Infiltrating mast cells promote renal cell carcinoma angiogenesis by modulating PI3K→︀AKT→︀GSK3β→︀AM signaling.
Infiltrating mast cells promote renal cell carcinoma angiogenesis by modulating PI3K→︀AKT→︀GSK3β→︀AM signaling.
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作者：
Chen Y;Li C;Xie H;Fan Y;Yang Z;Ma J;He D;Li L
从肿瘤微环境（tumor microenvironment， TME）中募集血管内皮细胞促进血管生成在肾细胞癌（renal cell carcinoma， RCC）的进展中起着关键作用。然而，TME中免疫细胞对RCC血管生成的潜在影响尚不清楚。在这里，我们发现肥大细胞的募集导致体外细胞系和体内小鼠模型中RCC血管生成增加。机制分析显示，RCC通过调节PI3K→AKT→GSK3β→AM信号募集肥大细胞。一项人类RCC样本的临床研究也表明，PI3K→AKT→GSK3β→AM信号通路的高表达与血管生成增加相关。通过特异性抑制剂阻断PI3K→AKT→GSK3β→AM信号通路导致肥大细胞募集减少，在异种移植小鼠模型中，通过AKT特异性抑制剂靶向浸润肥大细胞相关信号通路可抑制RCC血管生成。总之，这些结果确定了浸润性肥大细胞在RCC血管生成和转移中的新作用，并提出了针对这一新发现的信号通路治疗RCC的新策略。
The recruitment of vascular endothelial cells from the tumor microenvironment (TME) to promote angiogenesis plays key roles in the progression of renal cell carcinoma (RCC). The potential impact of immune cells in the TME on RCC angiogenesis, however, remains unclear. Here, we found that recruitment of mast cells resulted in increased RCC angiogenesis in both in vitro cell lines and in vivo mouse models. Mechanistic analyses revealed that RCC recruited mast cells by modulating PI3K→AKT→GSK3β→AM signaling. A clinical survey of human RCC samples also showed that higher expression of the PI3K→AKT→GSK3β→AM signaling pathway correlated with increased angiogenesis. Interruption of PI3K→AKT→GSK3β→AM signaling via specific inhibitors led to decreased recruitment of mast cells, and targeting this infiltrating mast cell-related signaling via an AKT-specific inhibitor suppressed RCC angiogenesis in xenograft mouse models. Together, these results identified a novel role of infiltrating mast cells in RCC angiogenesis and metastasis and suggest a new strategy for treating RCC by targeting this newly identified signaling pathway.