Myeloma Cell-Osteoclast Interaction Enhances Angiogenesis Together with Bone Resorption: A Role for Vascular Endothelial Cell Growth Factor and Osteopontin

Tanaka, Yoïchi; Abe, Masahiro; Hiasa, Masahiro; Oda, Asuka; Amou, Hiroe; Nakano, Ayako; Takeuchi, Kyoko; Kitazoe, Ken-ichi; Kido, Shinsuke; Inoue, Daisuke; Moriyama, Keiji; Hashimoto, Toshihiro; Ozaki, Shuji; Matsumoto, Toshio

doi:10.1158/1078-0432.ccr-06-2258

Cited by 151 publications

(114 citation statements)

References 42 publications

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“…It inhibits bFGF-induced proliferation (11), adhesion, migration, and survival of human umbilical vascular endothelial cells (26); decreases bone tumor -associated angiogenesis in the murine 5T2 multiple myeloma model (27); inhibits revascularization of the ventral prostate gland in castrated rats treated with testosterone (12); modulates a v h 3 and a v h 5 integrins (28); inhibits matrix metalloproteinase-2 and matrix metalloproteinase-9 (29); and modulates in cancer patients serum levels of proangiogenic growth factors including VEGF and bFGF (30). In vivo, zoledronic acid antiangiogenic activity may be also mediated via inhibition of osteoclasts, which actually produce angiogenic factors (31).…”

Section: Resultsmentioning

confidence: 99%

Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma

Scavelli¹,

Pietro²,

Cirulli³

et al. 2007

Molecular Cancer Therapeutics

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Therapeutic doses of zoledronic acid markedly inhibit in vitro proliferation, chemotaxis, and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma. Zoledronic acid also induces a sizeable reduction of angiogenesis in the in vivo chorioallantoic membrane assay. These effects are partly sustained by gene and protein inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in an autocrine loop. Mevastatin, a specific inhibitor of the mevalonate pathway, reverts the zoledronic acid antiangiogenic effect, indicating that the drug halts this pathway. Our results provide evidence of a direct antiangiogenic activity of zoledronic acid on multiple myeloma patient-derived endothelial cells due to at least four different mechanisms identified either in vitro or in vivo. Tentatively, we suggest that the zoledronic acid antitumoral activity in multiple myeloma is also sustained by antiangiogenesis, which would partly account for its therapeutic efficacy in multiple myeloma. [Mol Cancer Ther 2007;6(12):3256-62]

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Section: Resultsmentioning

confidence: 99%

Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma

Scavelli¹,

Pietro²,

Cirulli³

et al. 2007

Molecular Cancer Therapeutics

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“…These effects were only partially blocked by an antibody to IL-6, but were completely abrogated by inhibition of cellular contact, demonstrating the critical role of direct contact between myeloma cells and osteoclasts (50). Interactions between myeloma cells and osteoclasts have also been shown to result in an increase in the secretion of proangiogenic factors, and an increase in vascular tubule formation, suggesting a link between myeloma cells, osteoclasts and angiogenesis (40).…”

Section: Cell-cell Interactionsmentioning

confidence: 99%

“…In addition, VEGF can substitute for M-CSF in the induction of in vitro osteoclast differentiation (39). A recent study has demonstrated that blockade of both VEGF and osteopontin almost completely abrogated angiogenesis and bone resorption enhanced by coculture of myeloma cells and osteoclasts (40), suggesting VEGF may support osteoclastic bone resorption in myeloma.…”

Section: Vegfmentioning

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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“…22 Among the up-regulated genes, SPP1 was reported to enhance MM cell survival, migration, angiogenesis, and bone destruction. [23][24][25][26] Melanoma 2 (AIM2) was recently shown to be 1 of the 70 high-risk signature genes in MM, 11 and transcription factor Dp-1 (TFDP1) was reported to facilitate cell-cycle progression. [27][28][29][30] High expression of RAS p21 protein activator 1 (RASA1) in myeloma cells from patients with RAR␣2 ϩ myeloma suggested that Ras-Raf-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling pathways may be the RAR␣2-mediated downstream signaling pathway.…”

Section: Identification Of Molecular Pathways Associated With Rar␣2 Ementioning

confidence: 99%

RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

Wang

Tricot

Shi

et al. 2009

Blood

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IntroductionMultiple myeloma (MM) is a plasma cell malignancy. 1,2 Although high-dose therapy and tandem bone marrow autotransplantation can produce higher response rates and longer survival than standard chemotherapy, MM remains largely incurable by current therapeutic strategies. 3,4 Furthermore, clinical outcomes of patients with MM are extremely heterogeneous, with survival ranging from only a few months to more than 15 years. [4][5][6] Increasing evidence suggests that genetic heterogeneity in MM cells largely accounts for the divergent clinical outcomes. 6 We have been pursuing the genetic characteristics of MM for nearly 10 years, which has contributed to the classification of MM diseases. [7][8][9][10][11] However, it remains unknown how to transform MM into a curable disease. Therefore, identification of new targets and genetic alterations, especially those for which there are available drugs, is important.All-trans retinoic acid (ATRA)-based regimens have been used in the therapy of acute promyelocytic leukemia (APL) for more than 20 years and have dramatically raised the 5-year disease-free survival to more than 70%. Furthermore, the toxicity of ATRA has been limited compared with conventional cytotoxic chemotherapy. 12 The high efficacy of retinoic acid (RA)-based therapy in APL and its well-documented safety profile have stimulated considerable interests in the treatment of other malignancies, [13][14][15] including myeloma. 16,17 Despite many efforts, however, clinical benefits of ATRA treatment in other tumors have been minor. RAR␣ has 2 major isoforms, RAR␣1 and RAR␣2, which differ in their expression patterns and N-terminal AF-1 functional domains. 18 Both RAR␣1 and RAR␣2 are considered specific receptors for RA-based reagents. However, the specific cellular roles of RAR␣1 and RAR␣2 are still unclear. In this study, we found that RAR␣2 plays a crucial role in myeloma progression, and more importantly, in mediating RA-based therapy of RAR␣2 ϩ MM diseases. Methods Study subjectsCD138 ϩ myeloma cell samples were obtained from patients who were enrolled on the National Institutes of Health (NIH)-sponsored clinical trials UARK 98-026 (Total Therapy 2 [TT2]) and UARK 03-033 (TT3). The Institutional Review Board of the University of Arkansas for Medical Sciences approved the research studies, and all subjects provided written informed consent in accordance with the Declaration of Helsinki.We have an inventory of more than 30 myeloma cell lines in our laboratory. Cells from these cell lines were cultured in RPMI 1640 containing 10% heat-inactivated fetal calf serum (FCS), 2 mM L-glutamine (Gibco), penicillin (100 U/mL), and streptomycin (100 g/mL) in a humidified incubator at 37°C in 5% CO 2 . Gene expression profilingPlasma cell purifications and gene expression profiling, using the Affymetrix U133Plus2.0 microarray, were performed as previously described. 9,11 Signal intensities were preprocessed and normalized by GCOS1.1 software (Affymetrix). 9,11 Myeloma cell samples from 80 newly diagnosed patien...

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Myeloma Cell-Osteoclast Interaction Enhances Angiogenesis Together with Bone Resorption: A Role for Vascular Endothelial Cell Growth Factor and Osteopontin

Cited by 151 publications

References 42 publications

Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma

Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma

The pathogenesis of the bone disease of multiple myeloma

RARα2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma

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