The role of
VLA-4 integrin in liver
metastasis of
lymphoma cells was investigated. ESbL-lacZ
lymphoma cells in vitro exhibited high surface expression of
VLA-4, adhered to
CS-1 fibronectin and
VCAM-1 and cell adhesion was inhibited by anti-VLA-4 MAb PS/2. When injected in vivo, however, PS/2 did not interfere with spontaneous liver
metastasis and had no effect on survival. Ex vivo analysis of
VLA-4 surface expression was facilitated by a new reisolation method for
tumor and host cells derived from metastatic target organs. Freshly ex vivo isolated
tumor cells from metastatic livers revealed
VLA-4 surface downregulation as early as 3 days after
tumor injection, which continued during the course of
metastasis.
VLA-4 downregulation in liver
metastasis was also seen at the
mRNA transcriptional level. Primary
tumor cells showed similar
VLA-4 downregulation suggesting that the in vivo phenotype was induced by the microenvironment at the primary
tumor site. In support of this hypothesis, re-isolated
tumor cells from metastatic livers recovered the high
VLA-4 expression in host-depleted cell cultures. This study suggests that
VLA-4 expression on
tumor cells can be modulated in situ during
tumor growth and
metastasis formation.