Microfabricated collagen tracks facilitate single cell metastatic invasion in 3D.
Microfabricated collagen tracks facilitate single cell metastatic invasion in 3D.
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DOI：
10.1039/c3ib20196a
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发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
Reinhart-King CA
中科院分区：
文献类型：
--
作者：
Kraning-Rush CM;Carey SP;Lampi MC;Reinhart-King CA
虽然转移性癌细胞迁移所采用的机制仍然知之甚少，但已广泛接受的是，转移性癌细胞可以通过用基质金属蛋白酶（MMP）降解细胞外基质（ECM）来侵入肿瘤基质。虽然MMP抑制剂在动物模型中显示出预防转移的早期前景，但它们在临床上基本上失败了。最近，研究表明，一些癌细胞可以使用蛋白水解来机械地重新排列它们的ECM，以形成管状的“微轨道”，其他细胞可以在不使用MMPs的情况下跟随这些微轨道。我们推测，在次生细胞中的这种迁移模式可能是在次生细胞中没有内源性蛋白酶活性的情况下可能发生的迁移的一个例子。在这里，我们提出了一种技术来研究这种迁移在3D，胶原蛋白为基础的环境，模仿的大小和地形的轨道产生的蛋白水解活性癌细胞。使用延时相差显微镜，我们发现这些微轨道允许非侵入性MCF 10A乳腺上皮细胞的快速和持久迁移，这些细胞无法在3D胶原蛋白中迁移。此外，虽然高转移性MDAMB 231乳腺癌细胞能够侵入3D胶原基质，但在图案化的微轨道内接种诱导细胞迁移速度显著增加，而药理学MMP抑制不会降低细胞迁移速度。总之，这些数据表明，3D ECM内的微轨道可以以MMP-独立的方式促进细胞的迁移，并可能揭示MMP抑制剂面临的临床挑战的新见解。
While the mechanisms employed by metastatic cancer cells to migrate remain poorly understood, it has been widely accepted that metastatic cancer cells can invade the tumor stroma by degrading the extracellular matrix (ECM) with matrix metalloproteinases (MMPs). Although MMP inhibitors showed early promise in preventing metastasis in animal models, they have largely failed clinically. Recently, studies have shown that some cancer cells can use proteolysis to mechanically rearrange their ECM to form tube-like “microtracks” which other cells can follow without using MMPs themselves. We speculate that this mode of migration in the secondary cells may be one example of migration which can occur without endogenous protease activity in the secondary cells. Here we present a technique to study this migration in a 3D, collagen-based environment which mimics the size and topography of the tracks produced by proteolytically active cancer cells. Using time-lapse phase-contrast microscopy, we find that these microtracks permit the rapid and persistent migration of noninvasive MCF10A mammary epithelial cells, which are unable to otherwise migrate in 3D collagen. Additionally, while highly metastatic MDAMB231 breast cancer cells are able to invade a 3D collagen matrix, seeding within the patterned microtracks induced significantly increased cell migration speed, which was not decreased by pharmacological MMP inhibition. Together, these data suggest that microtracks within a 3D ECM may facilitate the migration of cells in an MMP-independent fashion, and may reveal novel insight into the clinical challenges facing MMP inhibitors.
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7.8
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