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Cytomatrix 
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A Model for the In Vitro and In Vivo Growth of Multiple Myeloma in the Bone Marrow Microenvironment |
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Richard LeBlanc*, Laurence Catley*, Teru Hideshima*, Erika von Schild, Todd Upton, Kenneth C. Anderson
Cytomatrix, Woburn MA, 01801 *Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 20115 |
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The importance of the bone marrow microenvironment (BMM) in the pathogenesis of multiple myeloma (MM) is becoming increasingly recognized. For example, adhesion of MM cells to the extracellular matrix proteins and the bone marrow stromal cells (BMSCs) confers protection against drug induced apoptosis, triggers secretion of cytokines such as IL-6 and VEGF, and mediates MM cell growth and survival. To further characterize the role of the BMM in the pathogenesis of MM, new in vitro and in vivo models are needed. In this study we have used The Cytomatrix™, a highly porous three-dimensional matrix, to provide the substrate for the growth of BMSCs. We first show that BMSCs, in vitro, grow on The Cytomatrix, and secrete IL-6 and VEGF. Binding of MM cells to these BMSCs upregulates both IL-6 (412.7±9.3 to 841.7±22.4 pg/mL; p<0.001) and VEGF (737.6±48.3 to 14001.9±64.3 pg/mL; p<0.001). To examine the potential in vivo utility of The Cytomatrix, the matrix was implanted subcutaneously in 17 triple immune deficient beige-nude-xid mice, either matrix alone (8), or matrix pre-grown with human BMSCs (9) in the Cytomatrix Spinner System. After 14 to 28 days, the matrices were explanted and examined for neoangiogenesis, as well as human BMSC viability and function. The mice tolerated the implantation of the matrix without complications. When matrices containing BMSCs were implanted, their function was preserved at 20 days, evidenced by increased IL-6 secretion triggered by adherence of MM cells (from 33.6±1.6 to 46.7±0.56 pg/mL, p=0.008) when assayed after explantation. The matrices were infiltrated with mouse tissue as early as 7 days after implantation. Importantly, blood vessels were visible by light microscopy, and neoangiogenesis was increased in implanted matrices containing BMSCs compared to those without BMSCs. These studies demonstrate that Cytomatrix can support the growth of viable BMSCs both in vitro and in vivo, and can be used for the characterization of MM cell growth in the BMM as well as angiogenesis. Ongoing studies will utilize this model both to characterize cellular and molecular events regulating in vivo MM cell growth, and to evaluate novel anti-MM therapies. |
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