Establishment of highly metastatic models for human gastric cancer in nude mice and analysis of factors that regulate the metastatic modes.

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The actual mechanisms that regulate various models of metastasis by human gastric cancer are still unclear, and there is a need to establish in vivo experimental models suitable for the investigation of hematogenous, lymphogenous and peritoneal metastases. For the purpose, we established highly liver-metastasizing line, designated AZH5G, lymph node-metastasizing line, AZL5G, and peritoneum-metastasizing line, AZ-P7a, which were derived from the same human gastric cancer cell line, AZ521, with low metastatic potential using in vivo stepwise selection in nude mice.All of three high-metastatic lines showed clearly increased motility and growth activity compared with the parental AZ521 cells, indicating that those properties are involved in the enhancement of metastatic potential regardless of metastatic modes. Concerning cell surface adhesion molecules, AZL5G expressed suggestive up-regulation of α2, α3, α5, α6 and αυβ3 integrins while AZH5G showed increased expression of α3 and α5 integrins and decreased expression of α6 integrin. The other adhesion molecules such as CD44 family, immunoglobulin superfamily or cadherin were not expressed in any cell lines. The adhesive activity of AZL5G cells to type-4 collagen and fibronectin was clearly increased than that of AZ521 cells, while contrast, the adhesive activity of AZ-P7a cells to these extracellular matrix proteins (ECMPs) was significantly decreased than that of AZ521 cells. These findings suggest that changes both in the expression of integrins and in adhesiveness to ECMPs may be involved in the regulation of metastatic mode in human gastric carcinomas.