Cancer‐associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. In the present study, we investigated the role for CAFs in breast cancer progression and underlying molecular mechanisms. Human breast cancer MDA‐MB‐231 cells treated with the CAF‐conditioned media manifested a more proliferative phenotype, as evidenced by enhanced messenger RNA (mRNA) expression of Cyclin D1, c‐Myc, and proliferating cell nuclear antigen. Analysis of data from The Cancer Genome Atlas revealed that fibroblast growth factor‐2 (FGF2) expression was well correlated with the presence of CAFs. We noticed that the mRNA level of FGF2 in CAFs was higher than that in normal fibroblasts. FGF2 exerts its biological effects through interaction with FGF receptor 1 (FGFR1). In the breast cancer tissue array, 42% estrogen receptor‐negative patients coexpressed FGF2 and FGFR1, whereas only 19% estrogen receptor‐positive patients exhibited coexpression. CAF‐stimulated MDA‐MB‐231 cell migration and invasiveness were abolished when FGF2‐neutralizing antibody was added to the conditioned media of CAFs. In a xenograft mouse model, coinjection of MDA‐MB‐231 cells with activated fibroblasts expressing FGF2 dramatically enhanced tumor growth, and this was abrogated by silencing of FGFR1 in cancer cells. In addition, treatment of MDA‐MB‐231 cells with FGF2 enhanced expression of Cyclin D1, a key molecule involved in cell cycle progression. FGF2‐induced cell migration and upregulation of Cyclin D1 were abolished by siRNA‐mediated FGFR1 silencing. Taken together, the above findings suggest that CAFs promote growth, migration and invasion of MDA‐MB‐231 cells via the paracrine FGF2‐FGFR1 loop in the breast tumor microenvironment.

中文翻译：

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成纤维细胞生长因子2（衍生自癌症相关的成纤维细胞）通过FGFR1信号传导刺激人乳腺癌细胞的生长和进程。

癌症相关的成纤维细胞（CAF）构成了肿瘤微环境的主要部分。在本研究中，我们调查了CAF在乳腺癌进展和潜在分子机制中的作用。用CAF条件培养基处理的人乳腺癌MDA-MB-231细胞表现出更强的增殖表型，细胞周期蛋白D1，c-Myc的信使RNA（mRNA）表达增强和增殖的细胞核抗原证明了这一点。癌症基因组图谱的数据分析表明，成纤维细胞生长因子2（FGF2）的表达与CAF的存在密切相关。我们注意到，CAFs中FGF2的mRNA水平高于正常成纤维细胞。FGF2通过与FGF受体1（FGFR1）相互作用发挥其生物学作用。在乳腺癌组织阵列中，42％的雌激素受体阴性患者共表达FGF2和FGFR1，而只有19％的雌激素受体阳性患者表现出共表达。将FGF2中和抗体添加到CAF的条件培养基中后，就消除了CAF刺激的MDA-MB-231细胞迁移和侵袭性。在异种移植小鼠模型中，MDA-MB-231细胞与表达FGF2的活化成纤维细胞共注射可显着增强肿瘤的生长，而癌细胞中FGFR1的沉默可消除肿瘤的生长。此外，用FGF2处理MDA-MB-231细胞可增强细胞周期蛋白关键分子Cyclin D1的表达。siRNA介导的FGFR1沉默消除了FGF2诱导的细胞迁移和细胞周期蛋白D1的上调。综上所述，以上发现表明CAF可以促进增长，