Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview.
Molecular Mechanisms Driving Cholangiocarcinoma Invasiveness: An Overview.
复制标题
DOI：
10.3727/105221617x15088670121925
复制
发表时间：
2018-03-21
期刊：
影响因子：
--
通讯作者：
Strazzabosco M
中科院分区：
文献类型：
--
作者：
Brivio S;Cadamuro M;Fabris L;Strazzabosco M
肿瘤细胞获得侵袭功能是转移发展的第一步也是关键的一步，转移是当今癌症相关死亡的主要原因。胆管癌（CCA）是一种起源于胆管上皮的原发性肝癌，通常在早期发生肝内或淋巴结转移，从而使大多数患者无法接受根治性治疗，这与他们非常差的预后一致。与大多数癌症一样，CCA 细胞逐渐采取活动的间质样表型，使它们能够穿过基底膜，与原发肿瘤分离，并侵入周围的间质。不幸的是，人们对协同协调这种促侵袭表型转换的分子机制知之甚少。渗透到肿瘤微环境中的自分泌和旁分泌信号（细胞/趋化因子、生长因子、形态发生素）无疑在这方面发挥着重要作用。此外，许多最近发现的信号系统目前作为 CCA 细胞侵袭的推定机制决定因素而引起人们的关注。它们包括转录因子、蛋白激酶和磷酸酶、泛素连接酶、接头蛋白和 miRNA，其异常表达可能是由于随机突变或上游促癌途径的异常激活造成的。在此，我们试图总结该领域最相关的分子，并讨论它们在 CCA 中的作用机制和潜在的预后相关性。希望对 CCA 侵袭性分子决定因素的更深入了解将有助于识别临床上有用的生物标志物和新的药物靶标，最终目标是开发治疗这种毁灭性恶性肿瘤的创新方法。
The acquisition of invasive functions by tumor cells is a first and crucial step towards the development of metastasis, which nowadays represents the main cause of cancer-related death. Cholangiocarcinoma (CCA), a primary liver cancer originating from the biliary epithelium, typically develops intrahepatic or lymph node metastases at early stages, thus preventing the majority of patients from undergoing curative treatments, consistent with their very poor prognosis. As in most carcinomas, CCA cells gradually adopt a motile, mesenchymal-like phenotype, enabling them to cross the basement membrane, detach from the primary tumor, and invade the surrounding stroma. Unfortunately, little is known about the molecular mechanisms that synergistically orchestrate this pro-invasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, morphogens) permeating the tumor microenvironment undoubtedly play a prominent role in this context. Moreover, a number of recently identified signaling systems are currently drawing attention as putative mechanistic determinants of CCA cell invasion. They encompass transcription factors, protein kinases and phosphatases, ubiquitin ligases, adaptor proteins, and miRNAs, whose aberrant expression may result from either stochastic mutations or the abnormal activation of upstream pro-oncogenic pathways. Herein, we sought to summarize the most relevant molecules in this field, and to discuss their mechanism of action and potential prognostic relevance in CCA. Hopefully, a deeper knowledge of the molecular determinants of CCA invasiveness will help to identify clinically useful biomarkers and novel druggable targets, with the ultimate goal to develop innovative approaches to the management of this devastating malignancy.