The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma

Tian, Erming; Zhan, Fenghuang; Walker, Ronald C.; Rasmussen, Erik; Ma, Yupo; Barlogie, Bart; Shaughnessy, John D.

doi:10.1056/nejmoa030847

Cited by 1,377 publications

(1,091 citation statements)

References 38 publications

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“…DKK1 was initially identified as an inhibitor of WNT-induced axis duplication in Xenopus development (Glinka et al, 1998). Subsequent studies implicated DKK1 in the pathogenesis of osteolytic lesions in patients with multiple myeloma (Tian et al, 2003). During our study, Hall et al (2005) reported that PC-3 prostate cancer cells express DKK1 and showed by genetic manipulation of DKK1 in C4-2b prostate cancer cells that WNT signaling participates in prostate cancerinduced new bone formation.…”

Section: Discussionmentioning

confidence: 62%

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

Yang

Vázquez

et al. 2007

Oncogene

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The tendency of prostate cancer to produce osteoblastic bone metastases suggests that cancer cells and osteoblasts interact in ways that contribute to cancer progression. To identify factors that mediate these interactions, we compared gene expression patterns between two bonederived prostate cancer cell lines that produce osteoblastic (MDA PCa 2b) or osteolytic lesions (PC-3). Both cell lines expressed Wnt ligands, including WNT7b, a canonical Wnt implicated in osteogenesis. PC-3 cells expressed 50 times more Dickkopf-1 (DKK1), an inhibitor of Wnt pathways, than did MDA PCa 2b cells. Evaluation of the functional role of these factors (in cocultures of prostate cancer cells with primary mouse osteoblasts (PMOs) or in bone organ cultures) showed that MDA PCa 2b cells activated Wnt canonical signaling in PMOs and that DKK1 blocked osteoblast proliferation and new bone formation induced by MDA PCa 2b cells. MDA PCa 2b cells did not induce bone formation in calvaria from mice lacking the Wnt co-receptor Lrp5. In human specimens, WNT7b was not expressed in normal prostate but was expressed in areas of high-grade prostate intraepithelial neoplasia, in three of nine primary prostate tumor specimens and in 16 of 38 samples of bone metastases from prostate cancer. DKK1 was not expressed in normal or cancerous tissue but was expressed in two of three specimens of osteolytic bone metastases (P ¼ 0.0119). We conclude that MDA PCa 2b induces new bone formation through Wnt canonical signaling, that LRP5 mediates this effect, and that DKK1 is involved in the balance between bone formation and resorption that determines lesion phenotype.

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Section: Discussionmentioning

confidence: 62%

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

Yang

Vázquez

et al. 2007

Oncogene

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“…Over-expression of Dkk1 in bone marrow aspirates from patients with multiple myeloma was initially identified by cDNA microarray. Dkk1 concentrations were increased in bone marrow plasma and peripheral blood of patients with multiple myeloma, as compared to healthy individuals or to patients with MGUS (56). In addition, osteoblast differentiation was blocked by bone marrow serum from patients with myeloma, and the inhibitory effect was found to be the result of Dkk1 in the serum.…”

Section: Inhibition Of Wnt Signalingmentioning

confidence: 90%

“…Recent evidence suggests a role for each of these classes of inhibitors in the development of myeloma bone disease. The soluble, extracellular antagonist of the Wnt signaling pathway, Dkk-1, has been identified as a potential mediator of osteoblast dysfunction in myeloma bone disease (56). Dkk1 is expressed by osteoblasts and bone marrow stromal cells, and has been demonstrated to inhibit bone formation in osteoblasts in vitro (57).…”

Section: Inhibition Of Wnt Signalingmentioning

confidence: 99%

The pathogenesis of the bone disease of multiple myeloma

Edwards

Zhuang

Mundy

2008

Bone

152

120

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Multiple myeloma is a fatal hematologic malignancy associated with clonal expansion of malignant plasma cells within the bone marrow and the development of a destructive osteolytic bone disease. The principal cellular mechanisms involved in the development of myeloma bone disease are an increase in osteoclastic bone resorption, and a reduction in bone formation. Myeloma cells are found in close association with sites of active bone resorption, and the interactions between myeloma cells, and other cells within the specialized bone marrow microenvironment are essential, both for tumor growth and the development of myeloma bone disease. This review discusses the many different factors which have been implicated in myeloma bone disease, including the evidence for their role in myeloma and subsequent therapeutic implications.

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“…Examples include multiple myeloma (Tian et al, 2003) and some forms of prostate cancer (Hall et al, 2005). Damage of the bone by malignancy can increase the severity of the disease by providing a permissive microenvironment for tumour growth and metastatic events.…”

mentioning

confidence: 99%

“…Damage of the bone by malignancy can increase the severity of the disease by providing a permissive microenvironment for tumour growth and metastatic events. In multiple myeloma, Dkk-1 is readily detectable in the blood of individuals in the later stages of the disease who have characteristic osteolytic bone lesions (Tian et al, 2003).…”

mentioning

confidence: 99%

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

et al. 2007

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Canonical Wnt signalling is an osteoinductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signalling and thus inhibits osteogenesis. To examine a potential osteoinhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in paediatric patients with OS (median age, 13.4 years) and found it to be significantly elevated. We also found that Dkk-1 was maximally expressed by the OS cells at the tumour periphery and in vitro, Dkk-1 and RANKL are coexpressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduce osteogenesis by human mesenchymal cells and by immunodepletion of Dkk-1, or by adding a GSK3b inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumours was similar to the human tumour biopsies in that human Dkk-1 was present in the serum of recipient animals. These data demonstrate that systemic levels of Dkk-1 are elevated in OS. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumour probably contributes to its expansion by inhibiting repair of the surrounding bone. These data demonstrate that Dkk-1 may serve as a prognostic or diagnostic marker for evaluation of OS and furthermore, immunodepletion of Dkk-1 or administration of GSK3b inhibitors could represent an adjunct therapy for this disease.

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The Role of the Wnt-Signaling Antagonist DKK1 in the Development of Osteolytic Lesions in Multiple Myeloma

Abstract: The production of DKK1, an inhibitor of osteoblast differentiation, by myeloma cells is associated with the presence of lytic bone lesions in patients with multiple myeloma.

Cited by 1,377 publications

References 38 publications

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone

The pathogenesis of the bone disease of multiple myeloma

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

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