Purpose

The current treatment outcomes in cholangiocarcinoma are poor with cure afforded only by surgical extirpation. The efficacy of targeting the tumoural endothelial marker CD105 in cholangiocarcinoma, as a basis for potential microbubble-based treatment, is unknown and was explored here.

Methods

Tissue expression of CD105 was quantified using immunohistochemistry in 54 perihilar cholangiocarcinoma samples from patients who underwent resection in a single centre over a ten-year period, and analysed against clinicopathological data. In vitro flow assays using microbubbles functionalised with CD105 antibody were conducted to ascertain specificity of binding to murine SVR endothelial cells. Finally, CD105-microbubbles were intravenously administered to 10 Balb/c nude mice bearing heterotopic subcutaneous human extrahepatic cholangiocarcinoma (TFK-1 and EGI-1) xenografts after which in vivo binding was assessed following contrast-enhanced destruction replenishment ultrasound application.

Results

Though not significantly associated with any examined clinicopathological variable, we found that higher CD105 expression was independently associated with poorer patient survival (median 12 vs 31 months; p = 0.002). In vitro studies revealed significant binding of CD105-microbubbles to SVR endothelial cells in comparison to isotype control (p = 0.01), as well as in vivo to TFK-1 (p = 0.02) and EGI-1 (p = 0.04) mouse xenograft vasculature.

Conclusion

Our results indicate that CD105 is a biomarker eminently suitable for cholangiocarcinoma targeting using functionalised microbubbles.

中文翻译：

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CD105是胆管癌微泡平台的预后标志物和有效的内皮靶标。

目的

胆管癌目前的治疗效果很差，只能通过手术切除才能治愈。靶向胆管癌中肿瘤内皮标记物CD105的功效，作为潜在的基于微泡的治疗的基础，尚不明确，在此进行了探讨。

方法

使用免疫组织化学技术对来自十年在同一中心接受切除手术的患者的54例肝门胆管癌样本中的CD105的组织表达进行定量，并根据临床病理数据进行分析。使用CD105抗体功能化的微泡进行体外血流测定，以确定与鼠SVR内皮细胞结合的特异性。最后，将CD105-微泡静脉内注射给10只带有异位皮下人肝外胆管癌（TFK-1和EGI-1）异种移植物的Balb / c裸鼠，然后在应用造影剂增强破坏补充超声后评估其体内结合。

结果

尽管与任何检查过的临床病理变量均无显着相关性，但我们发现较高的CD105表达与较差的患者存活率独立相关（中位12 vs 31个月；p  = 0.002）。体外研究表明，与同型对照（p  = 0.01）相比，CD105微气泡与SVR内皮细胞具有显着结合（在体内），并且与TFK-1（p  = 0.02）和EGI-1（p  = 0.04）小鼠异种移植相比，体内有明显的结合脉管系统。

结论

我们的结果表明CD105是非常适合使用功能化微泡靶向胆管癌的生物标志物。