-treatment specimens revealed the presence of two juxtaposed tissue components containing either sarcomatoid-like mesenchymal cells or well- to moderately-differentiated hepatocellular carcinoma cells. Cancer cells retain a high a-fetoprotein expression in both components. However, while cells from carcinoma expressed E-cadherin but no vimentin, cancer cells from the mesenchymal component highly expressed vimentin and lost E-cadherin protein expression as measured by immunostaining. HMGA2 and Ki67 mRNA were also expressed at higher levels in mesenchymal than in carcinoma cells.Conclusion: This case report suggests the occurrence of an epithelial-to-mesenchyrnal transition in discrete areas of hepatocellular carcinomas developing resistance to sunitinib. (C) 2011 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.