Background Intrahepatic cholangiocarcinoma (iCCA) is a malignancy that arises from the intrahepatic biliary tree, showing high mortality rates due to its late clinical presentation and limited treatment options. iCCA is characterized by a dense, reactive desmoplastic stroma marked by a dramatic accumulation of extracellular matrix (ECM). Although recent results strongly suggest a relationship between increasing desmoplastic stroma and the enhanced malignant behaviour of iCCA, the importance of ECM proteins in the pathogenesis of iCCA still have to be addressed. Methods iCCA ECM fibrillar structural organization was characterized by histological analysis. ECM proteome profiles from decellularized iCCA and surrounding noncancerous tissues were analysed by nLC coupled to MALDI-TOF/TOF analysis. Results iCCA tissues displayed high levels of collagen fibers and low abundance of reticular and elastic fibers, suggesting stiffness and loss of polarity. The ECM proteome profiles of iCCA samples, when compared to those obtained from the surrounding noncancerous tissues showed a dismantling of the basement membrane, a reduced angiogenesis and a downregulation of oncosuppressive activity. In particular, we focused on the effects of the overexpression of collagen type III alpha 1 chain (COL3A1) in iCCA, thus providing evidences that COL3A1 promotes iCCA cells migration and is a component of tumor-associated aligned collagen. Conclusions Overall, this study contributes to the understanding of molecular basis underlying desmoplasia in iCCA and indicates the type III collagen as a promising therapeutic target.

中文翻译：

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肝内胆管癌的基质体分析揭示了一种特殊的与癌症相关的细胞外基质结构。

背景 肝内胆管癌 (iCCA) 是一种起源于肝内胆管树的恶性肿瘤，由于其晚期临床表现和有限的治疗选择而显示出高死亡率。iCCA 的特点是密集的、反应性的促纤维增生基质，其特征是细胞外基质 (ECM) 的显着积累。尽管最近的结果强烈表明增加的促纤维化基质与 iCCA 的恶性行为增强之间存在关系，但 ECM 蛋白在 iCCA 发病机制中的重要性仍有待解决。方法iCCA ECM纤维状结构组织通过组织学分析进行表征。通过与 MALDI-TOF/TOF 分析相结合的 nLC 分析来自脱细胞 iCCA 和周围非癌组织的 ECM 蛋白质组谱。结果 iCCA 组织显示出高水平的胶原纤维和低丰度的网状和弹性纤维，表明僵硬和极性丧失。iCCA 样本的 ECM 蛋白质组图谱与从周围非癌组织中获得的图谱相比，显示基底膜解体、血管生成减少和抑癌活性下调。特别是，我们专注于 iCCA 中 III 型胶原蛋白 α1 链 (COL3A1) 过表达的影响，从而提供证据表明 COL3A1 促进 iCCA 细胞迁移并且是肿瘤相关排列的胶原蛋白的组成部分。结论 总体而言，这项研究有助于了解 iCCA 中结缔组织增生的分子基础，并表明 III 型胶原蛋白是一种有前途的治疗靶点。