Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis
Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis
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DOI：
10.1073/pnas.0604460103
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发表时间：
2006-07-18
影响因子：
11.1
通讯作者：
Matsudaira, Paul
中科院分区：
文献类型：
--
作者：
Zaman, Muhammad H.;Trapani, Linda M.;Matsudaira, Paul
细胞在二维表面上的迁移是由对抗牵引力和粘附力之间的平衡决定的。虽然生物化学因素，如粘附受体和配体的浓度和结合，通过细胞粘附复合物的信号，和细胞骨架结构的组装/拆卸已在2D上下文中详细研究，影响细胞迁移的关键生化和生物物理参数在3D矩阵尚未定量研究。我们证明，除了附着力和牵引力，矩阵刚度是一个关键因素，影响细胞在3D运动。其中基质胶密度、纤连蛋白浓度和131整合素结合系统地变化的细胞迁移测定显示，在特定基质胶密度下，DU-145人前列腺癌细胞的迁移速度是牵引力和粘附力之间的平衡。然而，当生化参数，如基质配体和细胞整合素受体水平保持恒定时，最大细胞运动转移到表现出较小刚度的基质。这种行为与当前的2D模型相矛盾，但最近基于力的3D矩阵中细胞运动的计算模型预测。正如预期的那样，通过孔径远小于细胞尺寸的细胞外环境的这种3D运动性确实取决于蛋白水解活性，因为广谱基质金属蛋白酶（MMP）抑制剂限制DU-145细胞以及HT-1080纤维肉瘤细胞的迁移。据我们所知，我们的实验结果表明，发现了一组以前未描述的细胞和基质性质的平衡，这些性质决定了肿瘤细胞在3D环境中迁移的能力。
Cell migration on 2D surfaces is governed by a balance between counteracting tractile and adhesion forces. Although biochemical factors such as adhesion receptor and ligand concentration and binding, signaling through cell adhesion complexes, and cytoskeletal structure assembly/disassembly have been studied in detail in a 2D context, the critical biochemical and biophysical parameters that affect cell migration in 3D matrices have not been quantitatively investigated. We demonstrate that, in addition to adhesion and tractile forces, matrix stiffness is a key factor that influences cell movement in 3D. Cell migration assays in which Matrigel density, fibronectin concentration, and 131 integrin binding are systematically varied show that at a specific Matrigel density the migration speed of DU-145 human prostate carcinoma cells is a balance between tractile and adhesion forces. However, when biochemical parameters such as matrix ligand and cell integrin receptor levels are held constant, maximal cell movement shifts to matrices exhibiting lesser stiffness. This behavior contradicts current 2D models but is predicted by a recent force-based computational model of cell movement in a 3D matrix. As expected, this 3D motility through an extracellular environment of pore size much smaller than cellular dimensions does depend on proteolytic activity as broad-spectrum matrix metalloproteinase (MMP) inhibitors limit the migration of DU-145 cells and also HT-1080 fibrosarcoma cells. Our experimental findings here represent, to our knowledge, discovery of a previously undescribed set of balances of cell and matrix properties that govern the ability of tumor cells to migration in 3D environments.