Serum concentrations of DKK‐1 decrease in patients with multiple myeloma responding to anti‐myeloma treatment

Heider, Ulrike; Kaiser, Martin; Mieth, Maren; Lamottke, Britta; Rademacher, Jessica; Jakob, Christian; Braendle, Edgar; Stover, David R.; Sezer, Orhan

doi:10.1111/j.1600-0609.2008.01164.x

Cited by 64 publications

(52 citation statements)

References 26 publications

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“…33 The serum concentration of DKK1 has been also shown to decrease with response to therapy. 34 Such association with DKK1 and bone disease has also been established in other malignancies including breast, esophageal, lung, prostate, and colon cancers, 12,13,[15][16][17][18] making DKK1 an important target to improve bone disease in cancer in general and myeloma in particularly, where suppression of OB function is perhaps the greatest. Figure 4.…”

Section: Discussionmentioning

confidence: 93%

Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma

Fulciniti

Tassone

Hideshima

et al. 2009

Blood

369

294

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Decreased activity of osteoblasts (OBs) contributes to osteolytic lesions in multiple myeloma (MM). IntroductionA cardinal clinical feature of multiple myeloma (MM) is the presence of osteolytic bone lesions. Myeloma cells disrupt the delicate balance between bone formation and bone resorption. 1,2 Various clinical observations 3 and experimental studies 4,5 have linked the level of MM bone disease with disease burden. Increased osteoclastic activity and its molecular basis have long been considered a primary pathogenic event in MM bone disease. However, a molecular basis for the well recognized lack of osteoblast (OB) function, specifically DKK-1, in the MM bone disease has only recently been described. 6,7 Canonical Wnt pathway plays an important role in controlling proliferation, differentiation, and survival of OB. [8][9][10][11] Previous studies have reported high expression levels of the canonical Wnt inhibitor DKK1 and osteolytic bone lesions in various tumor types including breast, 12,13 neuroblastoma, 14 esophageal, and lung cancer, 15 and conversely enhanced OB activity and osteoblastic bone lesions associated with decreased DKK1 levels in prostate and colon cancers. [16][17][18] In MM, high serum DKK1 levels were correlated with focal bone lesions. 19 The DKK1 produced by MM cells can inhibit the differentiation of OB precursor cells 19 and bone formation in vitro 20 through a DKK1-mediated attenuation of Wnt3a-induced stabilization of ␤-catenin. 21 These findings confirm DKK1 as an important regulator of bone formation in the bone microenvironment. The importance of DKK1 secretion in diseases associated with bone destruction is reinforced by a recent study showing that DKK1 mediates the bone destructive effects of rheumatoid arthritis and that a neutralizing antibody to DKK1 could inhibit the bone destructive process in that disease. 22 There is also emerging evidence that the cellular bone compartment affects MM cell growth and progression. This is supported by the observation that osteoclasts can support long-term survival and proliferation of primary MM cells, 23,24 and OB may impede MM cell growth. 7,25 Thus, targeting these cellular elements may also favorably affect disease control. Therefore, we have evaluated DKK1 as a therapeutic target in MM in the context of the bone marrow (BM) microenvironment, analyzing the effect of a human DKK1 neutralizing antibody (BHQ880). We show that this clinically applicable antibody increases OB function and number and also has anti-MM effect when evaluated in the presence of the BM milieu. Methods ReagentsBHQ880 is a phage-derived DKK1 neutralizing human immunoglobulin G1 (IgG1) antibody (provided by Novartis, Cambridge, MA). BHQ880 has a high affinity for and can neutralize both human DKK1 and murine DKK1. IgG1 isotype antibody was used as control. CellsBone marrow mononuclear cells (BMMNCs) and primary MM cells were isolated using Ficoll-Hypaque density gradient sedimentation from BM Submitted November 25, 2008; accepted April 20, 2009. Prepublished online ...

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Section: Discussionmentioning

confidence: 93%

Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma

Fulciniti

Tassone

Hideshima

et al. 2009

Blood

369

294

View full text Add to dashboard Cite

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“…On the other hand, high levels of DKK1 in patients' serum are associated with poor prognosis in various cancers including oesophageal squamous cell carcinoma [136] , lung cancer [137] , breast cancer [138] and cervical cancer [138] , suggesting that the serum level of DKK1 may also reflect the prognosis of HCC patients. In multiple myeloma, high DKK1 serum levels are associated with osteolytic bone lesions [139] and patients responding to anti-myeloma treatment show a decrease in DKK1 serum levels [140] , suggesting the involvement of DKK1 in this aspect. Recently, Fulciniti et al [141] evaluated the effect of anti-DKK1 monoclonal antibody (BHQ880) in a multiple myeloma mouse model and found that it induced bone formation and inhibited tumour-induced osteolytic bone lesions.…”

Section: Dkk1mentioning

confidence: 99%

Dickkopfs and Wnt/β-catenin signalling in liver cancer

Fatima¹

2011

WJCO

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Liver cancer is the fifth and seventh most common cause of cancer in men and women, respectively. Wnt/β-catenin signalling has emerged as a critical player in both the development of normal liver as well as an oncogenic driver in hepatocellular carcinoma (HCC). Based on the current understanding, this article summarizes the possible mechanisms for the aberrant activation of this pathway with specific focus on HCC. Furthermore, we will discuss the role of dickkopfs (DKKs) in regulating Wnt/β-catenin signalling, which is poorly understood and understudied. DKKs are a family of secreted proteins that comprise at least four members, namely DKK1-DKK4, which act as inhibitors of Wnt/β-catenin signalling. Nevertheless, not all members antagonize Wnt/β-catenin signalling. Their functional significance in hepatocarcinogenesis remains to be further characterized for which these studies should provide new insights into the regulatory role of DKKs in Wnt/β-catenin signalling in hepatic carcinogenesis. Because of the important oncogenic roles, there are an increasing number of therapeutic molecules targeting β-catenin and the Wnt/ β-catenin pathway for potential therapy of HCC. hepatocellular carcinoma anD the unmet meDical neeDSLiver cancer ranks the fifth most common cancer in men and the second leading cause of cancer-related death. In women, it is the seventh most frequent cancer and sixth leading cause of cancer death [1] . Hepatocellular carcinoma (HCC) is the most common primary malignancy of liver. Men are three times more likely to develop HCC than women and the incidence increases with age [2] . HCC is prevalent in Asia and Africa, but recently it is on the rise in the Western world due to an increase in hepatitis C virus (HCV) infection [3] . Risk factors for HCC include chronic hepatitis B virus (HBV) and HCV infections, cirrhosis, chronic alcohol abuse, aflatoxin ingestion, non-alcoholic steatohepatitis and other metabolic liver diseases [4,5] . Much of HCC occurs in the background of cirrhosis. About 80%-90% of patients with cirrhosis go on to develop HCC eventually and the remaining 10%-20% of cases develop HCC without cirrhosis. Furthermore, HBV and HCV infections increase the risk of developing cirrhosis and later HCC. Among the HCC

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“…Furthermore, serum DKK-1 correlated with the number of bone lesions [45]. In a recent study, DKK-1 serum levels were examined in MM patients receiving different treatment regimens, also including novel agents [46]. Serum DKK-1 decreased in myeloma patients responding to therapy, irrespective of the regimen chosen, but not in nonresponders.…”

Section: Myeloma Cells Suppress Osteoblast Differentiation and Functionmentioning

confidence: 99%

Myeloma Bone Disease: Recent Advances in Biology, Diagnosis, and Treatment

Sezer

2009

The Oncologist

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Bone disease is a hallmark of multiple myeloma (MM).Occurring in the majority of MM patients, it is associated with bone pain, fractures, and hypercalcemia and has major impacts on quality of life. Furthermore, bone resorption activity has been shown to be an independent risk factor for overall survival in patients with symptomatic MM. Myeloma is characterized by a unique form of bone disease with lytic bone destruction that is not followed by reactive bone formation (uncoupling).This review focuses on recent advances in our understanding of the biology of osteoclast activation and osteoblast inhibition in MM, diagnostic standards, and recent progress in treatment options for myeloma bone disease. Translational research has enabled a rapid transfer of mechanistic insights from the bench to the bedside and will hopefully result in better treatment options and outcome for patients in near future. The Oncologist 2009;14:276 -283 Editor's note: This review focuses on recent advances in our understanding of the biology of osteoclast activation and osteoblast inhibition in multiple myeloma, diagnostic standards, and recent progress in treatment options for myeloma bone disease. See also the article by Silvestris et al. in this issue of the Journal.

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Serum concentrations of DKK‐1 decrease in patients with multiple myeloma responding to anti‐myeloma treatment

Cited by 64 publications

References 26 publications

Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma

Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma

Dickkopfs and Wnt/β-catenin signalling in liver cancer

Myeloma Bone Disease: Recent Advances in Biology, Diagnosis, and Treatment

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