Peritoneal dissemination frequently occurs after surgery in patients with gastric cancer. The presence of peritoneal metastasis after surgery affects prognosis. 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-b1 in this process, using 4 cell lines derived from human gastric cancers. NUGC-4 cells, which disseminate early after inoculation into the abdominal cavity of nude mice, predominantly express CD44H and b 1 integrin. We found that NUGC-4 cells adhered to monolayers of mesothelial cells more firmly than to other cell lines.
Adhesion of NUGC-4 cells to mesothelial cells was partially inhibited by antibodies against CD44H or
the b 1 subunit of integrin and was completely blocked by a combination of these 2 antibodies. Treatment with ligands for CD44H and b 1 integrin also inhibited adhesion. In the NUGC-4 cell culture medium, larger amounts of TGF-b 1 were detected in relation to the increase in cancer cells than in the other cell lines. TGF-b1 increased the expression of CD44H in NUGC-4 cells and in mesothelial cells and augmented adhesion and implantation of NUGC-4 cells to mesothelial cells accompanied by accumulation of extracellular matrix (ECM) components. Treatment with antibodies against both CD44H and b 1 integrin inhibited the dissemination of NUGC-4 cells in the peritoneal cavity of nude mice and prolonged their survival time. Our findings suggest that CD44H and integrins mediate the initial attachment of gastric cancer cells to mesothelial cells and that TGF-b1 participates in the promotion of the disease. Increased expression of CD44H and of the amount of ligands for CD44H and integrins induced by TGF-b1 promotes early development of peritoneal dissemination.