The association of metastasis with the expression of adhesion molecules in cell lines derived from human gastric cancer.
Peritoneal dissemination and hepatic metastasis commonly occur after patients with gastric cancer have undergone surgery. The presence of metastasis after surgery is sure to affect the prognosis of patients with gastric cancer. We conducted in vitro and in vivo studies to assess the role of adhesion molecules in this process, using 2 cell lines derived from human gastric cancer. Although both cell lines expressed several adhesion molecules to varying degrees, NUGC-4 cells, which disseminated early after inoculation into the abdominal cavity of nude mice accompanied by the formation of bloody ascitic fluid, predominantly expressed CD44H. However, MKN74 cells, which demonstrated hematogenous metastasis in the liver after inoculation into the spleen of nude mice, strongly expressed the sialyl Lewis(x) antigen (s-Le(x)), but did not express CD44H at all. When the binding of both these cancer cells to human umbilical vein endothelial cells was examined it was found that MKN74 cells adhered more strongly than NUGC-4 cells. The adhesion of cancer cells to endothelial cells was inhibited by treatment with antibodies against s-Le(x) and E-selectin. In the liver metastasis model of nude mice, treatment with anti-s-Le(x) antibodies significantly inhibited the development of MKN74 cell liver metastasis, both in the number of tumor nodules and in liver weight. NUGC-4 cells adhered to monolayers of mesothelial cells more strongly than MKN74 cells. The adhesion of NUGC-4 cells to these cells was partially inhibited by antibodies either against CD44H or the beta 1 subunit of integrin, but was completely blocked by a combination of these 2 antibodies. These antibodies markedly inhibited the dissemination of NUGC-4 cells in the peritoneal cavity of nude mice, and prolonged their mean survival time. These findings suggest that s-Le(x) and E-selectin mediate the adhesion of gastric cancer cells to endothelial cells, and CD44H and beta 1 integrin play important roles in the initial attachment of gastric cancer cells to mesothelial cells. It is possible that compounds that interfere with the function of cell adhesion molecules may decrease the incidence of gastric cancer metastasis.
Nakashio
T
T
Department of Surgery II, Nagoya University School of Medicine, Japan.
Narita
T
T
Sato
M
M
Akiyama
S
S
Kasai
Y
Y
Fujiwara
M
M
Ito
K
K
Takagi
H
H
Kannagi
R
R
D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000502:physiology*; D019040:E-Selectin / Q000502:physiology; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D019012:Integrin beta1 / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D013274:Stomach Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D018960:Hyaluronan Receptors; D019012:Integrin beta1