Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou 646000, China.
Department of Genetics, Xuzhou Medical University, Xuzhou 221004, China.
Cells. 2024 Nov 5;13(22):1824. doi: 10.3390/cells13221824.
As the predominant stromal cells in the ccRCC surrounding environment, cancer-associated fibroblasts (CAFs) have been established as supportive of tumor growth. However, the detailed molecular mechanisms underlying the supporting role of CAFs in ccRCC have not been well characterized. Evidence from the clustering consensus analysis, single-cell analysis, and the experimental results illustrate that CAF-derived FGF7 plays a crucial role as a signaling mediator between CAFs and ccRCC tumor cells. Mechanistically, CAF-derived FGF7 triggers AKT activation to promote cell growth and cell invasion of ccRCC tumor cells. As a response, ccRCC tumor cells stimulate STAT3-mediated transcriptional regulation, directly increasing FGF7 expression at the chromatin level in CAFs. Moreover, there exists a positive clinical correlation between the abundance of CAFs, FGF7 expression, and the infiltration of M2 type macrophages. The RENCA in vivo mouse model also confirmed that FGF7 depletion could impede RCC development by reducing the recruitment of M2 type macrophages. Overall, this study delineates a key signaling axis governing the crosstalk between CAFs and ccRCC tumor cells, highlighting FGF7 as a promising therapeutic target of ccRCC.
作为 ccRCC 周围环境中的主要基质细胞，癌症相关成纤维细胞 (CAFs) 已被确定为支持肿瘤生长的细胞。然而，CAFs 在 ccRCC 中支持作用的详细分子机制尚未得到很好的描述。聚类共识分析、单细胞分析和实验结果的证据表明，CAF 衍生的 FGF7 作为 CAFs 和 ccRCC 肿瘤细胞之间的信号介质发挥着关键作用。从机制上讲，CAF 衍生的 FGF7 触发 AKT 激活，促进 ccRCC 肿瘤细胞的生长和细胞侵袭。作为一种反应，ccRCC 肿瘤细胞刺激 STAT3 介导的转录调节，直接增加 CAFs 染色质水平上的 FGF7 表达。此外，CAFs 的丰度、FGF7 表达和 M2 型巨噬细胞的浸润之间存在正相关的临床相关性。RENCA 体内小鼠模型也证实，通过减少 M2 型巨噬细胞的募集，FGF7 的耗竭可以阻碍 RCC 的发展。总的来说，这项研究描绘了一个关键的信号轴，它控制着 CAFs 和 ccRCC 肿瘤细胞之间的串扰，突出了 FGF7 作为 ccRCC 有前途的治疗靶点。
