The Microenvironment and Molecular Biology of the Multiple Myeloma Tumor

Lemaire, Miguel; Deleu, Sarah; Bruyne, Elke De; Valckenborgh, Els Van; Menu, Eline; Vanderkerken, Karin

doi:10.1016/b978-0-12-386469-7.00002-5

Cited by 69 publications

(69 citation statements)

References 143 publications

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“…BMSCs or 5T33MMvt cells were incubated in medium containing 1,3,39,) (red) cell-labeling solution for 20 minutes at 37°C and washed with medium 3 times. Exosome suspension was labeled with DIO (green) and repelleted, using ExoQuick-TC exosome precipitation solution, 3 times.…”

Section: Fluorescent Labeling and Confocal Microscopymentioning

confidence: 99%

“…3 It is well known that the BM microenvironment and the interaction between BMSCs and MM cells contribute to drug resistance of these cells by cell-to-cell adhesion and secretion of soluble factors by BMSCs. 24,55 As a consequence, several pathways related to drug resistance and cell survival such as Notch1, 56,57 signal transducer and activator of transcription 3, 58 Akt, 5 and NF-kB 59 are activated to protect the MM cells from death.…”

Section: Bmsc Exosomes Induce MM Growth and Drug Resistance 563mentioning

confidence: 99%

“…3 MM cells depend on the BM microenvironment for their growth and survival through interaction with the BM stromal cells (BMSCs). BMSCs consist mainly of fibroblasts and can secrete different kinds of cytokines, chemokines, growth factors, and small molecular mediators.…”

Section: Introductionmentioning

confidence: 99%

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Bone marrow stromal cell–derived exosomes as communicators in drug resistance in multiple myeloma cells

Wang

Hendrix

Hernot

et al. 2014

Blood

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Vrije Universiteit Brussels, Brussel, Belgium Key Points• BMSCs and MM cells mutually communicate through exosomes, which carry selective cytokines.• BMSC-derived exosomes favor MM cell proliferation, migration, and survival and induce drug resistance to bortezomib.The interplay between bone marrow stromal cells (BMSCs) and multiple myeloma (MM) cells performs a crucial role in MM pathogenesis by secreting growth factors, cytokines, and extracellular vesicles. Exosomes are membranous vesicles 40 to 100 nm in diameter constitutively released by almost all cell types, and they mediate local cell-to-cell communication by transferring mRNAs, miRNAs, and proteins. Although BMSC-induced growth and drug resistance of MM cells has been studied, the role of BMSC-derived exosomes in this action remains unclear. Here we investigate the effect of BMSC-derived exosomes on the viability, proliferation, survival, migration, and drug resistance of MM cells, using the murine 5T33MM model and human MM samples. BMSCs and MM cells could mutually exchange exosomes carrying certain cytokines. Both naive and 5T33 BMSC-derived exosomes increased MM cell growth and induced drug resistance to bortezomib. BMSC-derived exosomes also influenced the activation of several survival relevant pathways, including c-Jun N-terminal kinase, p38, p53, and Akt. Exosomes obtained from normal donor and MM patient BMSCs also induced survival and drug resistance of human MM cells. Taken together, our results demonstrate the involvement of exosome-mediated communication in BMSC-induced proliferation, migration, survival, and drug resistance of MM cells. (Blood. 2014;124(4):555-566) IntroductionMultiple myeloma (MM) is a deadly hematological malignancy characterized by the uncontrolled growth and accumulation of monoclonal plasma cells in the bone marrow (BM), the presence of a monoclonal immunoglobulin fraction in the serum or urine, 1,2 renal failure, and osteolytic bone lesions.3 MM cells depend on the BM microenvironment for their growth and survival through interaction with the BM stromal cells (BMSCs). BMSCs consist mainly of fibroblasts and can secrete different kinds of cytokines, chemokines, growth factors, and small molecular mediators. 4 These functional components trigger MM growth, survival, and progression through several signaling pathways, such as mitogen-activated protein kinase kinase/mitogen-activated protein kinase, focal adhesion kinase, phosphatidylinositol 3-kinase/Akt, MEK/extracellular signal-regulated kinase, and signal transducer and activator of transcription 3, 5 which will ultimately lead to angiogenesis, bone disease, and drug resistance.Exosomes are small (40-100 nm) membrane vesicles secreted by various cell types, including dendritic cells, B cells, T cells, mast cells, epithelial cells, and tumor cells, 6 through the fusion of multivesicular bodies with the plasma membrane.7 Exosomes mediate local cell-to-cell communication by transferring mRNAs, miRNAs, and proteins. Because of their ability to transfer functional com...

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Section: Fluorescent Labeling and Confocal Microscopymentioning

confidence: 99%

Section: Bmsc Exosomes Induce MM Growth and Drug Resistance 563mentioning

confidence: 99%

See 1 more Smart Citation

Bone marrow stromal cell–derived exosomes as communicators in drug resistance in multiple myeloma cells

Wang

Hendrix

Hernot

et al. 2014

Blood

Self Cite

378

314

View full text Add to dashboard Cite

show abstract

“…A combinatorial effect was observed in the patient responding to PPP (data not shown). The BM microenvironment plays an important role in the expansion and survival of the MM cells (45). The 5T33MM model offers a unique possibility to study the benefits of in vivo drug combinations in a therapeutic setting because the tumor grows in a syngeneic BM microenvironment (28).…”

Section: Discussionmentioning

confidence: 99%

The HDAC Inhibitor LBH589 Enhances the Antimyeloma Effects of the IGF-1RTK Inhibitor Picropodophyllin

Lemaire

Fristedt

Agarwal

et al. 2012

Clinical Cancer Research

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Purpose: We have previously shown the use of the insulin-like growth factor type 1 receptor tyrosine kinase (IGF-1RTK) inhibitor picropodophyllin (PPP) as an attractive strategy to combat multiple myeloma (MM) in vitro and in vivo. After a combinatorial drug screening, the histone deacetylase inhibitor LBH589 was shown to act in synergy with PPP reducing survival of MM cells. In this study, we tried to elucidate the molecular mechanisms underlying this combinatorial effect.Experimental Design: The in vitro anti-MM effects of PPP and LBH589 alone and in combination were evaluated by studying apoptosis, cell cycle distribution, and downstream transcriptome using both human MM cell lines and cells from the murine 5T3MM model. In vivo the effect on survival of 5T33MM-inoculated mice was evaluated.Results: In the human MM cell line RPMI8226, treatment with PPP and LBH589 in combination resulted in a five-fold increase of apoptosis, and an additive effect on the cleavage of the active forms of caspase-8 was observed as compared with the single drug treatments. Cell cycle analysis revealed an accumulation of cells in the G 2 -M phase and subsequent downregulation of cell cycle regulating proteins. These data were also confirmed in the 5T33MM cells in vitro. Also, the transcriptome was analyzed by Affymetrix arrays showing gene expression alterations mainly in categories of genes regulating apoptosis and cell adhesion. Combined treatment in vivo resulted in a significantly prolonged survival of 5T33MM-inoculated mice. Conclusions:The results indicate an improved MM treatment opportunity in using a combination of PPP and LBH589.

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“…In addition to intrinsic genetic changes in MM cells, the progression of MM is facilitated by the bone marrow microenvironment skewed by MM cells, which underlies the unique pathophysiology of MM [12][13][14]. MM cells enhance osteoclastogenesis and stimulate angiogenesis in concert with bone marrow stromal cells and osteoclasts, whereas they suppress osteoblastic differentiation from bone marrow stromal cells, leading to devastating bone destruction and the rapid loss of bone [15,16].…”

Section: Bone Marrow Microenvironment Suited For MM Growth (Mm Niche)mentioning

confidence: 99%

Guest editorial: understanding the pathogenesis and the evolving treatment paradigm for multiple myeloma in the era of novel agents

Abe

2011

Int J Hematol

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The Microenvironment and Molecular Biology of the Multiple Myeloma Tumor

Cited by 69 publications

References 143 publications

Bone marrow stromal cell–derived exosomes as communicators in drug resistance in multiple myeloma cells

Bone marrow stromal cell–derived exosomes as communicators in drug resistance in multiple myeloma cells

The HDAC Inhibitor LBH589 Enhances the Antimyeloma Effects of the IGF-1RTK Inhibitor Picropodophyllin

Guest editorial: understanding the pathogenesis and the evolving treatment paradigm for multiple myeloma in the era of novel agents

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