title: Peritoneal dissemination is inhibited by treatment with antibodies against CD44H, beta(1) integrin, and carcinostatic agents in NUGC-4 human gastric cancer cells.
abstract: Peritoneal dissemination frequently occurs after surgery in patients with gastric cancer. The presence of peritoneal metastasis after surgery affects the prognosis, therefore, a way must be found to effectively prevent the development of peritoneal dissemination. Very little is known about the biochemical processes involved in the initial attachment of gastric cancer cells to peritoneal mesothelial cells. We conducted in vitro and in vivo studies to assess the role of adhesion molecules and TGF-beta 1 in this process, using 4 gastric cancer cell lines. NUGC-4 cells, which disseminate early after inoculation into the abdominal cavity of nude mice, predominantly expressed CD44H and beta(1) integrin. We found that NUGC-4 cells adhered to monolayers of mesothelial cells more firmly than other cell lines. Adhesion of NUGC-4 cells to mesothelial cells was partially inhibited by antibodies against CD44H or the beta(1) subunit of integrin, and was completely blocked by a combination of these 2 antibodies. Treatment with ligands for CD44H and beta(1) integrin also inhibited this adhesion. In the NUGC-4 cell culture medium, larger amounts of transforming growth factor beta 1(TGF-beta 1) was detected in proportion to the increase in cancer cells than in the other cell lines. TGF-beta 1 increased the expression of CD44H in NUGC-4 cells and in mesothelial cells, and augmented the adhesion and implantation of NUGC-4 cells to mesothelial cells accompanied by accumulation of extracellular matrix (ECM) components. Carcinostatic agents decreased the expression of CD44H but increased the expression of E-cadherin in NUGC-4 cells. Treatment with carcinostatic agents and antibodies against CD44H and beta(1) integrin inhibited the dissemination of NUGC-4 cells in the peritoneal cavity of nude mice, and prolonged their survival time. These findings suggest that CD44H and integrins mediate in the initial attachment of gastric cancer cells to mesothelial cells, and TGF-beta 1 participates in the promotion of the disease. It is possible that a treatment strategy that interferes with CD44H or integrins function and increases the functions of E-cadherin immediately after surgery may result in the decreased intra-abdominal spread of gastric cancer.
authors.affiliation: AICHI CANC CTR,RES INST,LAB EXPT PATHOL,NAGOYA,AICHI 464,JAPAN.
authors.forename: T
authors.initials: T
authors.lastname: Nakashio
authors.forename: T
authors.initials: T
authors.lastname: Narita
authors.forename: S
authors.initials: S
authors.lastname: Akiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Kasai
authors.forename: K
authors.initials: K
authors.lastname: Kondo
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: H
authors.initials: H
authors.lastname: Takagi
authors.forename: R
authors.initials: R
authors.lastname: Kannagi