THE DEVELOPMENT OF A MODEL FOR THE HOMING OF MULTIPLE-MYELOMA CELLS TO HUMAN BONE-MARROW

Prior in vitro studies have suggested a role of adhesion molecules, bo ne marrow stromal cells (BMSCs), and cytokines in the regulation of hu man multiple myeloma (MM) cell growth and survival. Although in vivo m odels have been developed in severe combined immunodeficient (SCID) mi ce that support the growth of human MM within the murine BM microenvir onment, these xenograft models do not permit a study of the role of ad hesion proteins in human MM cell-human BMSC interactions. We therefore established an in vivo model of human MM using SCID mice implanted wi th bilateral human fetal bone grafts (SCID-hu mice). For the initial t umor innoculum, human MM derived cell lines (1 x 10(4) or 5 x 10(4) AR H-77, OCI-My5, U-266, or RPMI-8226 cells) were injected directly into the BM cavity of the left bone implants in irradiated SCID-hu mice. MM cells engrafted and proliferated in the left human fetal bone implant s within SCID-hu mice as early as 4 weeks after injection of as few as 1 x 10(4) MM cells, To determine whether homing of tumor cells occurr ed, animals were observed for up to 12 weeks after injection and kille d to examine for tumor in the right bone implants. Of great interest, metastases to the right bone implants were observed at 12 weeks after the injection of 5 x 10(4) MM cells, without spread of human MM cells to murine BM. Human MM cells were identified on the basis of character istic histology and monoclonal human Ig, Importantly, monoclonal human Ig and human interleukin-6 (IL-6), but not human IL-1 beta or tumor n ecrosis factor-alpha, were detectable in sera of SCID-hu mice injected with MM cells, In addition, specific monoclonal Ig light chain deposi tion was evident within renal tubules, This in vivo model of human MM provides for the first time a means for identifying adhesion molecules that are responsible for specific homing of human MM cells to the hum an, as opposed to murine, BM microenvironment. Moreover, induction of human IL-6 suggests the possibility that regulation of MM cell growth by this cytokine might also be investigated using this in vivo model. (C) 1997 by The American Society of Hematology.