Pigment epithelium-derived factor inhibits lung cancer migration and invasion by upregulating exosomal thrombospondin 1

• Published in: Cancer letters 2019-02, Vol.442, p.287-298
• Main Authors: Huang, Wen-Tsung, Chong, Inn-Wen, Chen, Hsiu-Lin, Li, Chia-Yang, Hsieh, Chong-Chao, Kuo, Hsuan-Fu, Chang, Chia-Yuan, Chen, Yung-Hsiang, Liu, Yu-Peng, Lu, Chi-Yu, Liu, Yu-Ru, Liu, Po-Len
• Format: Article
• Language: English
• Subjects: Alpha-smooth muscle actin; Angiogenesis; Cell adhesion & migration; Cell aggregation; Cell migration; Cytoskeletal remodeling; Cytoskeleton; Epithelium; Exosome; Exosomes; Invasion; Lung cancer; Metastases; Metastasis; Microscopy; Migration; Motility; Non-small cell lung cancer; Non-small cell lung carcinoma; NSCLC; PEDF; Pigment epithelium-derived factor; Proteins; Secretion; THBS1; Thrombospondin; Thrombospondin 1; Tumorigenicity; Xenografts; α-SMA
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.10.031

Exosomes are implicated in cancer cell development, migration and invasion. Pigment epithelium-derived factor (PEDF) is a secreted anticancer protein that can regulate lung cancer progression; however, the role of PEDF in non-small cell lung cancer (NSCLC), including metastasis and cancer cell-derived exosome secretion, is unclear. In this study, we analyzed the effects of PEDF on exosome-mediated migration, invasion, and tumorigenicity of cultured NSCLC cells. The results showed that PEDF overexpression significantly reduced NSCLC invasion and migration, while inducing cell aggregation, whereas PEDF knockdown had the opposite effects. Exosomes from NSCLC cells treated with recombinant PEDF had a significantly reduced ability to promote cancer cell motility, migration, and invasion compared to exosomes from untreated cells. Exosomes from PEDF-treated cells contained thrombospondin 1 (THBS1), which inhibited cytoskeletal remodeling and exosome-induced lung cancer cell motility, migration, and invasion. Furthermore, PEDF-overexpressing NSCLC cells formed smaller xenograft tumors with higher THBS1 expression compared to control tumors. Our findings indicate that PEDF decreases the metastatic potential of NSCLC cells through regulation of THBS1 release in cancer cell-derived exosomes, thus uncovering a new mechanism of lung cancer progression. •PEDF induces aggregation and reduces invasion and migration of lung cancer cells.•Exosomes from PEDF-treated cancer cells inhibit metastatic behavior of NSCLC cells.•PEDF-expressing NSCLC cells have reduced tumorigenicity in vivo.•PEDF increases thrombospondin 1 content in lung cancer cell-derived exosomes.•Thrombospondin 1 inhibits exosome-induced lung cancer cell migration and invasion.