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内皮细胞特异性LAT1切除使瘤血管系统正常化

Jun-Ichi Suehiro¹, Toru Kimura¹, Toshiyuki Fukutomi¹

¹Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.

|August 20, 2024

概括

向瘤内皮细胞中的LAT1载体,使血管系统正常化,并减少转移. 这涉及托芬剥夺,MEK/ERK通路激活和硫化生产,改善化疗治疗.

科学领域:

在瘤学瘤学.
血管生物学血管生物学
分子生物学分子生物学

背景情况:

瘤血管表现出独特的特征,包括系统L氨基酸载体LAT1在某些内皮细胞上的表达.
LAT1在氨基酸运输中发挥作用,可能会影响瘤微环境和转移.

研究的目的:

为了研究LAT1在瘤内皮细胞中的作用.
确定针对癌症中LAT1的治疗潜力.

主要方法:

产生的内皮细胞特异性的LAT1条件淘汰小鼠 (Slc7a5flox/flox;Cdh5-Cre-ERT2).
在细胞培养和动物模型中使用LAT1抑制剂 (nanvuranlat) 和诱导的酸盐剥夺.
分析了瘤血管形态,转移,炎症标志物 (VCAM1,E-selectin) 和细胞内信号通路 (MEK/ERK).

主要成果:

在内皮细胞中LAT1的有条件淘汰使瘤血管结构形状正常化并减少了肺转移.
LAT1抑制和托芬剥夺降低了HUVECs上的VCAM1和E-选择蛋白表达,减少了单细胞的附着.
托芬剥夺激活了MEK1/2-ERK1/2通路,导致囊氨酸γ酶 (CTH) 诱导.
通过CTH介导的硫化 (H2S) 生产有助于血管正常化和加强化疗输送.

结论:

LAT1是瘤内皮细胞功能和转移的关键调节者.
用抑制剂或基质剥夺向LAT1提供了癌症治疗的治疗策略.
该机制涉及H2S的生产,导致血管正常化和改善药物输送到瘤.

关键词:

氨基酸代谢氨基酸代谢血管新生的产生.内皮细胞是内皮细胞.交通运输交通运输交通运输交通运输血管生物学血管生物学

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