Role of Collagen Fiber Morphology on Ovarian Cancer Cell Migration Using Image-Based Models of the Extracellular Matrix
Role of Collagen Fiber Morphology on Ovarian Cancer Cell Migration Using Image-Based Models of the Extracellular Matrix
复制标题
基于细胞外基质图像模型的胶原纤维形态在卵巢癌细胞迁移中的作用
DOI：
10.3390/cancers12061390
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发表时间：
2020-06-01
期刊：
影响因子：
5.2
通讯作者：
Campagnola, Paul J.
中科院分区：
文献类型：
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作者：
Alkmin, Samuel;Brodziski, Rebecca;Campagnola, Paul J.
细胞外基质(ECM)的重塑在许多上皮性癌的发生发展中起重要作用。然而，胶原蛋白改变在卵巢癌中的生物学意义尚未得到很好的证实。在这里，我们基于卵巢肿瘤的高分辨率二次谐波(SHG)图像，使用组织工程支架研究了胶原纤维形态在癌细胞迁移中的作用。胶原基支架是通过多光子激发聚合(MPE)制备的，这是一种自由形式的3D方法，提供了亚微米级的特征尺寸(类似于0.5微米)。这种能力允许复制胶原纤维结构，我们构建了代表正常间质、高危组织、良性肿瘤和高级别肿瘤的模型。将这些细胞与正常细胞系和卵巢癌细胞系一起播种，以研究细胞类型和基质形态对迁移动力学的单独作用。初步发现，细胞-基质之间的相互作用，如运动性、细胞铺展、f-肌动蛋白排列、焦点黏附和钙粘附素的表达，主要由胶原纤维的形态决定，而不是最初的细胞类型。此外，我们发现，对于高度排列的高级别肿瘤模型中的细胞，这些方面都得到了增强。相反，在更随机的网状正常基质基质上观察到最弱的相应反应，部分排列的良性肿瘤和高危模型表现出中等行为。这些结果都与接触导向机制相一致。这些模型不能通过其他传统的制造方法来合成，我们建议这种方法将使癌症生物学中的各种研究成为可能。
Remodeling of the extracellular matrix (ECM) is an important part in the development and progression of many epithelial cancers. However, the biological significance of collagen alterations in ovarian cancer has not been well established. Here we investigated the role of collagen fiber morphology on cancer cell migration using tissue engineered scaffolds based on high-resolution Second-Harmonic Generation (SHG) images of ovarian tumors. The collagen-based scaffolds are fabricated by multiphoton excited (MPE) polymerization, which is a freeform 3D method affording submicron resolution feature sizes (similar to 0.5 mu m). This capability allows the replication of the collagen fiber architecture, where we constructed models representing normal stroma, high-risk tissue, benign tumors, and high-grade tumors. These were seeded with normal and ovarian cancer cell lines to investigate the separate roles of the cell type and matrix morphology on migration dynamics. The primary finding is that key cell-matrix interactions such as motility, cell spreading, f-actin alignment, focal adhesion, and cadherin expression are mainly determined by the collagen fiber morphology to a larger extent than the initial cell type. Moreover, we found these aspects were all enhanced for cells on the highly aligned, high-grade tumor model. Conversely, the weakest corresponding responses were observed on the more random mesh-like normal stromal matrix, with the partially aligned benign tumor and high-risk models demonstrating intermediate behavior. These results are all consistent with a contact guidance mechanism. These models cannot be synthesized by other conventional fabrication methods, and we suggest this approach will enable a variety of studies in cancer biology.