Our recent finding that resistance to lymphoma cell metastasis in intercellular adhesion molecule-1-(ICAM-1)-deficient mice was manifested after homing suggested that the mechanism could involve the capacity of ICAM-1 to induce, via leukocyte function-associated antigen-1 (LFA-1) signaling, the expression of new genes necessary for migration and survival of lymphoma cells after homing. This hypothesis would imply that lymphoma cells, on repeated metastatic cycles, would acquire such a highly aggressive phenotype that they no longer require contact with ICAM-1 at later stages of metastasis. We addressed this question by generating highly aggressive lymphoma variants to determine if increased tumorigenicity would allow lymphoma cells to grow into tumors in ICAM-1-deficient mice. We found that on repeated in vivo passages, a selective pressure favored the lymphoma cells that constitutively express high levels of matrix metalloproteainse-9 (MMP-9), a gene associated with a poor clinical outcome in non-Hodgkins's lymphoma. We further found that although the parent lymphoma cells could not grow tumors in ICAM-1-deficient mice, the aggressive lymphoma variants could. This indicates that, at late stages of the disease, tumor cells with a high metastatic efficiency, encoded by the repertoire of selected genes, no longer require some of the signals normally delivered by cell adhesion molecules. In light of these findings, the possibility of inhibiting dissemination of lymphoma cells at the late stage of the disease by acting against cell adhesion molecules must be reconsidered. (Blood. 2000;95:314-319)