Pernet-Gallay Karin, Jouneau Pierre-Henri, Bertrand Anne, Delaroche Julie, Farion Régine, Rémy Chantal, Barbier Emmanuel L
1 INSERM, U 1216, Grenoble, France.
2 Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, Grenoble, France.
J Cereb Blood Flow Metab. 2017 Apr;37(4):1264-1275. doi: 10.1177/0271678X16654157. Epub 2016 Jan 1.
This study evaluates the extravasation pathways of circulating macromolecules in a rat glioma model (RG2) which was observed by both magnetic resonance imaging using ultrasmall superparamagnetic iron oxide and electron microscopy. Although magnetic resonance imaging signal enhancement was observed as soon as 10 min after injection (9.4% 2 h after injection), electron microscopy showed that endothelial cells were still tightly sealed. However, circulating immunoglobulin G and ultrasmall superparamagnetic iron oxide were found in large membrane compartments of endothelial cells, in the basal lamina (7.4 ± 1.2 gold particles/µm in the tumor versus 0.38 ± 0.17 in healthy tissue, p = 1.4.10) and between tumoral cells. Altogether, this strongly suggests an active transport mediated by macropinocytosis. To challenge this transport mechanism, additional rats were treated with amiloride, an inhibitor of macropinocytosis, leading to a reduction of membrane protrusions (66%) and of macropinosomes. Amiloride however also opened tumoral tight junctions allowing a larger extravasation of ultrasmall superparamagnetic iron oxide (magnetic resonance imaging signal enhancement of 35.7% 2 h after injection). Altogether, these results suggest that ultrasmall superparamagnetic iron oxide and immunoglobulin G in the RG2 glioma model follow an active extravasation pathway mediated by a macropinocytosis process. Amiloride also appears as a potential strategy to facilitate the extravasation of chemotherapeutic drugs in glioma.
本研究在大鼠胶质瘤模型（RG2）中评估循环大分子的外渗途径，该模型通过使用超小超顺磁性氧化铁的磁共振成像和电子显微镜进行观察。尽管在注射后10分钟就观察到磁共振成像信号增强（注射后2小时为9.4%），但电子显微镜显示内皮细胞仍紧密密封。然而，在内皮细胞的大膜隔室、基膜中（肿瘤中为7.4±1.2个金颗粒/μm，而健康组织中为0.38±0.17个，p = 1.4×10）以及肿瘤细胞之间发现了循环免疫球蛋白G和超小超顺磁性氧化铁。总之，这强烈提示由巨胞饮作用介导的主动转运。为验证这种转运机制，用巨胞饮作用抑制剂阿米洛利对额外的大鼠进行处理，导致膜突起（66%）和巨胞饮体减少。然而，阿米洛利也会打开肿瘤紧密连接，使超小超顺磁性氧化铁有更大的外渗（注射后2小时磁共振成像信号增强35.7%）。总之，这些结果表明RG2胶质瘤模型中的超小超顺磁性氧化铁和免疫球蛋白G遵循由巨胞饮作用过程介导的主动外渗途径。阿米洛利似乎也是促进胶质瘤中化疗药物外渗的一种潜在策略。
