In situ downregulation of VLA-4 integrin cell surface expression during lymphoma growth and liver metastasis

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.