scholarly journals Hypoxia: Progressive Multiple Myeloma and Its Therapy Resistance

2021 ◽  
Author(s):  
Ogechi Charity Obayi ◽  
Emmanuella Ogbonna ◽  
Catherine Chinonye Eleje ◽  
Nwabueze Enukaorah Permsec Umerah
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Plasma Cells ◽  
Treatment Resistance ◽  
Hypoxic Condition ◽  
Therapy Resistance ◽  
Growth And Survival ◽  
Initial Stage ◽  
Pubmed Search

This study critically reviews the role of hypoxia in the progression of Multiple Myeloma (MM) and its therapy resistance. It explains the existence and role played by Hypoxia Inducible Factors (HIF) including HIF-1α and HIF-β in tumor (MM) progression. These HIF are key transcription factors of hypoxia and they aid the cellular adaptation of both normal and cancer cells to reduction in oxygen concentration. At initial stage of MM, the bone marrow environment sufficiently supports the growth and survival of the MM cells, but as the disease progresses and the plasma cells goes deeper into the bone marrow, they experience a more hypoxic condition. This then activates HIF1 and HIF-2 which ultimately stimulates angiogenic factors. This is a description of the step by step approaches through which a review of Hypoxia: progressive multiple myeloma and its drug resistance was conducted using Google scholar and PubMed search engines to search articles published from 2000 to May 2020 using the following key words: hypoxia, progressive multiple myeloma, treatment resistance, hypoxia and multiple myeloma. This review suggests that agents capable of inhibiting the action of HIF’s, as well as those that would act specifically on the hypoxic zones will be helpful in minimizing/eliminating drug resistance and relapses in MM patients and would invariably improves the patient life expectancy.

Targeting the Serine-Threonine Kinase PIM2: Implications in IL-6 Mediated Survival in Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3401-3401
Author(s):  
Jayakumar R Nair ◽  
Tyger L Howell ◽  
Justin Caserta ◽  
Carmen M Baldino ◽  
Gerald Fetterly ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Death ◽  
Plasma Cells ◽  
Serine Threonine Kinase ◽  
Myeloma Cells ◽  
Threonine Kinase ◽  
Equity Ownership ◽  
Microarray Expression

Abstract Despite major advances in chemotherapy, multiple myeloma remains incurable and in need of new therapies that target novel pathways. Insufficient understanding of the molecular pathways that regulate survival in myeloma is a major impediment towards designing better therapies to prolong survival in patients or even cure the disease. This necessitates the identification of new protein targets that are crucial for the growth and survival of multiple myeloma. Just like normal plasma cells, MM cells also depend on their interactions with bone marrow stromal cells (BMSC) for survival and production of essential growth factors. We have previously shown that MM cells interact with dendritic cells (DC) in the microenvironment and in vitro can stimulate DC to produce IL-6 (ASH2010#132, ASH2011 #147, ASH2012#722). Our recent publications show that when MM cells are not in direct contact with DC, the IL-6 produced by DC can protect MM cells against dexamethasone induced cell death, while neutralizing the IL-6 with antibodies can reverse that effect (Nair et al., 2011). Unfortunately, exactly how this survival response is mediated in MM is not very clear. PIM2, a serine threonine kinase, part of the proto-oncogene group of PIM kinases has been implicated in survival in several types of cancers including prostate cancer and multiple myeloma. In our lab, microarray gene expression analysis of publicly available datasets (Figure 1) show a trend towards increased expression of PIM2 in plasma cells from myeloma patients (left panel), and significantly in the poor prognosis subgroup MAF (Zhan et al., 2006) (right panel). For the first time we show that IL-6 produced by DC may be protecting myeloma cells by up regulating PIM2 and inactivating a major protein translation inhibitor 4EBP1, which also happens to be a PIM2 target. We show that silencing PIM2 with siRNA down regulates PIM2 activity and reverses the inactivation of 4EBP1, while the latter is known to cause cell death in myeloma. We also demonstrate that neutralizing IL-6 in MM cells that either don’t produce IL-6 on their own (MM.1S) or those that do (U266), abrogates extraneous DC-IL6 ability to induce PIM2 and its downstream target 4EBP1. Recombinant IL-6 also provided similar induction of PIM2 in myeloma and increased 4EBP1 phosphorylation, which was again reversed by neutralizing the antibody against IL-6. In myeloma patients, the use of dexamethasone in frontline therapies is often complicated by the ability of the bone marrow environment to produce IL-6 that not only induce increased proliferation of MM but also help resist dexamethasone mediated cell death in myeloma. Interestingly, when we used a novel PIM2 inhibitor, JP_11646 (kindly provided by Jasco Pharmaceuticals, LLC), it not only arrested IL-6 induced proliferation even at sub-lethal doses, but also prevented IL-6 mediated rescue of myeloma cells (Figure 2). This suggests that PIM2 might be a major player in IL-6 mediated drug resistance in myeloma and targeting it may help to subvert IL-6 mediated survival in myeloma. Through RT-PCR and westerns, we also show that IL-6 modulates PIM2 expression and activity resulting in increased 4EBP1 phosphorylation (Figure 3). This was abrogated when PIM2 activity was inhibited by JP_11646 (Figure 3). We also present data that suggests IL-6 via PIM2 may be regulating other anti-apoptotic molecules downstream of IL-6 receptors including MCL-1, that is vital to MM survival. Developing PIM2 targeted therapies provides an exciting opportunity to affect the myeloma tumor microenvironment where MM induced IL-6 production from BM could be inducing drug resistance. Figure 1: Microarray expression ofPIM2 in myeloma and MAF Figure 1:. Microarray expression ofPIM2 in myeloma and MAF Figure 2: PIM2 inhibition abrogates IL-6 induced MM proliferation (A) and protection (B). Figure 2:. PIM2 inhibition abrogates IL-6 induced MM proliferation (A) and protection (B). Figure 3: Inhibiting PIM2 activity prevents PIM2 induced phosphorylation of 4EBP1 by IL-6 in myeloma Figure 3:. Inhibiting PIM2 activity prevents PIM2 induced phosphorylation of 4EBP1 by IL-6 in myeloma Disclosures Caserta: Jasco Pharmaceuticals LLC: Equity Ownership. Baldino:Jasco Pharmaceuticals LLC: Equity Ownership.

Targeting EXT1 reveals a crucial role for heparan sulfate in the growth of multiple myeloma

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 601-604 ◽  
Author(s):  
Rogier M. Reijmers ◽  
Richard W. J. Groen ◽  
Henk Rozemuller ◽  
Annemieke Kuil ◽  
Anneke de Haan-Kramer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Heparan Sulfate ◽  
Cell Fate ◽  
Plasma Cells ◽  
Core Protein ◽  
Strong Increase ◽  
Growth And Survival ◽  
Xenotransplantation Model

Abstract Expression of the heparan sulfate proteoglycan syndecan-1 is a hallmark of both normal and multiple myeloma (MM) plasma cells. Syndecan-1 could affect plasma cell fate by strengthening integrin-mediated adhesion via its core protein and/or by accommodating and presenting soluble factors via its HS side chains. Here, we show that inducible RNAi-mediated knockdown of syndecan-1 in human MM cells leads to reduced growth rates and a strong increase of apoptosis. Importantly, knockdown of EXT1, a copolymerase critical for HS chain biosynthesis, had similar effects. Using an innovative myeloma xenotransplantation model in Rag-2−/−γc−/− mice, we demonstrate that induction of EXT1 knockdown in vivo dramatically suppresses the growth of bone marrow localized myeloma. Our findings provide direct evidence that the HS chains of syndecan-1 are crucial for the growth and survival of MM cells within the bone marrow environment, and indicate the HS biosynthesis machinery as a potential treatment target in MM.

scholarly journals Multiple Myeloma Macrophages: Pivotal Players in the Tumor Microenvironment

2013 ◽  
Vol 2013 ◽  
pp. 1-6 ◽  
Author(s):  
Simona Berardi ◽  
Roberto Ria ◽  
Antonia Reale ◽  
Annunziata De Luisi ◽  
Ivana Catacchio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Proteolytic Enzymes ◽  
Vasculogenic Mimicry ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Growth And Survival

Tumor microenvironment is essential for multiple myeloma (MM) growth, progression, and drug resistance through provision of survival signals and secretion of growth and proangiogenic factors. This paper examines the importance of macrophages within MM bone marrow (BM) microenvironment, referred to as MM-associated macrophages, as a potential niche component that supports tumor plasma cells. These macrophages are derived from peripheral blood monocytes recruited into the tumor. Upon activation by MM plasma cells and mesenchymal stromal cells, macrophages can release growth factors, proteolytic enzymes, cytokines, and inflammatory mediators that promote plasma cell growth and survival. Macrophages promote tumor progression through several mechanisms including angiogenesis, growth, and drug resistance. Indeed, these macrophages are essential for the induction of an angiogenic response through vasculogenic mimicry, and this ability proceeds in step with progression of the plasma cell tumors. Data suggest that macrophages play an important role in the biology and survival of patients with MM, and they may be a target for the MM antivascular management.

MCL1 Inhibitors in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-12-SCI-12
Author(s):  
Karin Vanderkerken ◽  
Kim De Veirman ◽  
Ken Maes ◽  
Eline Menu ◽  
Elke De Bruyne
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Conflicts Of Interest ◽  
Therapeutic Option ◽  
Therapy Resistance ◽  
Bone Marrow Microenvironment ◽  
Molecular Heterogeneity

Apoptosis plays a key role, not only in normal homeostasis but also in protection against genomic instability. Protection against apoptosis is a hallmark of cancer and is mainly regulated by the overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-Xl or Mcl-1. This results in increased survival of the tumor cells and resistance to therapy. This presentation will focus on MCL-1 (myeloid cell leukemia 1), its expression and its role as potential target in multiple myeloma (MM). MCL1 gene regions are one the most amplified gene regions in several human cancers and Mcl-1 activity is often associated with therapy resistance and relapse. Mcl-1 binds to and sequesters the pro-apoptotic BH3 proteins, thereby preventing apoptosis. Mcl-1 is overexpressed on MM cells from newly diagnosed patients compared to normal plasma cells and in MM cells at relapse. This overexpression is furthermore associated with a shorter survival of these patients. Increased Mcl-1 expression can result either from genetic lesions or by induction through interaction with the bone marrow microenvironment. Its expression is correlated with the molecular heterogeneity of the myeloma patients; while the CCDN1 group has high BCL2 and low MCL-1 expression; the MMSET and MAF group has high MCL-1 and low BCL2 expression. Unlike Bcl-2 and Bcl-Xl, Mcl-1 has a large unstructured aminoterminus and its activity is mainly dependent on posttranslational modifications. The bone marrow microenvironment, by producing high levels of interleukin 6, also induces the upregulation of Mcl-1. Furthermore, our group recently demonstrated that not only stromal cells in the bone marrow microenvironment, but also MDSC (myeloid derived suppressor cells) induce survival of MM cells by increasing Mcl-1 levels through the AMPK pathway. As such, these data suggest the potential therapeutic benefit of targeting Mcl-1 in MM patients. Developing the first-generation inhibitors appeared to be challenging, especially in view of the occurrence of unwanted off target effects. Recent preclinical data with new, selective Mcl-1 inhibitors show promising anti-tumor effects both in vitro and in in vivo myeloma models, either alone or in combination with the Bcl-2 selective inhibitor, venetoclax, especially as it was demonstrated that high levels of MCL-1 are associated with venetoclax resistance in MM. In addition, it was also shown that proteasome inhibition can trigger Mcl-1 accumulation, further pointing to the importance of Mcl-1 inhibition. Induction of NOXA, as an inhibitor of Mcl-1, is also suggested as a therapeutic option, especially in combinations with other drugs. Clinically, following preclinical results, several new Mcl-1 inhibitors have entered phase I trials. Most of them are still recruiting patients, and as such too early to have results. Disclosures No relevant conflicts of interest to declare.

scholarly journals Influence of metformin on HIF-1 pathway in multiple myeloma

2020 ◽  
Vol 72 (5) ◽  
pp. 1407-1417
Author(s):  
Kinga A. Kocemba-Pilarczyk ◽  
Sonia Trojan ◽  
Barbara Ostrowska ◽  
Małgorzata Lasota ◽  
Paulina Dudzik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Treatment Strategies ◽  
Annexin V ◽  
Growth And Survival ◽  
Hypoxic Conditions ◽  
New Treatment ◽  
First Time ◽  
Pcr Techniques

Abstract Background Multiple myeloma (MM) is defined as plasma cells malignancy, developing in the bone marrow. At the beginning of the disease, the malignant plasma cells are dependent on bone marrow microenvironment, providing growth and survival factors. Importantly, the recent studies pointed hypoxia as an important factor promoting progression of MM. In particular, hypoxia-triggered HIF-1 signaling was shown to promote chemoresistance, angiogenesis, invasiveness and induction of immature phenotype, suggesting that strategies targeting HIF-1 may contribute to improvement of anti-myeloma therapies. Methods The Western Blot and RT-PCR techniques were applied to analyze the influence of metformin on HIF-1 pathway in MM cells. To evaluate the effect of metformin on the growth of MM cell lines in normoxic and hypoxic conditions the MTT assay was used. The apoptosis induction in metformin treated hypoxic and normoxic cells was verified by Annexin V/PI staining followed by FACS analysis. Results Our results showed, for the first time, that metformin inhibits HIF-1 signaling in MM cells. Moreover, we demonstrated the effect of metformin to be mainly oxygen dependent, since the HIF-1 pathway was not significantly affected by metformin in anoxic conditions as well as after application of hypoxic mimicking compound, CoCl2. Our data also revealed that metformin triggers the growth arrest without inducing apoptosis in either normoxic or hypoxic conditions. Conclusions Taken together, our study indicates metformin as a promising candidate for developing new treatment strategies exploiting HIF-1 signaling inhibition to enhance the overall anti-MM effect of currently used therapies, that may considerably benefit MM patients.

Promotion of human multiple myeloma cell growth in vitro and bone marrow invasion in vivo by Notch receptors and the CXCR4/SDF1 axis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8591-8591 ◽  
Author(s):  
Maurizio Chiriva-Internati ◽  
Leonardo Mirandola ◽  
Elisa Lazzari ◽  
Michela Colombo ◽  
Marialuigia Lancellotti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Growth ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Notch Receptors ◽  
Associated Lesions

8591 Background: Multiple myeloma (MM) originates from post-germinal center B cells, and is caused by malignant plasma cells accumulating in the bone marrow. Interactions of MM cells with the bone marrow stroma promote tumor growth, migration and drug resistance. The chemokine receptor CXCR4 and its ligand SDF1 are critical regulators of this process. MM cells frequently hyper-express CXCR4 and respond to SDF1,2 enhancing MM cell infiltration, proliferation and osteolysis. Notch receptors similarly promote MM cell growth, drug resistance and the associated osteolytic process. We hypothesized that the CXCR4/SDF1 axis mediates the effects of Notch signals in MM. Methods: We used real-time PCR, flow-cytometry, E.L.I.S.A. and chemotaxis assay to explore the effects of CXCR4 in cultured human MM cell lines after Notch inhibition or over-stimulation. Additionally, we validated our findings in a NOD/SCID murine model xenografted with human MM cells. Results: Our results show that Notch blocking reduced CXCR4 and SDF1 expression by MM cells. Further, Notch activation was required for MM cell chemotactic and proliferative response to SDF1 in vitro. We then investigated the outcome of anti-Notch treatment on human MM cells bone invasion in NOD/SCID mice. Interfering with Notch activity dramatically reduced xenografted MM cell ability to infiltrate the bone marrow, ultimately resulting in diminished tumor burden. Notably, such effect was associated with a decrease of CXCR4 expression. Conclusions: This was the first time that Notch receptors were reported to regulate the CXCR4/SDF1 axis and bone marrow invasion in human MM. These findings indicate that specific Notch-tailored therapies may effectively hamper CXCR4-mediated bone infiltration and associated lesions, and are expected to significantly improve treatment outcome and survival.

scholarly journals Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma

2020 ◽  
Vol 21 (2) ◽  
pp. 613 ◽  
Author(s):  
Roberto Ria ◽  
Angelo Vacca
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Plasma Cell ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Plasma Cells ◽  
Complex Structure ◽  
Cell Lineage ◽  
Marrow Stromal Cells

Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), there is improvement in patient survival, and multiple myeloma (MM) remains a non-curable disease. The bone marrow microenvironment is a complex structure composed of cells, extracellular matrix (ECM) proteins, and cytokines, in which tumor plasma cells home and expand. The role of the bone marrow (BM) microenvironment is fundamental during MM disease progression because modification induced by tumor plasma cells is crucial for composing a “permissive” environment that supports MM plasma cells proliferation, migration, survival, and drug resistance. The “activated phenotype” of the microenvironment of multiple myeloma is functional to plasma cell proliferation and spreading and to plasma cell drug resistance. Plasma cell drug resistance induced by bone marrow stromal cells is mediated by stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs dysregulation. These processes represent novel targets for the ever-increasing anti-MM therapeutic armamentarium.

Survivin Expression, Regulation and Biological Role in Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1420-1420
Author(s):  
Mathilde Romagnoli ◽  
Régis Bataille ◽  
Sophie Barillé-Nion
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Survivin Expression ◽  
Drug Induced ◽  
Myeloma Cells ◽  
Stable Transfectants

Abstract Multiple myeloma (MM) is characterized by the accumulation within the bone marrow of malignant plasma cells with an enhanced survival capacity. Myeloma cells often develop drug resistance leading to treatment failure in patients. Survivin is a member of the inhibitor of apoptosis (IAP) gene family that has been implicated in both cell viability and regulation of mitosis in cancer cells. In this study, we have evaluated survivin expression and its biological involvement in viability, proliferation, cell cycle and drug resistance in myeloma cells. First by western blotting we detected survivin expression in 17 human myeloma cell lines (HMCL) from moderate level in the HMCL XG6 to strong level in the HMCL U266. Survivin was also detectable in primary myeloma cells purified from blood or bone marrow samples of 20 patients in contrast to purified B lymphocytes from tonsil samples or autologous EBV infected B lymphocytes. Survivin expression peaked at G2/M phase as obtained by drug-induced cell-cycle arrest. Second, we demonstrated that both major myeloma growth factors, IL-6 and IGF-1, induced upregulation of survivin expression through JAK/STAT and PI3K/AKT signalling pathways. In order to elucidate survivin role in myeloma cells, we established XG6 stable transfectants overexpressing survivin and extinguished survivin expression by siRNA in U266. Preliminary data suggest that survivin may participate in spontaneous cell death regulation, cell proliferation and drug sensitivity in those HMCL. In summary, our findings tend to show that survivin may be playing an important role in the pathogenesis of MM. A more defined understanding of survivin biology should enhance the rational development of drugs to inhibit its function in myeloma cells.

The Role of Stromal Cells in Multiple Myeloma: Actors or Spectators?.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2506-2506
Author(s):  
A. Corso ◽  
E. Ferretti ◽  
A. Gallì ◽  
A. M. Tenore ◽  
C. Pascutto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Growth Factors ◽  
Stromal Cells ◽  
Linear Models ◽  
Plasma Cells ◽  
Growth And Survival ◽  
Better Than

Abstract Multiple myeloma (MM) is a B cell neoplasia characterized by an accumulation of clonal plasma cells (PCs) in the bone marrow (BM). The growth and survival of MM plasma cells is regulated by their network with the microenvironment, mainly with the stromal cells. However, although bone marrow stromal cells have been shown to take part in the pathogenesis of the disease, it is still unknown whether these cells play an active or passive role. Namely, whether normal stromal cells simply supply the demand of MM plasma cells, or, during the course of the disease, they acquire abnormal characteristics becoming pathological. To address this question, we designed an in vitro co-culture model in which PCs isolated by immuno-magnetic separation from MGUS and MM patients are crossed with BM stromal cells (BMSCs) derived from MGUS and MM patients. As a result, four type of co-cultures were obtained: MM-BMSCs/MM-PCs, MM-BMSCs/MGUS-PCs, MGUS-BMSCs/MM-PCs, MGUS-BMSCs/MGUS-PCs. After two days of co-culture in a serum free medium, we evaluated the survival of MM-PCs or MGUS-PCs for each combination. We also quantified by ELISA assays in the supernatants of the same cultures, the level of several growth factors (IL-6, IL-8, VEGF, MIP-1a, MIP-1b, RANTES, MCP-1, TGF-b, SDF-1) to evaluate the possible influence of these cytokines on plasma cells. Multivariate general linear models were applied to compare survival in the different combinations of BMSCs and PCs, also accounting for the various growth factors. MM-BMSCs showed to support the survival of both MM-PCs and MGUS-PCs significantly better than MGUS-BMSCs (p=0.0007). However, in the combination MGUS-PCs/MGUS-BMSCs plasma cells survived statistically better than in that MM-PCs/MGUS-BMSCs (p=0.00003). As regards the cytokines, IL-6, IL-8, VEGF, MIP-1a, MIP-1b, and RANTES did not show to be significantly associated with plasma cell survival in all settings. TGF-B and SDF-1 levels were significantly associated with better survival of both MM-PCs and MGUS-PCs when cultured with MM-BMSCs compared to MGUS-BMSCs (p=0.0001 and p=0.038, respectively), while MCP-1 was significantly associated with reduced survival of MM-PCs and MGUS-PCs in the same setting (p=0.006). In conclusion, these data favours the concept that the behaviour of stromal cells may change during the transition from the condition of MGUS to the overt state of myeloma, evolving from a simple role of a spectator to that of an actor. It also appears that overt MM plasma cells have the highest need for cytokine supply and therefore are more dependent on BMSCs activity.

scholarly journals Mesenchymal stem cells from bone marrow regulate invasion and drug resistance of multiple myeloma cells by secreting chemokine CXCL13

2019 ◽  
Author(s):  
Guihua Zhang ◽  
Faan Miao ◽  
Jinge Xu ◽  
Rui Wang
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Mesenchymal Stem Cells ◽  
Western Blot ◽  
Plasma Cells ◽  
Bone Marrow Microenvironment ◽  
Protein Expressions ◽  
Mdr 1

Multiple myeloma (MM) is a hematologic cancer arising from plasma cells. Mesenchymal stem cells (MSCs) are a heterogeneous cell population in the bone marrow microenvironment. In this study, we evaluated the regulatory effects of MSCs on the invasion and drug resistance of MM cells U266 and LP-1. Bone marrow samples from MM patients and normal subjects were collected. MSCs were extracted from bone marrow and cultured, and their phenotypes were identified by flow cytometry. The level of CXCL13 in the supernatant of cultured MSCs was detected by ELISA. The protein expression of CXCR5 (a specific receptor of CXCL13) in U266 and LP-1 cells was detected by Western blot. The effects of MSCs on the invasion of U266 and LP-1 cells and the resistance to bortezomib were assessed by Transwell and CCK-8 assay, respectively. The mRNA and protein expressions of BTK, NF-κB, BCL-2, and MDR-1 were detected by RT-PCR and Western blot, respectively. CXCL13 was secreted by MSCs in the bone marrow microenvironment, and the level in MSCs from MM patients was significantly higher than that of healthy subjects. CXCR5 was expressed in both U266 and LP-1 cells. The resistance of MM cells to bortezomib was enhanced by MSCs through CXCL13 secretion. The invasion and proliferation of U266 and LP-1 cells were promoted, and the mRNA and protein expressions of BTK, NF-κB, BCL-2, and MDR-1 were upregulated by MSCs. The basic biological functions of MM cells U266 and LP-1 were affected by MSCs via the CXCL13-mediated signaling pathway. This study provides valuable experimental evidence for clinical MM therapy.

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