Tumor‐derived exosomes influence the cell cycle and cell migration of human esophageal cancer cell lines

• Published in: Cancer science Vol. 111; no. 12; pp. 4348 - 4358
• Main Authors: Matsumoto, Yasunori, Kano, Masayuki, Murakami, Kentaro, Toyozumi, Takeshi, Suito, Hiroshi, Takahashi, Masahiko, Sekino, Nobufumi, Shiraishi, Tadashi, Kamata, Toshiki, Ryuzaki, Takahiro, Hirasawa, Soichiro, Kinoshita, Kazuya, Matsubara, Hisahiro
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.12.2020; John Wiley and Sons Inc
• Subjects: Actin; Actins - genetics; Biomarkers; Cancer; Cell adhesion & migration; Cell culture; Cell cycle; Cell Cycle - genetics; Cell Line, Tumor; Cell migration; Cell Movement; Cell proliferation; Cell Proliferation - genetics; Disease Progression; DNA microarrays; Down-Regulation; Esophageal cancer; esophageal squamous cell carcinoma; Esophageal Squamous Cell Carcinoma - genetics; Esophageal Squamous Cell Carcinoma - pathology; Esophagus; exosome; Exosomes; Exosomes - physiology; Fluorescence; fucci; G1 Phase; Gene Expression; Gene set enrichment analysis; Genetic aspects; Humans; Life sciences; Medical prognosis; Medical research; Microscopy; migration; Neomycin; Optical Imaging; Original; Phenotype; Phenotypes; Proteins; Software; Squamous cell carcinoma; Time Factors; Tumor cell lines; Tumor cells; Tumors; Ubiquitination; Ultracentrifugation; Up-Regulation; Wound Healing; migration; esophageal squamous cell carcinoma; cell cycle; exosome; fucci; gene expression
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14660

Our laboratory previously reported the usefulness as biomarkers of exosomes in the plasma of esophageal squamous cell carcinoma (ESCC) patients. However, the influence of tumor‐derived exosomes on the tumor itself and underlying mechanisms remain unclear. We here report changes in the phenotype and gene expression when cancer cells exist in an environment with tumor‐derived exosomes. The exosomes were isolated from the culture medium of human ESCC cells (TE2, T.Tn) by ultracentrifugation; cell proliferation assay, wound‐healing assay, and fluorescence imaging of the cell cycle were performed to clarify the phenotypic changes in the high concentration of tumor‐derived exosomes. Gene expression changes were also assessed by mRNA microarray, and the data were analyzed by gene set enrichment analysis (GSEA). The data revealed that the proliferation of both TE2 and T.Tn was inhibited, and cell migration ability was upregulated in the exosome exposure group (P < .05). Fluorescence imaging using a fluorescent ubiquitination‐based cell cycle indicator expressing ESCC cells revealed that the ratio of G1‐phase cells was significantly increased in the exosome exposure group (P < .05). Findings of the GSEA clarified that high‐density exposure of cancer‐derived exosomes to their parent cancer cells downregulated the expression of genes related to cell proliferation and cell cycle, and upregulated the expression of genes related to actin filament length and extracellular structure organization. In conclusion, an environment of high‐density tumor‐derived exosomes induces changes in the gene expression and phenotype of tumor cells and may lead to tumor progression or malignant transformation. The wound closure rate was compared between groups with or without cancer‐derived exosome exposure. There was a significant difference between 10 μg/mL exosome concentration and control at 12 and 24 h in both TE2 and T.Tn (P < .05).