3D Collagen Alignment Limits Protrusions to Enhance Breast Cancer Cell Persistence
3D Collagen Alignment Limits Protrusions to Enhance Breast Cancer Cell Persistence
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DOI：
10.1016/j.bpj.2014.10.035
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发表时间：
2014-12-02
影响因子：
3.4
通讯作者：
Keely, Patricia J.
中科院分区：
文献类型：
--
作者：
Riching, Kristin M.;Cox, Benjamin L.;Keely, Patricia J.
乳房X线摄影致密乳腺组织的患者患乳腺癌的风险大大增加。致密的乳腺组织含有更多的基质胶原蛋白，这有助于增加基质硬度并改变正常的细胞反应。乳腺肿瘤内和周围的基质胶原经常与肿瘤边界垂直排列和重新定向。我们已经证明，排列的胶原蛋白预测乳腺癌患者的预后不良，并假设这是因为它通过提供细胞迁移出肿瘤的轨道来促进侵袭。然而，对齐可能促进迁移的机制尚不清楚。在这里，我们研究了基质刚度和排列对细胞迁移速度和持久性的贡献。将具有不同密度和排列的胶原基质的刚度的机械测量与3D微通道排列测定的结果进行比较，以量化细胞迁移。我们使用细胞迁移的计算模型进一步解释了实验结果。我们发现，胶原对齐赋予刚度增加，但不增加迁移细胞的速度。相反，对齐通过增加方向持久性和限制沿对齐纤维的突起沿着来提高迁移的效率，导致更大的行进距离。这些结果表明，基质拓扑结构，而不是刚度，是主要特征，对齐的基质可以通过3D胶原基质增强侵袭。
Patients with mammographically dense breast tissue have a greatly increased risk of developing breast cancer. Dense breast tissue contains more stromal collagen, which contributes to increased matrix stiffness and alters normal cellular responses. Stromal collagen within and surrounding mammary tumors is frequently aligned and reoriented perpendicular to the tumor boundary. We have shown that aligned collagen predicts poor outcome in breast cancer patients, and postulate this is because it facilitates invasion by providing tracks on which cells migrate out of the tumor. However, the mechanisms by which alignment may promote migration are not understood. Here, we investigated the contribution of matrix stiffness and alignment to cell migration speed and persistence. Mechanical measurements of the stiffness of collagen matrices with varying density and alignment were compared with the results of a 3D microchannel alignment assay to quantify cell migration. We further interpreted the experimental results using a computational model of cell migration. We find that collagen alignment confers an increase in stiffness, but does not increase the speed of migrating cells. Instead, alignment enhances the efficiency of migration by increasing directional persistence and restricting protrusions along aligned fibers, resulting in a greater distance traveled. These results suggest that matrix topography, rather than stiffness, is the dominant feature by which an aligned matrix can enhance invasion through 3D collagen matrices.