A Crosstalk Between Myeloma Cells and Marrow Stromal Cells Stimulates Production of DKK1 and Interleukin-6: A Potential Role in the Development of Lytic Bone Disease and Tumor Progression in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a malignancy of antibody-secreting plasma cells. B-cell plasmacytomas stimulate bone resorption and angiogenesis, resulting in osteolytic lesions in the skeleton which persist upon successful treatment of the malignancy with chemotherapy. We found that an interaction between MM cells and mesenchymal stem cells (MSCs) from bone marrow stroma results in the formation and persistence of osteolytic bone lesions. It is known that MM cells activate osteoclast activity and secrete high levels of the Wnt inhibitor, Dickkopf-1, which prevents MSCs from differentiating into osteoblasts. We show that the Wnt signaling activator 6-bromoindirubin-3-monoxime (BIO) releases MSCs from the osteoinhibitory effects of Dickkopf-1, whereas LiCl treatment does not. Additionally, we show that the >5-kDa fraction of MSC-conditioned medium promotes the proliferation of Dickkopf-1-secreting MM cells and that an interleukin-6 (IL-6)-neutralizing antibody blocks this effect. IL-6 expression levels were higher in undifferentiated MSCs than in MSCs treated with osteogenic medium, remained high in the presence of Dkk1, and were reduced by BIO treatment. Therefore, BIO treatment reduces the MSCstimulated proliferation of MM cells and may enable MSCs to repair existing osteolytic lesions. STEM CELLS 2006;24: 986 -991

A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies

“…In spite of the hosts' response to the implanted cells, human Dkk-1 could be detected in the blood of the recipient mice, demonstrating that tumour-derived Dkk-1 escapes into the blood It is unclear at this point whether the elevated systemic Dkk-1 in OS patients is derived solely from the tumour, since the human Dkk-1 circulating in the blood of recipient mice was much lower than the mean levels detected in the blood of the human OS patients. It is possible, however, that the host tissue interacts with the tumour, resulting in upregulation of the expression of Dkk-1, a phenomenon observed in the case of multiple myeloma (Gunn et al, 2005;Corre et al, 2007). The host microenvironment in the patients may be more readily affected by the tumour than the surrounding mouse tissue accounting for the reduced levels of Dkk-1 in the mouse blood when compared to the human blood.…”

“…Alkaline phosphatase assays were performed on monolayers in sixwell format as previously described (Gunn et al, 2005). Briefly, MSCs were seeded at a density of 5000 cells per cm 2 and cultured for 10 days in osteoinductive media.…”

“…Unless otherwise stated, all cell culture reagents were purchased from Invitrogen. Recombinant human Dkk-1 preparation was carried out as previously described from a stably expressing COS cell line (Gunn et al, 2005).…”

Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells

“…12,33 The bone marrow microenvironment is critical for myeloma cell survival and proliferation. [34][35][36][37] In addition, the bone marrow microenvironment has been reported to protect myeloma cells from chemotherapy. 38,39 We have shown that patient myeloma cell growth is dependent on human bone marrow microenvironment.…”

The pathogenesis of the bone disease of multiple myeloma

“…The development of myeloma bone disease is dependent upon interactions within the local bone marrow microenvironment and myeloma cells have been demonstrated to interact with osteoblasts and up-regulate expression of Dkk1 by osteoblasts (60). Furthermore, interactions between myeloma cells and mesenchymal stem cells have been demonstrated to promote the growth of myeloma cells, resulting in an increase in Dkk1 and consequent inhibition of mesenchymal stem cell differention into osteoblasts (61). Preclinical studies have demonstrated the potential for targeting Dkk1 in myeloma bone disease.…”