RRC ID 43702
Author Fowler JA, Mundy GR, Lwin ST, Edwards CM.
Title Bone marrow stromal cells create a permissive microenvironment for myeloma development: a new stromal role for Wnt inhibitor Dkk1.
Journal Cancer Res
Abstract 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.
Volume 72(9)
Pages 2183-9
Published 2012-5-1
DOI 10.1158/0008-5472.CAN-11-2067
PII 0008-5472.CAN-11-2067
PMID 22374979
PMC PMC3775476
MeSH Animals Bone Marrow Cells / metabolism Bone Marrow Cells / pathology* Female Gene Knockdown Techniques Intercellular Signaling Peptides and Proteins / biosynthesis* Intercellular Signaling Peptides and Proteins / genetics Mice Mice, Inbred C57BL Multiple Myeloma / genetics Multiple Myeloma / metabolism Multiple Myeloma / pathology* Stromal Cells / metabolism Stromal Cells / pathology* Tumor Microenvironment Wnt Proteins / antagonists & inhibitors
IF 9.727
Times Cited 51
Human and Animal Cells ST2(RCB0224)