Migration, adhesion and differentiation of malignant plasma cells in the 5T murine model of myeloma.

Multiple myeloma (MM) is a deadly malignancy of plasma cells, localized in the bone marrow (BM), a microenvironment which supports their survival and growth. The malignant cells secrete high levels of immunoglobulins (serum paraprotein) and induce activation of osteoclasts, which results in osteolytic bone disease. The MM cells may have a medullar or an extramedullar origin. The fact that the disease is spread over the whole BM at the time of diagnosis implies a (re)circulation of the MM cells in the peripheral blood and a (re)entrance into the BM. The mechanisms by which the MM cells migrate (home) from the intravascular into the extravascular compartment of the BM are not known. It is also not known which subset(s) of the MM cell population initially enter(s) the BM and induce(s) myeloma. We addressed these questions in the 5TMM experimental mouse model of myeloma. The characteristics of this model are very similar to the human disease. According to the model of Butcher and Picker the homing of MM cells to the BM is assumed a multistep process, in which chemoattractants and adhesion molecules play a central role. We previously reported that 5TMM (5T2MM and 5T33MM) cells selectively home to the BM. However which chemoattractants and adhesion molecules are involved is not known. We provide experimental evidence that 5TMM cells are attracted by BM fibroblasts and that IGF-I is one of the BM fibroblast-derived chemoattractants for the MM cells. We demonstrate that direct contact between 5TMM cells and BM endothelium up-regulates the expression of chemoattractant receptors and adhesion molecules such as IGF-I receptor and CD44v6, which confer homing to the MM cells to the BM and enhance their adhesion to BM stroma. Our results furthermore show that CD44v10 is involved in the adhesive interactions between 5TMM cells and BM endothelial cells and that in vivo blocking of this interaction results in a reduced BM homing. Analysis of the in vivo homing and differentiation characteristics of immature (CD45+) and mature (CD45-) 5TMM cells revealed homing of both subsets to the BM. Both subpopulations were able to induce myeloma and, moreover, (de)differentiated into each other.