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

Mingtian Wei,Jinliang Yang,Yangping Wu,Xiangbing Deng,Xiangzheng Chen,Wanbin He,Tinghan Yang,Ziqiang Wang

doi:10.18632/oncotarget.15040

Abstract

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 (α-SMA), and fibronectin, were increased after treatment of exosomes. In clinical samples test, TGF-β1 was found to be overexpressed in both malignant ascites and malignant ascites-derived exosomes, and the high volume of TGF-β1 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, α-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-β1 induced MMT.

Highlights

Exosomes are late endosomes-derived membrane vesicles with size ranging from 30 to 120 nm in diameter [1, 2]
TGF-β1 was found to be overexpressed in both malignant ascites and malignant ascites-derived exosomes, and the high volume of TGF-β1 may be responsible for peritoneum fibrosis
Peritoneal mesothelium is the alternative pathway for free tumor cells to colonize [12, 13]

Summary

Introduction

Exosomes are late endosomes-derived membrane vesicles with size ranging from 30 to 120 nm in diameter [1, 2]. As a star sub-cellular structure, tumor-derived exosomes display crucial roles in intercellular communications between tumor and stromal cells, and tumor and distant target cells or microenvironments, by selectively delivering its cargoes (membrane or inner www.impactjournals.com/oncotarget proteins, DNAs, and mRNAs) [5]. Pancreatic cancer-derived macrophage migration inhibitory factor (MIF)+ exosomes facilitate liver metastasis [6], and exosomal integrin α6β4 and α6β1 are associated with lung metastasis [7]. Carcinoma-associated fibroblasts (CAFs) are the prominent composition cell types which are involved in solid tumor seeding, angiogenesis, and formation of pre-metastatic niche to facilitate cancer cell dissemination [8]. In mechanism, transforming growth factor beta 1 (TGF-β1) mainly induces the conversion to CAFs via epithelial-mesenchymal transition (EMT), which facilitates the migration and invasion of tumor cells

Methods

Results

Conclusion