title: Therapeutic adenoviral gene transfer of a glycosyltransferase for prevention of peritoneal dissemination and metastasis of gastric cancer.
abstract: Increased expression of sialyl Lewis(x/a) carbohydrates, ligands for E-selectin, correlates with clinically advanced stages and metastasis of gastric and colon cancers. In contrast, Sd(a) carbohydrate is abundantly detected in the normal gastrointestinal mucosa but dramatically reduced or lost in cancer tissues. A glycosyltransferase, β1,4N-acetylgalactosaminyltransferase 2 (B4GALNT2) that catalyzes Sd(a) carbohydrate synthesis, is silenced in cancer. In the present study, we aimed at reducing the expression of sialyl Lewis(x/a) of cancer cells in vivo by forced expression of B4GALNT2 and Sd(a), thereby preventing dissemination/metastasis, especially metastasis triggered by surgical maneuvers. We used a fiber-modified adenovirus (Ad) vector that contained a chimeric construct with a serotype 5 shaft and a serotype 3 knob. Using this Ad5/3 vector, we successfully introduced the B4GALNT2 gene into a human gastric cancer cell line KATO III in vitro and confirmed replacement of sialyl Lewis(x) to Sd(a) with a decrease in E-selectin-dependent adhesion. Administration of Ad5/3-B4GALNT2 vectors into the peritoneal cavity of mice after inoculation of KATO III cells with laparotomy significantly reduced the incidence of metastasis. Our results indicate that the transfer of a single gene encoding B4GALNT2 modified carbohydrate chains of cancer cells in vivo and decreased tumor dissemination and metastasis.
authors.affiliation: 1] Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan [2] CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: Y I
authors.initials: YI
authors.lastname: Kawamura
authors.affiliation: Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Adachi
authors.affiliation: Division of Human Gene Therapy, Departments of Medicine, Obstetrics and Gynecology, Surgery, Pathology, and the Gene Therapy Center at UAB, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Curiel
authors.affiliation: 1] Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan [2] Department of Biochemistry, School of Allied Health Sciences, Kitasato University Graduate School of Medical Sciences, Kanagawa, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Kawashima
authors.affiliation: 1] CREST, Japan Science and Technology Agency, Tokyo, Japan [2] Program of Molecular Pathology, Aichi Cancer Center, Nagoya, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Kannagi
authors.affiliation: Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Nishimoto
authors.affiliation: 1] Department of Gastroenterology, Research Center for Hepatitis and Immunology, Research Institute, National Center for Global Health and Medicine, Chiba, Japan [2] CREST, Japan Science and Technology Agency, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Dohi
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D036022:Capsid Proteins / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics*; D016695:Glycosyltransferases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D010537:Peritoneum / Q000473:pathology; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D036022:Capsid Proteins; D019040:E-Selectin; C018315:hexon capsid protein, Adenovirus; D016695:Glycosyltransferases