Cancer-Associated Fibroblast-Derived FGF7 Promotes Clear Cell Renal Cell Carcinoma Progression and Macrophage Infiltration

• Published in: Cells (Basel, Switzerland) Switzerland), 2024-11, Vol.13 (22), p.1824
• Main Authors: Jia, Man, Xie, Mingyu, Luo, Xixi, Wang, Huiping, Duan, Chunyan, Lai, Wanni, Dai, Rongyang, Wang, Ronghao
• Format: Article
• Language: English
• Subjects: AKT protein; Analysis; Animals; Antibodies; Antimitotic agents; Antineoplastic agents; CAFs; Cancer; Cancer therapies; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; ccRCC; Cell activation; Cell growth; Cell Line, Tumor; Cell Proliferation; Chromatin; Clear cell-type renal cell carcinoma; Development and progression; Disease Progression; FGF7; Fibroblast Growth Factor 7 - genetics; Fibroblast Growth Factor 7 - metabolism; Fibroblast growth factor receptor 7; Fibroblast growth factors; Fibroblasts; Gene Expression Regulation, Neoplastic; Gene regulation; Growth factors; Health aspects; Humans; Infiltration; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kinases; Macrophages; Macrophages - metabolism; Macrophages - pathology; Medical prognosis; Metastases; Metastasis; Mice; Molecular modelling; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Stat3 protein; STAT3 Transcription Factor - metabolism; Stromal cells; Therapeutic targets; Transcription activation; Tumor cells; Tumors
• ISSN: 2073-4409; 2073-4409
• 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.