A Novel Role of E-Cadherin-Based Adherens Junctions in Neoplastic Cell Dissemination

• DOI: 10.1371/journal.pone.0133578
• Publication Date: 2015-07-24T18:18:43Z
• Authors: Svetlana N. Rubtsova; Irina Y. Zhitnyak; Natalya A. Gloush...
• Keywords: 0301 basic medicine; Science; Green Fluorescent Proteins; Nerve Tissue Proteins; Transfection; Cell Line; 03 medical and health sciences; Genes, Reporter; Transduction, Genetic; Animals; Neoplasm Invasiveness; RNA, Small Interfering; Cell Line, Transformed; Microscopy, Confocal; Microscopy, Video; Q; R; Transendothelial and Transepithelial Migration; Epithelial Cells; Adherens Junctions; Cadherins; Clone Cells; Rats; Mutation; Medicine; RNA Interference; Research Article

Using confocal microscopy, we analyzed the behavior of IAR-6-1, IAR1170, and IAR1162 transformed epithelial cells seeded onto the confluent monolayer of normal IAR-2 epithelial cells. Live-cell imaging of neoplastic cells stably expressing EGFP and of normal epithelial cells stably expressing mKate2 showed that transformed cells retaining expression of E-cadherin were able to migrate over the IAR-2 epithelial monolayer and invade the monolayer. Transformed IAR cells invaded the IAR-2 monolayer at the boundaries between normal cells. Studying interactions of IAR-6-1 transformed cells stably expressing GFP-E-cadherin with the IAR-2 epithelial monolayer, we found that IAR-6-1 cells established E-cadherin-based adhesions with normal epithelial cells: dot-like dynamic E-cadherin-based adhesions in protrusions and large adherens junctions at the cell sides and rear. A comparative study of a panel of transformed IAR cells that differ by their ability to form E-cadherin-based AJs, either through loss of E-cadherin expression or through expression of a dominant negative E-cadherin mutant, demonstrated that E-cadherin-based AJs are key mediators of the interactions between neoplastic and normal epithelial cells. IAR-6-1DNE cells expressing a dominant-negative mutant form of E-cadherin with the mutation in the first extracellular domain practically lost the ability to adhere to IAR-2 cells and invade the IAR-2 epithelial monolayer. The ability of cancer cells to form E-cadherin-based AJs with the surrounding normal epithelial cells may play an important role in driving cancer cell dissemination in the body.