Hammer Anisha M, Sizemore Gina M, Shukla Vasudha C, Avendano Alex, Sizemore Steven T, Chang Jonathan J, Kladney Raleigh D, Cuitiño Maria C, Thies Katie A, Verfurth Quinn, Chakravarti Arnab, Yee Lisa D, Leone Gustavo, Song Jonathan W, Ghadiali Samir N, Ostrowski Michael C
The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, USA.
Department of Biomedical Engineering, The Ohio State University, Columbus, OH, 43210, USA.
Neoplasia. 2017 Jun;19(6):496-508. doi: 10.1016/j.neo.2017.04.004. Epub 2017 May 11.
The extracellular matrix (ECM) is critical for mammary ductal development and differentiation, but how mammary fibroblasts regulate ECM remodeling remains to be elucidated. Herein, we used a mouse genetic model to activate platelet derived growth factor receptor-alpha (PDGFRα) specifically in the stroma. Hyperactivation of PDGFRα in the mammary stroma severely hindered pubertal mammary ductal morphogenesis, but did not interrupt the lobuloalveolar differentiation program. Increased stromal PDGFRα signaling induced mammary fat pad fibrosis with a corresponding increase in interstitial hyaluronic acid (HA) and collagen deposition. Mammary fibroblasts with PDGFRα hyperactivation also decreased hydraulic permeability of a collagen substrate in an in vitro microfluidic device assay, which was mitigated by inhibition of either PDGFRα or HA. Fibrosis seen in this model significantly increased the overall stiffness of the mammary gland as measured by atomic force microscopy. Further, mammary tumor cells injected orthotopically in the fat pads of mice with stromal activation of PDGFRα grew larger tumors compared to controls. Taken together, our data establish that aberrant stromal PDGFRα signaling disrupts ECM homeostasis during mammary gland development, resulting in increased mammary stiffness and increased potential for tumor growth.
细胞外基质（ECM）对乳腺导管发育和分化至关重要，但乳腺成纤维细胞如何调节ECM重塑仍有待阐明。在此，我们使用小鼠遗传模型在基质中特异性激活血小板衍生生长因子受体α（PDGFRα）。乳腺基质中PDGFRα的过度激活严重阻碍青春期乳腺导管形态发生，但不中断小叶腺泡分化程序。基质中PDGFRα信号增加诱导乳腺脂肪垫纤维化，同时间质透明质酸（HA）和胶原蛋白沉积相应增加。在体外微流控装置分析中，PDGFRα过度激活的乳腺成纤维细胞也降低了胶原底物的水力渗透性，通过抑制PDGFRα或HA可减轻这种情况。通过原子力显微镜测量，该模型中出现的纤维化显著增加了乳腺的整体硬度。此外，与对照组相比，在PDGFRα基质激活的小鼠脂肪垫中原位注射的乳腺肿瘤细胞生长出更大的肿瘤。综上所述，我们的数据表明，异常的基质PDGFRα信号在乳腺发育过程中破坏了ECM稳态，导致乳腺硬度增加和肿瘤生长潜力增加。
