LYMPHOCYTE ADHESION AND TRANSMIGRATION THROUGH KAPOSI'S SARCOMA CELLS. STUDY IN STATIC AND DYNAMIC FLOW MODELS.

Abstract

Kaposi's sarcoma is a tumor composed of a complex mixture of cell types including a prominent infiltrate of extravasated erythrocytes and leukocytes. The presence in the tumor of vascular splits without well characterized endothelium and basement membrane enable KS cells to be in close contact with circulating blood cells, and interaction between leukocytes and KS cells could contribute to the transmigration of leukocytes into the tumor. Understanding the mechanisms of KS cells/leukocytes interactions is becoming important to elucidate the physiopathology of KS. The present study was to investigate 1) whether KS cells could act as endothelial cells and can support adhesion and migration of leukocytes into the tumors: 2) which adhesion pathways are involved in such interactions. By using static (that measures firm adhesion) as well as dynamic flow (that measures tethering and rolling) adhesion models previously used to investigate endothelial cells/leukocytes interactions, we studied the adhesiveness properties of KS cells for lymphocytes and compared them to those of endothelial cells. We used the KSYI cell line, derived from pleural fluid of an AIDS patient suffering of pulmonary KS. This cell line has been described to promote persistent tumorigenesis, angiogenesis and metastasis in immunodeficient mice and then can constitute an excellent model to study cellular interactions for KS pathogenesis. KSYI cells have a higher potential of adhesiveness for lymphocytes than endothelial cells (HUVEC) in static as well as in dynamic flow condition. Basal adhesiveness of KSYI cell can be increased by PMA but not TNFα activation. Under dynamic flow condition, adhesion to TNFα-activated KSYI is decreased whereas adhesion to TNFα-activated HUVEC is increased. PMA activation of KSYI cells has no effect on lymphocyte adhesion under dynamic flow condition. Blockage of ICAMI (one of LFAI ligands) on KSYI totally reverses lymphocyte basal adhesion whereas it partially reverses adhesion to PMA-activated KSYI. CD29/VLA4 pathway is not involved in these interactions. KSYI cells also support higher transmigration of bound lymphocytes than HUVEC indicating that KSYI cell monolayer constitutes a selective barrier. All these data indicate that in vitro KS cells could mimick an endothelium like structure by regulating extravasation of lymphocytes into the KS tumor. Indeed KS cells have a great potential of adhesion for circulating blood cells that can even be increased by activation. KSYI cells and HUVEC share at least a common adhesion pathway LFAI/ICAMI but also exhibit different adhesion pathways that can reflect the differences in induction and/or regulation of adhesion receptor expression on these cells. We can hypothetized that in vivo such cellular interactions between KS cells and leukocytes occur and that cytokines as well as viral proteins present in close proximity of the KS tumor could contribute to enhance adhesiveness of KS cells for leukocytes and then favored their extravasation into the tumor.