Chlorpromazine (CP), an amphipathic, antipsychotic agent, causes concave membrane bending in red blood cells with formation of stomatocytic shapes by modulation of the phospholipid bilayer. This study was designed to investigate the effects of CP on the shape of bovine aortic endothelial cells (BAEC) and their membranes in confluent monolayers with phase-contrast and transmission electron microscopy. Exposure of BAECs to nanomolar levels of CP leads to membrane curvature changes. With increasing CP concentrations, the membrane assumed a shape with enhanced numbers of intracellular caveolae and projection of pseudopodia at all junctions. At higher CP concentrations (up to 150 microM), the endothelial cells assumed almost spherical shapes. The evidence suggests that CP may affect lipid bilayer bending of BAECs in analogy with previous observations on erythrocytes, supporting the formation of caveolae and pseudopodia in BAECs due to the induction of concave membrane bending, as well as an effect on endothelial cell membrane adhesion at higher CP concentrations with loss of cellular attachment at junctions.
Multicellular tumor spheroids (MCTS) are a reliable model of nonvascularized tumor cell aggregates showing a well defined three-dimensional growth pattern and are comparable with small metastatic cancer cell complexes in blood circulation. In the present study we have established a co-culture system of multicellular bladder tumor spheroids with human endothelial cells on extracellular matrix (ECM) in order to investigate morphological and proliferative changes of endothelial and tumor cells within a defined time of cell-cell interaction. The MCTS--endothelial cell--extracellular matrix complex was observed within coculture periods from 1/2 to seven days. Morphological changes (light microscopy, scanning and electron microscopy) indicated that MCTS are not influenced by cocultured endothelial cells. The tumor cells invaded into the ECM after degradation of endothelial cells in the center of the contact zone. Endothelial cells, however, showed degenerative changes as well as a complex reaction in their proliferation activities. We could recognize an initial increase of proliferation of endothelial cells next to the MCTS. Later on, endothelial cells next to invading tumor cells showed changes in morphological polarity. The model system used has the advantage of using human tumor tissue. It distinguishes between basic cellular mechanisms like adherence, migration, DNA synthesis and proliferation in the study of the contact of tumor cells and vascular endothelial cells as an important event in hematogenous tumor spread.
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