Malignant ascites-derived exosomes promote proliferation and induce carcinoma-associated fibroblasts transition in peritoneal mesothelial cells

Malignant ascites-derived exosomes have been demonstrated to participate in tumor metastasis. In peritoneal metastasis, normal mesothelial cells (MCs) can be converted into carcinoma-associated fibroblasts (CAFs) by mesothelial-mesenchymal transition (MMT). Herein, we evaluated the effect of malignant ascites-derived exosomes on peritoneal MCs in vitro and in vivo experiments to determine whether exosomes could educate MCs and contribute to peritoneal metastasis. Under the treatment of ascites-derived exosomes, peritoneal MCs showed increased ability to proliferate and migrate. Expression of CAFs specific proteins markers in MCs, including fibroblast activation protein (FAP), alpha-smooth muscle actin (alpha-SMA), and fibronectin, were increased after treatment of exosomes. In clinical samples test, TGF-beta 1 was found to be overexpressed in both malignant ascites and malignant ascites-derived exosomes, and the high volume of TGF-beta 1 may be responsible for peritoneum fibrosis. In addition, exosomes can increase xenograft tumor growth by suppressing the inhibitive ability on tumor cells by MCs. Besides, CAFs specific proteins markers including FAP, alpha-SMA, and vimentin were increased in clinical peritoneal biopsies. The immunohistochemical staining for mice tumor biopsies also revealed increased expression of fibronectin and FAP, along with decreased expression of E-cadherin and VCAM-1 after exosomes treatment. Thus, malignant ascites-derived exosomes may be of importance in the development of peritoneal metastasis by facilitating MCs to proliferate and convert into CAFs by TGF-beta 1 induced MMT.