Abstract
Collective cell migration of epithelial tumor cells is one of the important factors for elucidating cancer metastasis and developing novel drugs for cancer treatment. Especially, new roles of E-cadherin in cancer migration and metastasis, beyond the epithelial–mesenchymal transition, have recently been unveiled. Here, we quantitatively examined cell motility using micropatterned free edge migration model with E-cadherin re-expressing EC96 cells derived from adenocarcinoma gastric (AGS) cell line. EC96 cells showed increased migration features such as the expansion of cell islands and straightforward movement compared to AGS cells. The function of tight junction proteins known to E-cadherin expression were evaluated for cell migration by knockdown using sh-RNA. Cell migration and straight movement of EC96 cells were reduced by knockdown of ZO-1 and claudin-7, to a lesser degree. Analysis of the migratory activity of boundary cells and inner cells shows that EC96 cell migration was primarily conducted by boundary cells, similar to leader cells in collective migration. Immunofluorescence analysis showed that tight junctions (TJs) of EC96 cells might play important roles in intracellular communication among boundary cells. ZO-1 is localized to the base of protruding lamellipodia and cell contact sites at the rear of cells, indicating that ZO-1 might be important for the interaction between traction and tensile forces. Overall, dynamic regulation of E-cadherin expression and localization by interaction with ZO-1 protein is one of the targets for elucidating the mechanism of collective migration of cancer metastasis.
Highlights
Cell migration is essential for animal growth and physiological activity; the movements of various cell types have been investigated [1] and many cells in tissues such as developing neural and vasculatures or epithelial cells in the wound healing are known to migrate collectively rather than individually [2]
We evaluated the function of cell-cell junctions by E-cadherin during collective cell migration and studied the basic mechanism of Tight junctions (TJs) formation by ZO-1 and CLDN7 in the directionality of boundary cells within the cell collectives
To evaluate the effect of re-expression of E-cadherin on cell migration, we analyzed cell motility with a cell island model in which the number and density of clustered cells were controlled using a pattern of homogeneous size and shape (Figure 1a)
Summary
Cell migration is essential for animal growth and physiological activity; the movements of various cell types have been investigated [1] and many cells in tissues such as developing neural and vasculatures or epithelial cells in the wound healing are known to migrate collectively rather than individually [2]. The spread of tumor cells in epithelial tissues such as squamous carcinoma is known to be associated with the collective migration of cells [2,3,4]. Collective migration of cancer cells reflects movements of epithelial cells and can occur in the absence of the epithelial–mesenchymal transition (EMT), whereas individual cell migration occurs with the EMT like the movement of mesenchymal cells [5,6,7].
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