IN-SITU DOWN-REGULATION 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 i nvestigated. ESbL-lacZ lymphoma cells ill 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 expressio n 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 cou rse of metastasis. VLA-4 downregulation in liver metastasis was also s een at the mRNA transcriptional level. Primary tumor cells showed simi lar VLA-4 downregulation suggesting that the in vivo phenotype was ind uced by the microenvironment at the primary tumor site. In support of this hypothesis, re-isolated tumor cells from metastatic livers recove red the high VLA-4 expression in host-depleted cell cultures. This stu dy suggests that VLA-4 expression on tumor cells can be modulated in s itu during tumor growth and metastasis formation.