DYNAMIC EXPRESSION CHANGES IN-VIVO OF ADHESION AND COSTIMULATORY MOLECULES DETERMINE LOAD AND PATTERN OF LYMPHOMA LIVER METASTASIS

Although intradermal primary tumor growth and spontaneous liver metast asis of ESbL-lacZ lymphoma in syngeneic DBA/2 mice are progressive and malignant, they are characterized by a transient plateau period with a constant tumor diameter and a low number of metastasized cells in th e liver, This period, which was shown to be immune dependent, was foll owed by a second expansion phase characterized by a preferential local ization of tumor cells in the periportal areas of liver lobules (mosai c phenotype). To elucidate possible mechanisms leading to the plateau period as well as for the mosaic-like metastasis pattern, we investiga ted, using flow cytometry analysis, alterations in costimulatory and a dhesion molecule expression in liver sinusoidal cells as well as in tu mor cells isolated directly ex vivo throughout the kinetics of metasta sis, In tumor and sinusoidal cells, we found up-regulation in the expr ession of MHC class II and B7 molecules during the plateau period. The se molecules, which facilitate cell-mediated immune responses, were ag ain down-regulated during the final exponential tumor growth and metas tasis, In the final expansion phase, in which the mosaic phenotype of liver metastasis is seen, we detected a significant increase of leukoc yte function-associated antigen-1/intercellular adhesion molecule-1 ex pression in both tumor and sinusoidal cells, suggesting tumor cell-sin usoidal cell interactions, vascular cell adhesion molecule-1/very late activated antigen-4 did not show any modification during the whole me tastatic process, In vivo application of monoclonal antibodies directe d to leukocyte function-associated antigen-1 and intercellular adhesio n molecule-1 appeared to block the spread of metastasis, while no effe ct was seen with monoclonal antibodies directed to vascular cell adhes ion molecule-1 and very late activated antigen-4, This study reveals i n situ expression changes of cell surface molecules in tumor and host cells during metastasis, The changes seen during the plateau phase and during the second expansion phase differ, suggesting associations wit h mechanisms of immune control and tumor immune evasion, respectively.