Laboratory for Experimental Oncology and Radiobiology, Center of Experimental and Molecular Medicine, Cancer Center Amsterdam and Academic Medical Center, Amsterdam, the Netherlands.
Oncode Institute, Academic Medical Center, Amsterdam, the Netherlands.
Mol Cancer. 2018 Jun 14;17(1):95. doi: 10.1186/s12943-018-0842-9.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies to date, largely because it is associated with high metastatic risk. Pancreatic tumors have a characteristic tendency to metastasize preferentially to the liver. Over the past two decades, it has become evident that the otherwise hostile milieu of the liver is selectively preconditioned at an early stage to render it more conducive to the engraftment and growth of disseminated cancer cells, a concept defined as pre-metastatic niche (PMN) formation. Pancreatic cancer cells exploit components of the tumor microenvironment to facilitate their migration out of the primary tumor, which often involves conversion of pancreatic cancer cells from an epithelial to a mesenchymal phenotype via the epithelial-to-mesenchymal transition. Pancreatic stellate cells and matrix stiffness have been put forward as major drivers of invasiveness in PDAC. Even before the onset of pancreatic cancer cell dissemination, soluble factors and extracellular vesicles secreted by the primary tumor, and possibly even premalignant lesions, help shape a supportive niche in the liver by providing vascular docking sites for circulating tumor cells, enhancing vascular permeability, remodeling the extracellular matrix and recruiting immunosuppressive inflammatory cells. Emerging evidence suggests that some of these tumor-derived factors may represent powerful diagnostic or prognostic biomarkers. Though our understanding of the mechanisms driving PMN formation in PDAC has expanded considerably, many outstanding questions and challenges remain. Further studies dissecting the molecular and cellular events involved in hepatic PMN formation in PDAC will likely improve diagnosis and open new avenues from a therapeutic standpoint.
胰腺导管腺癌 (PDAC) 仍然是迄今为止最具侵袭性的恶性肿瘤之一，主要是因为它与高转移风险有关。胰腺肿瘤具有优先转移到肝脏的特征性倾向。在过去的二十年中，显然已经清楚的是，肝脏原本敌对的环境在早期就被选择性地预先调节，使其更有利于播散癌细胞的植入和生长，这一概念被定义为预先转移生态位 (PMN) 的形成。胰腺癌细胞利用肿瘤微环境的成分来促进其从原发性肿瘤中迁移，这通常涉及通过上皮间质转化将胰腺癌细胞从上皮表型转化为间充质表型。胰腺星状细胞和基质硬度被提出是 PDAC 侵袭性的主要驱动因素。甚至在胰腺癌细胞扩散之前，原发性肿瘤分泌的可溶性因子和细胞外囊泡，甚至可能是癌前病变，通过为循环肿瘤细胞提供血管停泊点、增强血管通透性、重塑细胞外基质和招募免疫抑制性炎症细胞，有助于在肝脏中形成支持性生态位。新出现的证据表明，其中一些肿瘤衍生的因素可能代表强大的诊断或预后生物标志物。尽管我们对 PDAC 中 PMN 形成的机制的理解已经大大扩展，但仍有许多悬而未决的问题和挑战。进一步研究剖析 PDAC 中肝脏 PMN 形成所涉及的分子和细胞事件，可能会改善诊断，并从治疗角度开辟新的途径。
