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The rapid progression of multiple myeloma is dependent upon cellular interactions within the bone marrow microenvironment. In vitro studies suggest that bone marrow stromal cells (BMSC) can promote myeloma growth and survival and osteolytic bone disease. However, it is not possible to recreate all cellular aspects of the bone marrow microenvironment in an in vitro system, and the contributions of BMSCs to myeloma pathogenesis in an intact, immune competent, in vivo system are unknown. To investigate this, we used a murine myeloma model that replicates many features of the human disease. Coinoculation of myeloma cells and a BMSC line, isolated from myeloma-permissive mice, into otherwise nonpermissive mice resulted in myeloma development, associated with tumor growth within bone marrow and osteolytic bone disease. In contrast, inoculation of myeloma cells alone did not result in myeloma. BMSCs inoculated alone induced osteoblast suppression, associated with an increase in serum concentrations of the Wnt signaling inhibitor, Dkk1. Dkk1 was highly expressed in BMSCs and in myeloma-permissive bone marrow. Knockdown of Dkk1 expression in BMSCs decreased their ability to promote myeloma and the associated bone disease in mice. Collectively, our results show novel roles of BMSCs and BMSC-derived Dkk1 in the pathogenesis of multiple myeloma in vivo.

Original publication

DOI

10.1158/0008-5472.can-11-2067

Type

Journal article

Journal

Cancer research

Publication Date

05/2012

Volume

72

Pages

2183 - 2189

Addresses

Department of Cancer Biology, Vanderbilt Center for Bone Biology, Vanderbilt University, Nashville, Tennessee, USA.

Keywords

Bone Marrow Cells, Stromal Cells, Animals, Mice, Inbred C57BL, Mice, Multiple Myeloma, Intercellular Signaling Peptides and Proteins, Female, Wnt Proteins, Gene Knockdown Techniques, Tumor Microenvironment