Exosomes in ascites from patients with human pancreatic cancer enhance remote metastasis partially through endothelial-mesenchymal transition

• Published in: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 2023-06, Vol.23 (4), p.377-388
• Main Authors: Kimoto, Ai, Kadoi, Yusuke, Tsuruda, Taisei, Kim, Yong-Sik, Miyoshi, Makoto, Nomoto, Yuna, Nakata, Yuna, Miyake, Mutsumi, Miyashita, Kumiko, Shimizu, Kazuya, Ajiki, Tetsuo, Hori, Yuichi
• Format: Article
• Language: English
• Subjects: Animals; Ascites - pathology; Cell Line, Tumor; Endothelial Cells - pathology; Endothelial-to-mesenchymal transition; Exosome; Exosomes; Humans; Metastasis; Mice; Mice, Nude; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; Permeability
• ISSN: 1424-3903; 1424-3911
• DOI: 10.1016/j.pan.2023.04.002

Despite advances in multidisciplinary treatment, the prognosis of pancreatic cancer remains poor. Since distant metastasis defines prognosis, elucidation of the mechanism of metastasis is important for improving survival. Exosomes are extracellular secretory vesicles and are responsible for intercellular communication. In this study, we investigated whether exosomes secreted by human pancreatic cancer cells are involved in promoting distant metastasis of cancer and the mechanism that underlies the promotion of metastasis. Exosomes were isolated from ascites of a patient with pancreatic cancer and a patient with liver cirrhosis as a control. Three days after the administration of exosomes to nude mice, GFP-labeled human pancreatic cancer cells were injected via the spleen or tail vein, and then the liver and lungs were histologically analyzed. To elucidate the mechanism, vascular permeability was estimated using FITC-dextran in place of pancreatic cancer cells in vivo and human umbilical vascular endothelial cells (HUVECs) were used to analyze vascular permeability and the induction of endothelial-mesenchymal transition (EndMT) in vitro. Distant metastasis and vascular permeability were significantly enhanced in mice treated with exosomes from pancreatic cancer patients in comparison to exosomes from a control patient in vivo. In addition, exosomes from pancreatic cancer patients significantly enhanced vascular permeability and the induction of EndMT in HUVECs in vitro. Exosomes derived from pancreatic cancer cells form a pre-metastatic niche and promote the extravasation and colonization of pancreatic cancer cells to remote organs, partially through endothelial-mesenchymal transition.