DevWeCan Laboratories of Excellence Network (Labex), Université de Lyon, Lyon Cancer Research Center, Inserm U1052-CNRS UMR5286, Lyon, France.
J Cell Biochem. 2014 Apr;115(4):666-77. doi: 10.1002/jcb.24706.
Interpatient heterogeneity of hepatocellular carcinoma has been in-depth addressed. Intrapatient heterogeneity is less known. Four clones were freshly isolated from an Edmondson grade I HCV-associated hepatocellular carcinoma. Biochemical approaches, functional assays and cytogenetics were used. Albumin inducibility was uncoupled from canonical cytokeratin profiles, suggesting pathological combinations of hepatospecific and biliary markers. Poor differentiation and TGFβ's proproliferative effect on all clones were observed. TGFβ, Interferon α and doxorubicin sensitivity levels were found highly heterogeneous. Progenitor and stem cells markers OV6 and EpCAM were mutually exclusively expressed. All clones were CD44+, while none expressed CD90, CD133, or CD117. Three clones displayed a liver progenitor OV6+ phenotype, and were susceptible to hepatocytic differentiation, among which one fibroblastoid clone displayed intrahepatic parenchymal engraftment capability. A fourth clone, the less motile, displayed a cancer stem cell EpCAM+ phenotype, was essentially β-catenin negative, and was as expected devoid of hepatocytic differentiation capability, yet the most sensitive to doxorubicin treatment. Cytogenetics evidenced in all clones a t(12;22)(p11;q11) translocation found in several myelodysplastic syndromes. All clones, that probably derive from EpCAM+ tumor cells, display aberrant E-cadherin cytosolic localization. Because of their diverse pathophysiolocal features, these freshly isolated, low population doubling-defined, HCC clones may provide novel opportunities to tackle HCC heterogeneity in a single patient background for therapy improvement purposes, especially regarding recently developed targeted strategies.
肝细胞癌的患者间异质性已得到深入研究。患者内异质性则知之甚少。从一个埃德尔曼分级 I HCV 相关的肝细胞癌中新鲜分离出四个克隆。采用生化方法、功能测定和细胞遗传学方法。白蛋白诱导与经典细胞角蛋白谱脱偶联，提示存在肝特异性和胆管标记物的病理性组合。观察到所有克隆均分化不良且 TGFβ 对所有克隆均具有促增殖作用。发现 TGFβ、干扰素α和多柔比星的敏感性水平高度异质性。祖细胞和干细胞标记物 OV6 和 EpCAM 相互排斥表达。所有克隆均为 CD44+，而无 CD90、CD133 或 CD117 表达。三个克隆表现出肝祖细胞 OV6+表型，易发生肝样分化，其中一个成纤维细胞样克隆显示出肝内实质植入能力。第四个克隆运动性较差，表现出癌症干细胞 EpCAM+表型，基本上β-连环蛋白阴性，且如预期的那样缺乏肝样分化能力，但对多柔比星治疗最敏感。细胞遗传学在所有克隆中均发现了几种骨髓增生异常综合征中存在的 t(12;22)(p11;q11)易位。所有克隆可能来源于 EpCAM+肿瘤细胞，均显示出 E-钙黏蛋白细胞浆定位异常。由于其具有不同的病理生理特征，这些新分离的、低群体倍增定义的 HCC 克隆可能为在单个患者背景下改善 HCC 异质性提供新的机会，特别是在最近开发的靶向治疗策略方面。
