文章：

血脑屏障连接受损促进黑色素瘤细胞嵌入与血管外渗

Compromised Blood-Brain Barrier Junctions Enhance Melanoma Cell Intercalation and Extravasation

原文发布日期：20 October 2023

DOI: 10.3390/cancers15205071

类型: Article

开放获取: 是

英文摘要：

Melanoma frequently metastasises to the brain, and a detailed understanding of the molecular and cellular mechanisms underlying melanoma cell extravasation across the blood-brain barrier (BBB) is important for preventing brain metastasis formation. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as an in vitro BBB model, we imaged the interaction of melanoma cells into pMBMEC monolayers. We observed exclusive junctional intercalation of melanoma cells and confirmed that melanoma-induced pMBMEC barrier disruption can be rescued by protease inhibition. Interleukin (IL)-1β stimulated pMBMECs or PECAM-1-knockout (-ko) pMBMECs were employed to model compromised BBB barrier properties in vitro and to determine increased melanoma cell intercalation compared to pMBMECs with intact junctions. The newly generated brain-homing melanoma cell line YUMM1.1-BrM4 was used to reveal increased in vivo extravasation of melanoma cells across the BBB of barrier-compromised PECAM-1-deficient mice compared to controls. Taken together, our data indicate that preserving BBB integrity is an important measure to limit the formation of melanoma-brain metastasis.

摘要翻译： 

黑色素瘤常转移至大脑，深入理解其细胞穿越血脑屏障（BBB）的分子与细胞机制对于预防脑转移至关重要。本研究以原代小鼠脑微血管内皮细胞（pMBMECs）构建体外血脑屏障模型，通过实时成像观察黑色素瘤细胞与pMBMEC单层的相互作用。研究发现黑色素瘤细胞特异性通过内皮细胞连接处进行穿插迁移，并证实蛋白酶抑制剂可修复黑色素瘤诱导的pMBMEC屏障损伤。通过白细胞介素（IL）-1β刺激的pMBMECs及PECAM-1基因敲除（-ko）的pMBMECs模拟体内血脑屏障功能受损状态，实验显示与连接结构完整的pMBMECs相比，这两种模型中的黑色素瘤细胞穿插迁移显著增强。利用新构建的脑靶向黑色素瘤细胞系YUMM1.1-BrM4进行体内实验，发现与对照组相比，在血脑屏障受损的PECAM-1缺陷小鼠模型中，黑色素瘤细胞穿越血脑屏障的体外迁移能力明显提升。综上所述，本研究证实维持血脑屏障完整性是限制黑色素瘤脑转移形成的重要调控策略。

原文链接：

Compromised Blood-Brain Barrier Junctions Enhance Melanoma Cell Intercalation and Extravasation