Predominant role of alpha 4-integrins for distinct steps of lymphoma metastasis

To analyze the role of alpha 4-integrins in lymphoma metastasis. sublines of the T-cell lymphoma LB were generated by retrovirus-mediated gene transfer that differ exclusively in the expression of alpha 4-integrins. Using LB-alpha 4 and control LB-NTK cells, we demonstrate that expression of alpha 4-integrins strongly suppresses metastasis formation of LB lymphoma cells in secondary lymphoid organs such as spleen, mesenteric and peripheral lymph nodes, or Peyer's patches after i.v. injection into syngeneic BALB/c mice. Moreover, alpha 4-integrin expression inhibited development of metastatic tumors in liver, lung, and kidney. Expansion of LB lymphoma cells in bone marrow was not affected by alpha 4-integrin expression. In vivo migration assays using Cr-51-labeled Lymphoma cells demonstrated that low-metastatic LB-alpha 4 cells accumulated with the same efficiency as high-metastatic LB-NTK cells in all target organs examined and were even enriched in mucosal lymphoid organs. Collectively, these results indicate that alpha 4-integrins inhibit metastasis formation of lymphoma cells at a stage subsequent to the invasion of target organs.