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

调节人胃癌各种转移模式的实际机制尚不清楚，需要建立适合研究血源性、淋巴性和腹膜性转移的体内实验模型。为此，我们采用裸鼠体内逐步筛选的方法，从具有低转移潜力的人胃癌细胞系AZ521中分离出高肝转移性细胞系AZH5G、淋巴结转移细胞系AZL5G和腹膜转移细胞系AZ-P7a。与亲代AZ521细胞相比，所有三种高转移细胞系的运动性和生长活性都明显增加，表明这些特性与转移潜能的增强有关，无论转移方式如何。在细胞表面粘附分子中，AZL5G表达α2、α3、α5、α6和α <s:1> β3整合素提示上调，AZH5G表达α3、α5整合素上调，α6整合素下调。其他粘附分子如CD44家族、免疫球蛋白超家族、钙粘蛋白等均未在细胞系中表达。AZL5G细胞对4型胶原和纤维连接蛋白的粘附活性明显高于AZ521细胞，而AZ-P7a细胞对这些细胞外基质蛋白（ECMPs）的粘附活性明显低于AZ521细胞。这些发现表明，整合素表达和对ECMPs粘附性的改变可能参与了人胃癌转移模式的调节。

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.