Osteosarcomas and rhabdomyosarcomas are vigorously invading tumors. Before they can extravasate to the parenchymal organs and form metastases, they have to adhere to the endothelial cells lining the blood vessels and then penetrate through the endothelium. We show that several human sarcoma cell lines, osteosarcomas HOS, MG-63, U2-0S, and a rhabdomyosarcoma RD, express VIA-4 molecule on their surface and bind to the VCAM-I -expressing activated endothelial cell line Ea.hy 926. The increased sarcoma-cell adhesion could be abolished by treating the sarcoma cells with monoclonal antibodies (MAbs) VIA4 (both a-and @chain, HPI/ I and 484 respectively) or treating endothelial cells with VCAM-I antibody (499). Furthermore, we show that sarcoma cells adhere to recombinant soluble VCAM-I protein. On the other hand, these sarcoma cell lines do not express marked amounts of other ligands (such as CD I I / 18 or sialyl-Lex) for other endothelial adhesion molecules (ICAM-I , ICAM-I, Eand P-selectin) indicating that the VIA-4-VCAM-I dependent pathway might be of major importance in sarcoma extravasation. VIA-4 is not always in an avid form and therefore the expression of VIA-4 does not directly predict adherence to VCAM-I. The avidity of VIA-4 (measured by adherence to soluble VCAM-I) of MG-63 and U2-0s cells could be increased by a 30-min PMA treatment, whereas the avidity of VIA-4 on HOS cells increased only after48 hr of PMA induction. Our results show that sarcoma cell lines (HOS, MG-63, U2-0s and RD) adhere to stimulated endothelium via VIA-4-VCAM-I adhesion molecules and that VIA-4 avidity on sarcoma cells can be differentially modulated by PMA.