title: Mesothelial Cells Create a Novel Tissue Niche That Facilitates Gastric Cancer Invasion.
abstract: Peritoneal mesothelial cells (PMC) cover organ surfaces in the abdominal cavity. In this study, lineage tracing revealed that the PMCs guide cancer cell invasion in the gastric wall and in peritoneal metastatic lesions. Serosal PMCs covering the stomach surface entered the gastric wall to create a novel niche that favored gastric cancer cell invasion. PMC infiltration was induced by incorporation of cancer cell-derived, Wnt3a-containing extracellular vesicles. Infiltrated PMCs in turn promoted subserosal invasion of cancer cells. Mutual attraction between cancer cells and PMCs accelerated tumor invasion in the gastric wall, and PMC-led cancer cell invasion in disseminated tumors within the abdominal wall and diaphragm. Addition of the carboxyl terminus of Dickkopf-1 attenuated directional invasion of PMCs toward cancer cells both in vitro and in the gastric wall in vivo PMCs were sensitive to the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF), as ALDH activity is elevated in PMCs. Wnt3a upregulated ALDH, and addition of DSF inhibited the invasive properties of PMCs, whereas DSF pretreatment suppressed gastric infiltration of PMCs and subserosal invasion by cancer cells. Our results suggest that stabilization of PMCs may become an effective therapy for the prevention of local invasion and metastasis of gastric cancer. Cancer Res; 77(3); 684-95. ©2016 AACR.
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan. mastanak@med.akita-u.ac.jp.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Kuriyama
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Itoh
authors.affiliation: Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Maeda
authors.affiliation: Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Akiteru
authors.initials: A
authors.lastname: Goto
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.|Department of Life Science, Faculty and Graduate School of Engineering and Resource Science, Akita University, Akita, Japan.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Tamiya
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.affiliation: Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Namiko
authors.initials: N
authors.lastname: Aiba
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004848:Epithelium / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010537:Peritoneum / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D013274:Stomach Neoplasms / Q000473:pathology*; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D060509:Wnt3A Protein; D051176:beta Catenin