Brivio Simone, Cadamuro Massimiliano, Fabris Luca, Strazzabosco Mario
School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy.
International Center for Digestive Health, University of Milan-Bicocca, Monza, Italy.
Gene Expr. 2018 Mar 21;18(1):31-50. doi: 10.3727/105221617X15088670121925. Epub 2017 Oct 25.
The acquisition of invasive functions by tumor cells is a first and crucial step toward 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 proinvasive phenotypic switch. Autocrine and paracrine signals (cyto/chemokines, growth factors, and 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.
肿瘤细胞获得侵袭性功能是转移发生的首要关键步骤，而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，通常在早期就发生肝内或淋巴结转移，因此大多数患者无法接受根治性治疗，预后极差。与大多数癌症一样，CCA细胞逐渐呈现出运动性的、间充质样表型，使其能够穿过基底膜，脱离原发肿瘤，并侵入周围基质。遗憾的是，对于协同调控这种促侵袭性表型转换的分子机制我们知之甚少。渗透于肿瘤微环境中的自分泌和旁分泌信号（细胞因子/趋化因子、生长因子和形态发生素）无疑在这一过程中发挥着重要作用。此外，一些最近发现的信号系统目前作为CCA细胞侵袭的假定机制决定因素正受到关注。它们包括转录因子、蛋白激酶和磷酸酶、泛素连接酶、衔接蛋白和微小RNA，其异常表达可能源于随机突变或上游促癌途径的异常激活。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可药物作用靶点，最终目标是开发创新方法来治疗这种毁灭性的恶性肿瘤。
