Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH 43210.
Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210.
Neoplasia. 2019 Jan;21(1):132-145. doi: 10.1016/j.neo.2018.10.010. Epub 2018 Dec 12.
The organization of the extracellular matrix has a profound impact on cancer development and progression. The matrix becomes aligned throughout tumor progression, providing "highways" for tumor cell invasion. Aligned matrix is associated with breast density and is a negative prognostic factor in several cancers; however, the underlying mechanisms regulating this reorganization remain poorly understood. Deletion of the tumor suppressor Pten in the stroma was previously shown to promote extracellular matrix expansion and tumor progression. However, it was unknown if PTEN also regulated matrix organization. To address this question, a murine model with fibroblast-specific Pten deletion was used to examine how PTEN regulates matrix remodeling. Using second harmonic generation microscopy, Pten deletion was found to promote collagen alignment parallel to the mammary duct in the normal gland and further remodeling perpendicular to the tumor edge in tumor-bearing mice. Increased alignment was observed with Pten deletion in vitro using fibroblast-derived matrices. PTEN loss was associated with fibroblast activation and increased cellular contractility, as determined by traction force microscopy. Inhibition of contractility abrogated the increased matrix alignment observed with PTEN loss. Murine mammary adenocarcinoma cells cultured on aligned matrices derived from Pten fibroblasts migrated faster than on matrices from wild-type fibroblasts. Combined, these data demonstrate that PTEN loss in fibroblasts promotes extracellular matrix deposition and alignment independently from cancer cell presence, and this reorganization regulates cancer cell behavior. Importantly, stromal PTEN negatively correlated with collagen alignment and high mammographic density in human breast tissue, suggesting parallel function for PTEN in patients.
细胞外基质的组织对癌症的发展和进展有深远的影响。在肿瘤进展过程中，基质会变得排列整齐，为肿瘤细胞的侵袭提供“高速公路”。排列整齐的基质与乳腺密度有关，并且是几种癌症的预后不良因素；然而，调节这种重排的潜在机制仍知之甚少。先前已经表明，基质中肿瘤抑制因子 Pten 的缺失会促进细胞外基质的扩张和肿瘤的进展。然而，尚不清楚 PTEN 是否也调节基质的组织。为了解决这个问题，使用了成纤维细胞特异性 Pten 缺失的小鼠模型来研究 PTEN 如何调节基质重塑。通过二次谐波产生显微镜观察到，Pten 缺失会促进正常腺体中的胶原与乳腺导管平行排列，并在荷瘤小鼠中进一步重塑为垂直于肿瘤边缘。在体外使用成纤维细胞衍生的基质进行实验时，也观察到 Pten 缺失会导致胶原排列更整齐。PTEN 缺失与成纤维细胞的激活和细胞收缩性增加有关，这可以通过牵引力显微镜来确定。抑制收缩性可以消除观察到的 Pten 缺失导致的基质排列增加。在源自 Pten 成纤维细胞的排列整齐的基质上培养的小鼠乳腺腺癌细胞比在源自野生型成纤维细胞的基质上迁移得更快。综合这些数据表明，成纤维细胞中 PTEN 的缺失会促进细胞外基质的沉积和排列，而与癌细胞的存在无关，这种重排调节癌细胞的行为。重要的是，基质中的 PTEN 与人类乳腺组织中的胶原排列和高乳腺密度呈负相关，提示在患者中 PTEN 具有平行功能。
