Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)‐1<i>α</i> and MIP‐1<i>β</i> correlates with lytic bone lesions in patients with multiple myeloma

Hashimoto, Toshihiro; Abe, Masahiro; Oshima, Takashi; Shibata, Hironobu; Ozaki, Shuji; Inoue, Daisuke; Matsumoto, Toshio

doi:10.1111/j.1365-2141.2004.04864.x

Cited by 85 publications

(50 citation statements)

References 18 publications

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“…CCL3 and CCL4 RNA expression in MM cell lines were analysed with RT-PCR and the secretion to the cell culture supernatant by MM cell lines and magnetic bead separated MM PCs from myeloma patients, by ELISA technique (Abe et al, 2002;Hashimoto et al, 2004). The differences in techniques, and especially, in analysed material (cell lines vs. MM patient PCs) may explain the discrepancy between literature data and ours.…”

Section: Ccl3 and Ccl4contrasting

confidence: 44%

“…In a semi-quantitative manner with RT-PCR and agarose gel electrophoresis it has been found that CCL3 and CCL4 were produced and secreted by a majority of MM cell lines, and is secreted to the culture supernatants by magnetic bead-separated MM PCs from MM patients (Abe et al, 2002). A correlation between MIP-1a and -b secretion in supernatants of cultured MM cells and the severity of OBD was demonstrated with enzyme-linked immunosorbent assay (ELISA) (Abe et al, 2002;Hashimoto et al, 2004).…”

Section: Ccl3 and Ccl4mentioning

confidence: 99%

“…Recently, the genes that encode for macrophage inflammatory protein-1 alpha (MIP-1a) and -beta (MIP-1b) (CCL3 and CCL4 respectively) have been identified as candidate genes for osteclastogenic factors (Choi et al, 2000;Han et al, 2001;Abe et al, 2002) and studies have shown that the majority of MM cells from patients and MM cell lines secrete MIP-1a and MIP1b (Abe et al, 2002;Uneda et al, 2003;Hashimoto et al, 2004) and serum MIP-1a levels correlate with the extent of OBD and survival (Terpos et al, 2005). These factors enhance osteoclast formation by binding to their cognate receptor, CCR5, on osteoclast precursors.…”

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confidence: 99%

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Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis

et al. 2007

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SummaryOsteolytic bone disease (OBD) in multiple myeloma (MM) is caused by interactions between MM cells and the bone marrow microenvironment and is characterized by increased osteoclastic bone resorption and decreased osteoblastic bone formation. Recently, the role of osteoblast inhibition has come into focus, especially the possible role of overexpression of DKK1, an inhibitor of the Wnt signalling pathway. Further, CKS2, PSME2 and DHFR have also been reported as candidate genes for OBD. We studied the gene expression by quantitative reverse transcription polymerase chain reaction of TNFSF11 (RANKL), TNFSF11A (RANK), TNFRSF11B (OPG), CCL3 (MIP1A), CCL4 (MIP1B), PTHR1 (PTHrp), DKK1, CKS2, PSME2 and DHFR in purified, immunophenotypic FACS‐sorted plasma cells from 171 newly diagnosed MM patients, 20 patients with monoclonal gammopathy of undetermined significance and 12 controls. The gene expressions of the analysed genes were correlated with radiographically assessed OBD. Only overexpression of DKK1 was correlated to the degree of OBD. Myeloma cells did not express TNFSF11A, TNFSF11, or TNFRSF11B, and very rarely expressed CCL3 and PTHR11. CCL4, CKS2, PSME2 and DHFR were variably expressed, but the expression of these genes showed no correlation with OBD. In contrast, loss of PSME2 expression in MM plasma cells was significantly correlated with OBD.

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Section: Ccl3 and Ccl4contrasting

confidence: 44%

Section: Ccl3 and Ccl4mentioning

confidence: 99%

mentioning

confidence: 99%

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Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis

et al. 2007

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“…Similarly, increasing b leads to more bone destruction, higher tumour burden and faster tumour progression. This behaviour is observed clinically, patients with higher MIP-1a levels (increasing b) tend to have more bone resorption and lytic bone lesions (Terpos et al, 2003;Hashimoto et al, 2004) and shorter survival due to a higher tumour burden (Terpos et al, 2003). Consequently, therapies which suppress or reduce b (inhibiting, e.g., MIP-1a secretion or IL-1b (Lust et al, 2009;Dinarello, 2009b)) should decrease the number of lytic lesions and the speed of disease progression, prolonging survival (Choi et al, 2001).…”

Section: Resultsmentioning

confidence: 73%

Cancer phenotype as the outcome of an evolutionary game between normal and malignant cells

et al. 2009

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BACKGROUND: There is variability in the cancer phenotype across individuals: two patients with the same tumour may experience different disease life histories, resulting from genetic variation within the tumour and from the interaction between tumour and host. Until now, phenotypic variability has precluded a clear-cut identification of the fundamental characteristics of a given tumour type. METHODS: Using multiple myeloma as an example, we apply the principles of evolutionary game theory to determine the fundamental characteristics that define the phenotypic variability of a tumour. RESULTS: Tumour dynamics is determined by the frequency-dependent fitness of different cell populations, resulting from the benefits and costs accrued by each cell type in the presence of others. Our study shows how the phenotypic variability in multiple myeloma bone disease can be understood through the theoretical approach of a game that allows the identification of key genotypic features in a tumour and provides a natural explanation for phenotypic variability. This analysis also illustrates how complex biochemical signals can be translated into cell fitness that determines disease dynamics. CONCLUSION: The present paradigm is general and extends well beyond multiple myeloma, and even to non-neoplastic disorders. Furthermore, it provides a new perspective in dealing with cancer eradication. Instead of trying to kill all cancer cells, therapies should aim at reducing the fitness of malignant cells compared with normal cells, allowing natural selection to eradicate the tumour.

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“…Levels of MIP-1a in marrow of patients with myeloma range between 100 and 2000 pg/ml. 27 Similarly, Hashimoto and co-workers 29 have shown that elevated levels of MIP-1a and MIP-1b are both detectable in patients with myeloma, and that high levels of MIP-1a are associated with an extremely poor prognosis. Most recently, Magrangeas and co-workers 30 have shown by gene-expression profiling that MIP-1a expression is the gene most highly correlated with bone destruction in myeloma patients.…”

Section: Macrophage Inflammatory Protein-1amentioning

confidence: 99%

Treatment strategies for bone disease

Roodman

2007

Bone Marrow Transplant

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Multiple myeloma is characterized by extensive bone destruction with little or no new bone formation. A multiplicity of factors including receptor activator NF-jB (RANKL), macrophage inflammatory protein-1a, interleukin-3 and interleukin-6 can induce osteoclast formation in myeloma and drive the bone destructive process. Furthermore, factors are also produced either in the microenvironment or by myeloma cells themselves, which inhibit osteoblast differentiation and new bone formation. The combination of increased osteoclast formation with little or no bone repair in response to the previous bone destruction explains the severity of the bone disease in myeloma. Studies of the pathophysiology of myeloma bone disease have identified several novel therapeutic targets. These include antibodies to RANKL, chemokine receptor antagonists, which block the effects of chemokines on osteoclast differentiation and proteasome antagonists, which can affect both RANKL production and osteoprotegerin levels as well as inhibit osteoclast and enhance osteoblast differentiation. In addition, many of the new biologic agents being used for the treatment of patients with myeloma also further inhibit the bone destructive process. New therapies that can target both the tumor as well as the severe bone disease should be on the horizon to treat this devastating complication of myeloma.

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Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)‐1α and MIP‐1β correlates with lytic bone lesions in patients with multiple myeloma

Abstract: These results provide further evidence for a causal role of MIP-1a and MIP1b in the development of lytic bone lesions, and suggest that MM cells suppress osteoblastic bone formation to cause an imbalance of bone turnover and development of destructive bone lesions.

Cited by 85 publications

References 18 publications

Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis

Myeloma cell expression of 10 candidate genes for osteolytic bone disease. Only overexpression of DKK1 correlates with clinical bone involvement at diagnosis

Cancer phenotype as the outcome of an evolutionary game between normal and malignant cells

Treatment strategies for bone disease

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