Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
J Histochem Cytochem. 2022 Jan;70(1):17-28. doi: 10.1369/00221554211048951. Epub 2021 Oct 4.
DLK1 is a maternally imprinted, paternally expressed gene coding for the transmembrane protein Delta-like homologue 1 (DLK1), a non-canonical NOTCH ligand with well-described roles during development, and tumor-supportive functions in several aggressive cancer forms. Here, we review the many functions of DLK1 as a regulator of stem cell pools and tissue differentiation in tissues such as brain, muscle, and liver. Furthermore, we review recent evidence supporting roles for DLK1 in the maintenance of aggressive stem cell characteristics of tumor cells, specifically focusing on central nervous system tumors, neuroblastoma, and hepatocellular carcinoma. We discuss NOTCH -dependent as well as NOTCH-independent functions of DLK1, and focus particularly on the complex pattern of DLK1 expression and cleavage that is finely regulated from a spatial and temporal perspective. Progress in recent years suggest differential functions of extracellular, soluble DLK1 as a paracrine stem cell niche-secreted factor, and has revealed a role for the intracellular domain of DLK1 in cell signaling and tumor stemness. A better understanding of DLK1 regulation and signaling may enable therapeutic targeting of cancer stemness by interfering with DLK1 release and/or intracellular signaling.
DLK1 是一个母系印记、父系表达的基因，编码跨膜蛋白 Delta-like 同源物 1（DLK1），它是一种非经典的 NOTCH 配体，在发育过程中具有明确的作用，并且在几种侵袭性癌症形式中具有支持肿瘤的功能。在这里，我们回顾了 DLK1 作为大脑、肌肉和肝脏等组织中的干细胞池和组织分化调节剂的许多功能。此外，我们还回顾了最近的证据，支持 DLK1 在维持肿瘤细胞的侵袭性干细胞特征中的作用，特别是集中在中枢神经系统肿瘤、神经母细胞瘤和肝细胞癌上。我们讨论了 DLK1 的 NOTCH 依赖性和非依赖性功能，并特别关注从时空角度精细调节的 DLK1 表达和切割的复杂模式。近年来的进展表明，细胞外可溶性 DLK1 作为旁分泌干细胞生态位分泌因子具有不同的功能，并且已经揭示了 DLK1 细胞内结构域在细胞信号转导和肿瘤干细胞特性中的作用。更好地理解 DLK1 的调控和信号转导可能通过干扰 DLK1 的释放和/或细胞内信号转导来实现对癌症干细胞特性的治疗靶向。
