Dynamic expression changes in vivo of adhesion and costimulatory molecules determine load and pattern of lymphoma...

Although intradermal primary tumor growth and spontaneous liver metastasis 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 the liver. This period, which was shown to be immune dependent, was followed by a second expansion phase characterized by a preferential localization of tumor cells in the periportal areas of liver lobules (mosaic phenotype). To elucidate possible mechanisms leading to the plateau period as well as for the mosaic-like metastasis pattern, we investigated, using flow cytometry analysis, alterations in costimulatory and adhesion molecule expression in liver sinusoidal cells as well as in tumor cells isolated directly ex vivo throughout the kinetics of metastasis. In tumor and sinusoidal cells, we found up-regulation in the expression of MHC class II and B7 molecules during the plateau period. These molecules, which facilitate cell-mediated immune responses, were again down-regulated during the final exponential tumor growth and metastasis. In the final expansion phase, in which the mosaic phenotype of liver metastasis is seen, we detected a significant increase of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 expression in both tumor and sinusoidal cells, suggesting tumor cell-sinusoidal cell interactions. vascular cell adhesion molecule-1/very late activated antigen-4 did not show any modification during the whole metastatic process. In vivo application of monoclonal antibodies directed to leukocyte function-associated antigen-1 and intercellular adhesion molecule-1 appeared to block the spread of metastasis, while no effect was seen with monoclonal antibodies directed to vascular cell adhesion molecule-1 and very late activated antigen-4. This study reveals in 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 with mechanisms of immune control and tumor immune evasion, respectively.