M. Lalancette et al., Resistance of ICAM-1-deficient mice to metastasis overcome by increased aggressiveness of lymphoma cells, BLOOD, 95(1), 2000, pp. 314-319
Our recent finding that resistance to lymphoma cell metastasis in intercell
ular adhesion molecule-1-(ICAM-1)-deficient mice was manifested after homin
g suggested that the mechanism could involve the capacity of ICAM-1 to indu
ce, via leukocyte function-associated antigen-1 (LFA-1) signaling, the expr
ession 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 th
ey no longer require contact with ICAM-1 at later stages of metastasis. We
addressed this question by generating highly aggressive lymphoma variants t
o determine if increased tumorigenicity would allow lymphoma cells to grow
into tumors in ICAM-1-deficient mice. We found that on repeated in vivo pas
sages, a selective pressure favored the lymphoma cells that constitutively
express high levels of matrix metalloproteainse-9 (MMP-9), a gene associate
d 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-de
ficient mice, the aggressive lymphoma variants could. This indicates that,
at late stages of the disease, tumor cells with a high metastatic efficienc
y, encoded by the repertoire of selected genes, no longer require some of t
he 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 mu
st be reconsidered.