TARGETED DISRUPTION OF THE BETA-1 INTEGRIN GENE IN A LYMPHOMA CELL-LINE GREATLY REDUCES METASTATIC CAPACITY

Integrins have been implicated in tumor metastasis. To investigate thi s, we generated beta 1 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 alpha 4 beta 1 and alp ha 6 beta 1 expression, was not altered, but their metastatic capacity was greatly reduced, Tail vein injection of 10(4) ESb and single-knoc kout 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 m uch 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 o rgans was rare, even after this prolonged period. Instead, skeletal mu scles were invaded extensively, Metastatic capacity was largely restor ed in a DKO clone, which had been transfected with beta 1 cDNA and exp ressed beta 1 at similar levels as ESb cells. We conclude that beta 1 integrins are essential for efficient liver and spleen colonization by the ESb lymphoma.