Abstract
Chitosan is sensitive to environmental pH values due to its electric property. This study investigates whether the pH-responsive chitosan assay can provide a simple method to evaluate the aggressive behavior of cancer cells with cell detachment ratio. The epithelial–mesenchymal transition (EMT) is induced with transforming growth factor-β1 (TGF-β1) in the human non-small cell lung cancer cell line (A549). EMT-induced cells and untreated cells are cultured on chitosan substrates at pH 6.99 for 24 h, followed by pH 7.65 for 1 h. The cell detachment ratio (CDR) on pH-responsive chitosan rises with an increasing of the TGF-β1 concentration. The protein array reveals that the expression levels of the α2, α3, α5, β2, and β3 integrins are higher in EMT-induced A549 cells than in untreated cells. A further inhibition assay shows that adding β3 integrin blocking antibodies significantly decreases the CDR of EMT-induced cells from 32.7 ± 5.7% to 17.8 ± 2.1%. The CDR of mesenchymal-type lung cancer cells increases on pH-responsive chitosan through the β3 integrin. Notably, the CDR can be theoretically predicted according to the individual CDR on the pH-responsive chitosan surface, irrespective of heterogeneous cell mixture. The pH-responsive chitosan assay serves as a simple in vitro model to investigate the aggressive behavior of lung cancer including the heterogeneous cell population.
Highlights
Cancer has become the top leading cause of death in recent years
This study aims to investigate the detachment of mesenchymal-type lung cancer on pH-responsive chitosan, and it further elucidates the detachment mechanism
Phase contrast microscopy revealed that untreated A549 cells, a cell line of human non-small cell lung cancer, on the tissue culture polystyrene (TCPS) had triangle-like forms and were mostly in aggregation in controls (Figure 1A)
Summary
Cancer has become the top leading cause of death in recent years. Tumor metastasis is a major factor in the severity of cancer and seems to be triggered by a specific mechanism called the epithelial–mesenchymal transition (EMT). The EMT plays a significant role in tumor metastasis. Most cancer cells at the original tumor location are epithelial-type cells that are stable and immobile. Cells undergoing the EMT become mesenchymal-type circulating tumor cells, which are more aggressive and have a better migratory ability. The regulation of cell migration requires the formation of focal adhesion and intermediate adhesion strength with the underlying matrix [1]. Integrins are a family of transmembrane receptors comprising two subunits, α and β. Researchers have identified the 18α and 8β subunits in mammals, subunits which can form at least 24 different integrin heterodimers [2]
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