内皮VEGFR2-PLCγ信号调节通过ENOS/Srcc通过血管透性和抗瘤免疫力
Elin Sjöberg1, Marit Melssen1, Mark Richards1
1Department of Immunology, Genetics and Pathology, Beijer and Science for Life Laboratories, Uppsala University, Uppsala, Sweden.
The Journal of clinical investigation
|August 31, 2023
概括
内皮脂酶Cγ (PLCγ) 通过破坏血管稳定,促进癌症的进展. 抑制这种途径可以增强抗瘤免疫力,并改善治疗反应.
科学领域:
- 血管生物学 血管生物学
- 癌症免疫学 癌症免疫学
- 分子信号传递是分子信号传递.
背景情况:
- 内皮脂酶Cγ (PLCγ) 对于血管发育至关重要,但其在成熟和病态血管,特别是癌症中的作用尚不清楚.
- PLCγ在各种人类癌症中高度表达,包括细胞癌 (RCC),其表达与血管生成和不良预后相关.
- 血管内皮生长因子受体2 (VEGFR2) 在酸Y1173 (pY1173) 的下游激活PLCγ.
研究的目的:
- 研究内皮PLCγ在癌症进展和抗瘤免疫中的作用.
- 阐明通过PLCγ信号影响内皮膜屏障功能和免疫细胞透的分子机制.
- 探索针对pY1173/PLCγ通路的治疗潜力.
主要方法:
- 在人类癌症组织中分析PLCγ表达,特别是RCC.
- 使用异合体Vegfr2Y1173F/+和内皮特异性的Plcg1淘汰 (Plcg1iECKO) 鼠标模型.
- 评估内皮屏障完整性,血管泄漏和免疫细胞透,以应对途径调节.
- 研究涉及Ca2+,蛋白激酶C,内皮氧化合成酶 (eNOS) 和Src.的下游信号通路.
主要成果:
- 在清晰细胞RCC中,高PLCγ表达与血管生成和不良预后相关,而低表达与免疫细胞激活有关.
- 对Vegfr2Y1173F或内皮PLCγ (Plcg1iECKO) 的遗传破坏稳定了内皮屏障,并减少了血管泄漏.
- 屏障稳定导致免疫抑制性细胞因子减少,B细胞,辅助T细胞和调节性T细胞的透减少,并改善对治疗的反应.
- 确定了pY1173/PLCγ/eNOS/Src通路,涉及Ca2+/PKC依赖的eNOS激活和Src介导的VE-cadherin酸化,作为内皮结扰乱的关键驱动因素.
结论:
- 内皮细胞PLCγ被激活在VEGFR2pY1173的下游,破坏内皮细胞屏障的稳定,导致瘤的进展.
- 这种途径通过改变瘤微环境并减少免疫细胞透来抑制抗瘤免疫力.
- 向pY1173/PLCγ通路是一种有前途的治疗策略,可以增强抗瘤免疫力并改善癌症治疗结果.
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