title: Exosomes Promote Ovarian Cancer Cell Invasion through Transfer of CD44 to Peritoneal Mesothelial Cells.
abstract: Epithelial ovarian cancer (EOC) cells metastasize within the peritoneal cavity and directly encounter human peritoneal mesothelial cells (HPMC) as the initial step of metastasis. The contact between ovarian cancer cells and the single layer of mesothelial cells involves direct communications that modulate cancer progression but the mechanisms are unclear. One candidate mediating cell-cell communications is exosomes, 30-100 nm membrane vesicles of endocytic origin, through the cell-cell transfer of proteins, mRNAs, or microRNAs. Therefore, the goal was to mechanistically characterize how EOC-derived exosomes modulate metastasis. Exosomes from ovarian cancer cells were fluorescently labeled and cocultured with HPMCs which internalized the exosomes. Upon exosome uptake, HPMCs underwent a change in cellular morphology to a mesenchymal, spindle phenotype. CD44, a cell surface glycoprotein, was found to be enriched in the cancer cell-derived exosomes, transferred, and internalized to HPMCs, leading to high levels of CD44 in HPMCs. This increased CD44 expression in HPMCs promoted cancer invasion by inducing the HPMCs to secrete MMP9 and by cleaning the mesothelial barrier for improved cancer cell invasion. When CD44 expression was knocked down in cancer cells, exosomes had fewer effects on HPMCs. The inhibition of exosome release from cancer cells blocked CD44 internalization in HPMCs and suppressed ovarian cancer invasion. In ovarian cancer omental metastasis, positive CD44 expression was observed in those mesothelial cells that directly interacted with cancer cells, whereas CD44 expression was negative in the mesothelial cells remote from the invading edge. This study indicates that ovarian cancer-derived exosomes transfer CD44 to HPMCs, facilitating cancer invasion.
  
  
  
  Mechanistic insight from the current study suggests that therapeutic targeting of exosomes may be beneficial in treating ovarian cancer. Mol Cancer Res; 15(1); 78-92. ©2016 AACR.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. daasawada@gyne.med.osaka-u.ac.jp.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Kinose
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Aska
authors.initials: A
authors.lastname: Toda
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Nakatsuka
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Mabuchi
authors.affiliation: Department of Obstetrics and Gynecology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Ken-Ichirou
authors.initials: KI
authors.lastname: Morishige
authors.affiliation: Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kurachi
authors.affiliation: Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, Illinois.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D002450:Cell Communication; D045744:Cell Line, Tumor; D048430:Cell Shape; D015536:Down-Regulation; D004790:Enzyme Induction; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000473:pathology*; D055354:Exosomes / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial; D009852:Omentum / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D010537:Peritoneum / Q000473:pathology*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases