Targeted disruption of the beta1 integrin gene in a lymphoma cell line greatly reduces metastatic capacity.

Integrins have been implicated in tumor metastasis. To investigate this, we generated beta1 integrin-negative double knockout (DKO) mutants of the highly metastatic ESb murine T-lymphoma cell line. The in vivo growth capacity of the mutants, which had lost alpha4beta1 and alpha6beta1 expression, was not altered, but their metastatic capacity was greatly reduced. Tail vein injection of 10(4) ESb and single-knockout cells led to death of all animals within 9-11 days. In contrast, only one-half of the animals injected with 10(4) DKO cells died, but much later, after 20-60 days. The other one-half remained disease-free for up to 100 days. Whereas ESb and single-knockout cells disseminated predominantly to liver and spleen, metastasis of DKO cells to these organs was rare, even after this prolonged period. Instead, skeletal muscles were invaded extensively. Metastatic capacity was largely restored in a DKO clone, which had been transfected with beta1 cDNA and expressed beta1 at similar levels as ESb cells. We conclude that beta1 integrins are essential for efficient liver and spleen colonization by the ESb lymphoma.