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Dive into the research topics where Isabelle Vande Broek is active.

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Featured researches published by Isabelle Vande Broek.


Blood | 2010

Targeting the multiple myeloma hypoxic niche with TH-302, a hypoxia-activated prodrug

Jinsong Hu; Damian Handisides; Els Van Valckenborgh; Hendrik De Raeve; Eline Menu; Isabelle Vande Broek; Qian Liu; Jessica Sun; Ben Van Camp; Charles P. Hart; Karin Vanderkerken

Hypoxia is associated with increased metastatic potential and poor prognosis in solid tumors. In this study, we demonstrated in the murine 5T33MM model that multiple myeloma (MM) cells localize in an extensively hypoxic niche compared with the naive bone marrow. Next, we investigated whether hypoxia could be used as a treatment target for MM by evaluating the effects of a new hypoxia-activated prodrug TH-302 in vitro and in vivo. In severely hypoxic conditions, TH-302 induces G(0)/G(1) cell-cycle arrest by down-regulating cyclinD1/2/3, CDK4/6, p21(cip-1), p27(kip-1), and pRb expression, and triggers apoptosis in MM cells by up-regulating the cleaved proapoptotic caspase-3, -8, and -9 and poly ADP-ribose polymerase while having no significant effects under normoxic conditions. In vivo treatment of 5T33MM mice induces apoptosis of the MM cells within the bone marrow microenvironment and decreases paraprotein secretion. Our data support that hypoxia-activated treatment with TH-302 provides a potential new treatment option for MM.


Clinical & Experimental Metastasis | 2008

Extravasation and homing mechanisms in multiple myeloma

Isabelle Vande Broek; Karin Vanderkerken; Benjamin Van Camp; Ivan Van Riet

Multiple myeloma (MM) is a malignant B-cell disorder characterized by a monoclonal expansion of plasma cells (PC) in the bone marrow (BM). During the main course of disease evolution, MM cells depend on the BM microenvironment for their growth and survival. Reciprocal interactions between MM cells and the BM mediate not only MM cell growth, but also protect them against apoptosis and cause bone disease and angiogenesis. A striking feature of MM represents the predominant localization and retention of MM cells in the BM. Although BM PC indeed represent the main neoplastic cell type, small numbers of MM cells can also be detected in the peripheral blood circulation. It can be assumed that these circulating cells represent the tumour-spreading component of the disease. This implicates that MM cells have the capacity to (re)circulate, to extravasate and to migrate to the BM (homing). In analogy to the migration and homing of normal leucocytes, the BM homing of MM cells is mediated by a multistep process of extravasation with adhesion to the endothelium, invasion of the subendothelial basement membrane, followed by further migration within the stroma, mediated by chemotactic factors. At the end stage of disease, MM cells are thought to develop autocrine growth supporting loops that enable them to survive and proliferate in the absence of the BM microenvironment and to become stroma-independent. In this stage, the number of circulating cells increases and growth at extramedullary sites can occur, associated with alteration in adhesion molecule and chemokine receptor expression. This review summarizes the recent progress in the study of the extravasation and homing mechanisms of MM cells.


Cancer Research | 2009

Bortezomib Alone or in Combination with the Histone Deacetylase Inhibitor JNJ-26481585: Effect on Myeloma Bone Disease in the 5T2MM Murine Model of Myeloma

Sarah Deleu; Miguel Lemaire; Janine Arts; Eline Menu; Els Van Valckenborgh; Isabelle Vande Broek; Hendrik De Raeve; Les Coulton; Ben Van Camp; Peter I. Croucher; Karin Vanderkerken

The proteasome inhibitor bortezomib (Velcade) is currently approved as second-line treatment of multiple myeloma (MM). MM-related bone disease is one of the most debilitating complications of MM. Besides supportive care with biphosphonates, which have proven efficacy in reducing and delaying skeletal-related events, there is no specific treatment of lytic bone lesions. The present study investigated the effect of bortezomib alone or in combination with a hydroxamate-based histone deacetylase inhibitor, JNJ-26481585 on tumor burden, and MM bone disease in the 5T2MM model. Injection of 5T2MM cells into C57Bl/KaLwRij mice resulted in MM bone disease, characterized by an increase in the percentage osteoclasts, a decrease in osteoblasts, trabecular bone volume, trabecular number, and the development of bone lesions. Treatment of 5T2MM-bearing mice with bortezomib significantly reduced tumor burden, angiogenesis, and MM bone disease. More importantly, the combination of bortezomib with JNJ-26481585 resulted in a more pronounced reduction of osteoclasts and increase of osteoblasts, trabecular bone volume, and trabecular number compared with bortezomib as single agent. These data suggest that bortezomib has bone remodeling properties that can be improved in combination with low dose JNJ-26481585. The study indicates that this combination therapy could be a useful strategy for the treatment of MM patients, especially in those patients with skeletal complications.


European Journal of Haematology | 2008

Multiple myeloma--an update on diagnosis and treatment.

Jo Caers; Isabelle Vande Broek; Hendrik De Raeve; Lucienne Michaux; Fabienne Trullemans; Rik Schots; Ben Van Camp; Karin Vanderkerken

Multiple myeloma is a plasma cell (PC) malignancy characterized by the accumulation of monoclonal PCs in the bone marrow and the production of large amounts of a monoclonal immunoglobulin or paraprotein. In the past years, new approaches in the diagnosis and treatment were introduced aiming to identify high‐risk patients who need proper anti‐myeloma treatment. Intensive therapy including autologous hematopoietic stem cell transplantation and the new agents bortezomib, thalidomide, and lenalidomide have improved patients’ responses. Further optimalization of the different treatment schedules in well‐defined patient groups may prolong their survival. Patient stratification is currently based on patient characteristics, extent of myeloma disease, and associated cytogenetic and laboratory anomalies. More and more gene expression studies are introduced to stratify patients and to individualize therapy.


Clinical & Experimental Metastasis | 2002

Monocyte chemoattractant protein-1 (MCP-1), secreted by bone marrow endothelial cells, induces chemoattraction of 5T multiple myeloma cells.

Karin Vanderkerken; Isabelle Vande Broek; Decio L. Eizirik; Els Van Valckenborgh; Kewal Asosingh; Ivan Van Riet; Ben Van Camp

Homing of multiple myeloma (MM) cells to the bone marrow (BM) requires transendothelial migration. In the present work we tested whether monocyte chemoattractant protein-1 (MCP-1) and CCR2, the high affinity receptor for MCP-1, are involved in this process. Murine 5T2 and 5T33MM cell lines were selected as source of MM cells and STR4, 10 and 12 of BM endothelial cells (BMEC). RT-PCR demonstrated transcripts for MCP-1 in BMEC and ELISA the presence of MCP-1 protein in culture medium. RNase protection assay showed mRNA expression for CCR2, and FACS analysis the presence of CCR2 protein on the MM cells. EC conditioned medium induced chemoattraction of MM cells, a phenomenon inhibited by anti-MCP-1 antibodies. In conclusion, MM cells express CCR2 and are attracted by MCP-1 secreted by BMEC. We suggest that local MCP-1 production by BMEC is one of the mechanisms involved in homing of myeloma cells to the BM.


Clinical Cancer Research | 2008

Epigenetic Silencing of the Tetraspanin CD9 during Disease Progression in Multiple Myeloma Cells and Correlation with Survival

Elke De Bruyne; Tomas Jan Bos; Kewal Asosingh; Isabelle Vande Broek; Eline Menu; Els Van Valckenborgh; Peter Atadja; Valérie Coiteux; Xavier Leleu; Kris Thielemans; Ben Van Camp; Karin Vanderkerken; Ivan Van Riet

Purpose: The purpose of this study was to investigate expression and epigenetic regulation of CD9 in multiple myeloma (MM) cells during disease progression. Experimental Design: CD9 expression was retrospectively analyzed on bone marrow myeloma samples from 81 patients by immunophenotyping. CD9 expression by murine 5TMM cells was detected by flow cytometric staining and quantitative PCR. The methylation status of the CD9 promoter was determined by bisulfite PCR sequencing. Results: Primary plasma cells in the majority of MM patients with nonactive disease (n = 28) showed CD9 expression, whereas most cases with active disease (n = 53) were CD9 negative. CD9 expression in diagnostic bone marrow samples (n = 74) correlated with survival. Moreover, CD9 expression on murine 5T33 and 5T2MM cells was significantly down-regulated during disease development. Treatment of CD9-nonexpressing 5T33MMvt cells with the clinically relevant histone deacetylase inhibitor LBH589 resulted in a significant increase in CD9 expression. In contrast, cells treated with the demethylation agent 5-aza-2′deoxycytidine barely showed any increase. A combination study with both compounds resulted in a strong synergistic reactivation of CD9. CD9-expressing 5T33MMvv cells and 5T33MMvt cells stably transduced with a mCD9 lentiviral transferplasmid were shown to be more susceptible to natural killer cell–mediated cytolysis than CD9-negative 5T33MMvt cells. Conclusions: CD9 expression correlates with disease status and survival of MM patients. In the murine 5T33MM model, we show that histone modifications, and to a lesser extent CpG methylation, are key epigenetic events in CD9 down-regulation. Furthermore, as CD9 expression becomes down-regulated, 5T33MM cells become less susceptible to natural killer cell–mediated cytolysis.


PLOS ONE | 2013

Upregulation of miR-135b is involved in the impaired osteogenic differentiation of mesenchymal stem cells derived from multiple myeloma patients.

Song Xu; Gaia Cecilia Santini; Kim De Veirman; Isabelle Vande Broek; Xavier Leleu; Ann De Becker; Ben Van Camp; Karin Vanderkerken; Ivan Van Riet

Previous studies have demonstrated that mesenchymal stem cells from multiple myeloma (MM) patients (MM-hMSCs) display a distinctive gene expression profile, an enhanced production of cytokines and an impaired osteogenic differentiation ability compared to normal donors (ND-hMSCs). However, the underlying molecular mechanisms are unclear. In the present study, we observed that MM-hMSCs exhibited an abnormal upregulation of miR-135b, showing meanwhile an impaired osteogenic differentiation and a decrease of SMAD5 expression, which is the target of miR-135b involved in osteogenesis. By gain and loss of function studies we confirmed that miR-135b negatively regulated hMSCs osteogenesis. We also found that MM cell-produced factors stimulated ND-hMSCs to upregulate the expression of miR-135b. Importantly, treatment with a miR-135b inhibitor promoted osteogenic differentiation in MM-hMSCs. Finally, we observed that MM cell-derived soluble factors could induce an upregulation of miR-135b expression in ND-hMSCs in an indirect coculture system and the miR-135b expression turned to normal level after the removal of MM cells. Collectively, we provide evidence that miR-135b is involved in the impaired osteogenic differentiation of MSCs derived from MM patients and might therefore be a promising target for controlling bone disease.


Acta Pharmacologica Sinica | 2013

Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells in vitro and bone formation in vivo.

Song Xu; Kim De Veirman; Holly Evans; Gaia Cecilia Santini; Isabelle Vande Broek; Xavier Leleu; Ann De Becker; Ben Van Camp; Peter I. Croucher; Karin Vanderkerken; Ivan Van Riet

Aim:Vorinostat, a histone deacetylase (HDAC) inhibitor currently in a clinical phase III trial for multiple myeloma (MM) patients, has been reported to cause bone loss. The purpose of this study was to test whether, and to what extent, vorinostat influences the osteogenic differentiation of mesenchymal stem cells (MSCs) in vitro and bone formation in vivo.Methods:Bone marrow-derived MSCs were prepared from both normal donors and MM patients. The MSCs were cultured in an osteogenic differentiation induction medium to induce osteogenic differentiation, which was evaluated by alkaline phosphatase (ALP) staining, Alizarin Red S staining and the mRNA expression of osteogenic markers. Naïve mice were administered vorinostat (100 mg/kg, ip) every other day for 3 weeks. After the mice were sacrificed, bone formation was assessed based on serum osteocalcin level and histomorphometric analysis.Results:Vorinostat inhibited the viability of hMSCs in a concentration-dependent manner (the IC50 value was 15.57 μmol/L). The low concentration of vorinostat (1 μmol/L) did not significantly increase apoptosis in hMSCs, whereas pronounced apoptosis was observed following exposure to higher concentrations of vorinostat (10 and 50 μmol/L). In bone marrow-derived hMSCs from both normal donors and MM patients, vorinostat (1 μmol/L) significantly increased ALP activity, mRNA expression of osteogenic markers, and matrix mineralization. These effects were associated with upregulation of the bone-specifying transcription factor Runx2 and with the epigenetic alterations during normal hMSCs osteogenic differentiation. Importantly, the mice treated with vorinostat did not show any bone loss in response to the optimized treatment regimen.Conclusion:Vorinostat, known as a potent anti-myeloma drug, stimulates MSC osteogenesis in vitro. With the optimized treatment regimen, any decrease in bone formation was not observed in vivo.


Acta Oncologica | 2000

Homing of the Myeloma Cell Clone

Karin Vanderkerken; Ben Van Camp; Catherine De Greef; Isabelle Vande Broek; Kewal Asosingh; Ivan Van Riet

The presence of myeloma cells in the blood circulation, implicates that these cells must have the potential to extravasate and home to the bone marrow environment. Using the 5T2 MM mouse model, we could demonstrate that the restricted localization of myeloma cells in the bone marrow is the result of selective migration of myeloma cells in the bone marrow combined with a selective growth of the tumour cells in the bone marrow microenvironment. Moreover, we showed that 5T2 MM cells bind in vitro selectively to bone marrow-derived endothelial cells (EC) and not to lung-derived EC. In order to identify which chemotactic molecules mediate the transendothelial migration of myeloma cells, we examined the motility-inducing effect of different extracellular matrix proteins on myeloma cell lines. We found that laminin-1, a major component of the basement membrane, triggers the motility of both human myeloma cells and 5T2 MM cells, through the 67 kD laminin receptor. Because of the broad distribution of laminin in extracellular matrices throughout the body, it is clear that this molecule on itself can not be the only factor that determines the specificity of myeloma cell homing. In the 5T2 MM model we identified IGF-1 as a more specific bone marrow derived chemoattractant for myeloma cells. In addition we demonstrated that the marrow microenvironment can upregulate the expression of the IGF-1 receptor on 5T mouse myeloma cells. In the end phase of the disease, increasing numbers of myeloma cells are detectable in the peripheral blood and extramedullary tumour growth can occur. We found that the stroma-independent variant of the human MM5 myeloma cell line showed an increased in vitro motility as compared to the stroma-dependent variant. By representational difference analysis we demonstrated that the stroma-dependent MM5 cells show a downregulation of the motility-related protein (MRP-1/CD9) which might reflect the involvement of this molecule in the regulation of myeloma cell extravasation.The presence of myeloma cells in the blood circulation. implicates that these cells must have the potential to extravasate and home to the bone marrow environment. Using the 5T2 MM mouse model, we could demonstrate that the restricted localization of myeloma cells in the bone marrow is the result of selective migration of myeloma cells in the bone marrow combined with a selective growth of the tumour cells in the bone marrow microenvironment. Moreover, we showed that 5T2 MM cells bind in vitro selectively to bone marrow-derived endothelial cells (EC) and not to lung-derived EC. In order to identify which chemotactic molecules mediate the transendothelial migration of myeloma cells, we examined the motility-inducing effect of different extracellular matrix proteins on myeloma cell lines. We found that laminin-1 a major component of the basement membrane, triggers the motility of both human myeloma cells and 5T2 MM cells, through the 67 kD laminin receptor. Because of the broad distribution of laminin in extracellular matrices throughout the body, it is clear that this molecule on itself can not be the only factor that determines the specificity of myeloma cell homing. In the 5T2 MM model we identified IGF-1 as a more specific bone marrow derived chemoattractant for myeloma cells. In addition we demonstrated that the marrow microenvironment can upregulate the expression of the IGF-1 receptor on 5T mouse myeloma cells. In the end phase of the disease, increasing numbers of myeloma cells are detectable in the peripheral blood and extramedullary tumour growth can occur. We found that the stroma-independent variant of the human MM5 myeloma cell line showed an increased in vitro motility as compared to the stroma-dependent variant. By representational difference analysis we demonstrated that the stroma-dependent MM5 cells show a downregulation of the motility-related protein (MRP-I CD9) which might reflect the involvement of this molecule in the regulation of myeloma cell extravasation.


Hematology Reviews | 2009

Histone deacetylase inhibitors in multiple myeloma

Sarah Deleu; Eline Menu; Els Van Valckenborgh; Ben Van Camp; Joanna Fraczek; Isabelle Vande Broek; Vera Rogiers; Karin Vanderkerken

Novel drugs such as bortezomib and high-dose chemotherapy combined with stem cell transplantation improved the outcome of multiple myeloma patients in the past decade. However, multiple myeloma often remains incurable due to the development of drug resistance governed by the bone marrow microenvironment. Therefore targeting new pathways to overcome this resistance is needed. Histone deacetylase (HDAC) inhibitors represent a new class of anti-myeloma agents. Inhibiting HDACs results in histone hyperacetylation and alterations in chromatine structure, which, in turn, cause growth arrest differentiation and/or apoptosis in several tumor cells. Here we summarize the molecular actions of HDACi as a single agent or in combination with other drugs in different in vitro and in vivo myeloma models and in (pre-)clinical trials.

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Ben Van Camp

Vrije Universiteit Brussel

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Ivan Van Riet

Vrije Universiteit Brussel

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Eline Menu

Imperial College London

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Michel Delforge

Katholieke Universiteit Leuven

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Sarah Deleu

Vrije Universiteit Brussel

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