Homing of the myeloma cell clone

The presence of myeloma cells in the blood circulation, implicates that the se cells must have the potential to extravasate and home to the bone marrow environment. Using the 5T2 MM mouse model, we could demonstrate that the r estricted localization of myeloma cells in the bone marrow is the result of selective migration of myeloma cells in the bone marrow combined with a se lective growth of the tumour cells in the bone marrow microenvironment. Mor eover, we showed that 5T2 MM cells bind in vitro selectively to bone marrow -derived endothelial cells (EC) and not to lung-derived EC. In order to ide ntify which chemotactic molecules mediate the transendothelial migration of myeloma cells, we examined the motility-inducing effect of different extra cellular matrix proteins on myeloma cell lines. We found that laminin-1, a major component of the basement membrane, triggers the motility of both hum an myeloma cells and 5T2 MM cells, through the 67 kD laminin receptor. Beca use of the broad distribution of laminin in extracellular matrices througho ut the body, it is clear that this molecule on itself can not be the only f actor that determines the specificity of myeloma cell homing. In the 5T2 MM model we identified IGF-1 as a more specific bone marrow derived chemoattr actant for myeloma cells. In addition we demonstrated that the marrow micro environment can upregulate the expression of the IGF-1 receptor on 5T mouse myeloma cells. In the end phase of the disease, increasing numbers of myel oma cells are detectable in the peripheral blood and extramedullary tumour growth can occur. We found that the stroma-independent variant of the human MM5 myeloma cell line showed an increased in vitro motility as compared to the stroma-dependent variant. By representational difference analysis we d emonstrated that the stroma-dependent MM5 cells show a downregulation of th e motility-related protein (MRP-1/CD9) which might reflect the involvement of this molecule in the regulation of myeloma cell extravasation.