E-cadherin suppression directs cytoskeletal rearrangement and intraepithelial tumor cell migration in 3D human skin equivalents
E-cadherin suppression directs cytoskeletal rearrangement and intraepithelial tumor cell migration in 3D human skin equivalents
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DOI：
10.1038/jid.2008.102
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发表时间：
2008-10-01
影响因子：
6.5
通讯作者：
Garlick, Jonathan A.
中科院分区：
文献类型：
--
作者：
Alt-Holland, Addy;Shamis, Yulia;Garlick, Jonathan A.
在皮肤癌进展的早期阶段，细胞-细胞粘附的丧失、细胞迁移的激活和上皮内（IE）肿瘤细胞的行为之间的联系尚不清楚。目前的研究特点的迁移行为的鳞状细胞癌细胞系（HaCaT-II-4）后，E-钙粘蛋白抑制在两个二维，单层培养和人体皮肤等效物，模拟癌前病变。肿瘤细胞的迁移行为首先通过开发模拟跨上皮肿瘤细胞迁移的模型在3D组织背景下进行分析。我们发现，细胞粘附的损失使单个IE肿瘤细胞在正常角质形成细胞之间迁移成为间质侵袭的先决条件。为了进一步了解这种迁移行为，在2D单层培养中分析了E-钙粘蛋白缺陷细胞，并显示出改变的细胞结构和增强的膜扩散活性，这与周向肌动蛋白组织和非肌肉β肌动蛋白亚型的诱导有关。这些特征与增加的运动性和随机的个体细胞迁移相关，以响应刮伤。因此，E-钙粘蛋白介导的粘附的丧失导致获得增强细胞运动性的表型特性，并指导皮肤样组织从癌前病变向癌症的转变。
The link between loss of cell-cell adhesion, the activation of cell migration, and the behavior of intraepithelial (IE) tumor cells during the early stages of skin cancer progression is not well understood. The current study characterized the migratory behavior of a squamous cell carcinoma cell line (HaCaT-II-4) upon E-cadherin suppression in both 2D, monolayer cultures and within human skin equivalents that mimic premalignant disease. The migratory behavior of tumor cells was first analyzed in 3D tissue context by developing a model that mimics transepithelial tumor cell migration. We show that loss of cell adhesion enabled migration of single, IE tumor cells between normal keratinocytes as a prerequisite for stromal invasion. To further understand this migratory behavior, E-cadherin-deficient cells were analyzed in 2D, monolayer cultures and displayed altered cytoarchitecture and enhanced membrane protrusive activity that was associated with circumferential actin organization and induction of the nonmuscle, beta actin isoform. These features were associated with increased motility and random, individual cell migration in response to scrape-wounding. Thus, loss of E-cadherin-mediated adhesion led to the acquisition of phenotypic properties that augmented cell motility and directed the transition from the precancer to cancer in skin-like tissues.