Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling

• Published in: Tumor biology Vol. 39; no. 7; p. 1010428317712592
• Main Authors: Sun, Yuanzhen, Fan, Xiaoli, Zhang, Qing, Shi, Xiaoyu, Xu, Guangwei, Zou, Cuimin
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.07.2017; Sage Publications Ltd; IOS Press
• Subjects: Adult; Aged; Animals; Authorship; Cadherins - genetics; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cell growth; Cell Line, Tumor; Cell Movement - genetics; Cell proliferation; Cell Proliferation - genetics; E-cadherin; Enzyme-linked immunosorbent assay; Ethics; Female; Fibroblast growth factor 1; Fibroblast Growth Factor 1 - biosynthesis; Fibroblast Growth Factor 1 - genetics; Fibroblast growth factor receptor 4; Fibroblasts; Gene Expression Regulation, Neoplastic - genetics; Growth factors; Humans; Kinases; Malignancy; MAP kinase; Matrix Metalloproteinase 3 - biosynthesis; Matrix Metalloproteinase 3 - genetics; Mesenchyme; Metastases; Middle Aged; Neoplasm Invasiveness - genetics; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Penicillin; Phosphorylation; Polymerase chain reaction; Protein kinase; Proteins; Receptor, Fibroblast Growth Factor, Type 4 - biosynthesis; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Recombination; Reverse transcription; Signal Transduction; Snail Family Transcription Factors - biosynthesis; Snail Family Transcription Factors - genetics; Tumorigenesis; fibroblast growth factor-1; migration; cancer-associated fibroblasts; proliferation; invasion; Ovarian cancer
• ISSN: 1010-4283; 1423-0380
• DOI: 10.1177/1010428317712592

Ovarian cancer is the most lethal gynecologic malignancy, due to its high propensity for metastasis. Cancer-associated fibroblasts, as the dominant component of tumor microenvironment, are crucial for tumor progression. However, the mechanisms underlying the regulation of ovarian cancer cells by cancer-associated fibroblasts remain little known. Here, we first isolated cancer-associated fibroblasts from patients’ ovarian tissues and found that cancer-associated fibroblasts promoted SKOV3 cells’ proliferation, migration, and invasion. Fibroblast growth factor-1 was identified as a highly increased factor in cancer-associated fibroblasts compared with normal fibroblasts by quantitative reverse transcription polymerase chain reaction (~4.6-fold, p < 0.01) and ELISA assays (~4-fold, p < 0.01). High expression of fibroblast growth factor-1 in cancer-associated fibroblasts either naturally or through gene recombination led to phosphorylation of fibroblast growth factor receptor 4 in SKOV3 cells, which is followed by the activation of mitogen-activated protein kinase/extracellular signal–regulated protein kinase pathway and epithelial-to-mesenchymal transition–associated gene Snail1 and MMP3 expression. Moreover, treatment of SKOV3 cell with fibroblast growth factor receptor inhibitor PD173074 terminated cellular proliferation, migration, and invasion, reduced the phosphorylation level of fibroblast growth factor receptor 4, and suppressed the activation of mitogen-activated protein kinase/extracellular signal–regulated protein kinase pathway. In addition, the expression level of Snail1 and MMP3 was reduced, while the expression level of E-cadherin increased. These observations suggest a crucial role for cancer-associated fibroblasts and fibroblast growth factor-1/fibroblast growth factor receptor 4 signaling in the progression of ovarian cancer. Therefore, this fibroblast growth factor-1/fibroblast growth factor receptor 4 axis may become a potential target for the treatment of ovarian cancer.