Induction of CXCL1 in Osteoblasts by Myeloma Cells Promotes Migration of Osteoclast Precursors

Abstract Abstract 441 Introduction Multiple myeloma (MM) causes a dysbalance in the bone microenvironment between bone building osteoblasts and bone resorbing osteoclasts (OCs), with an increase in OC recruitment, differentiation and activation, leading to myeloma bone disease (MBD). Presence of MBD has a major impact on the quality of life of MM patients and novel treatment approaches for MBD are urgently needed. Several factors have been identified that play a role in this process, e.g. receptor activator of NF-kB ligand (RANKL). However, the pathomechanism of increased osteoclast recruitment and activation is not completely understood. Here, we investigated the role of the chemokine CXCL1 and its receptor CXCR2 in the bone microenvironment in MM. Material and Methods Serum samples from 52 patients with newly diagnosed MM and from 22 healthy volunteers were assayed using a CXCL1 ELISA. Primary human mesenchymal stem cells (hMSCs) were cultured from bone marrow aspirates and primary human differentiated osteoblasts (hOBs) were cultured from trabecular bone fragments, both from healthy volunteers. Osteoclast precursors (pre-OCs) were generated by immunomagnetic sorting of CD14-positive cells from the peripheral blood of healthy volunteers. Human myeloma cell lines (HMCLs) U-266, RPMI-8226 and LP-1 and primary bone marrow myeloma cells (pMMCs) selected using CD138 immunomagnetic sorting were used for the experiments. Co-cultures of HMCLs and pMMCs with hMSCs or hOBs were performed using 0.45 μm transwell inserts, allowing for the exchange of soluble mediators. Migration assays were performed using 8 μm transwell inserts and human recombinant CXCL1. Immunohistochemistry was performed on paraffin-embedded bone marrow biopsies from MM patients using an anti-CXCR2 monoclonal antibody. All experimental procedures involving patient material were approved by the local ethics committee and conducted after informed consent was obtained. Results CXCL1 serum levels were found to be significantly higher in MM patients than in healthy individuals (193.4 pg/mL vs. 137 pg/mL, respectively, p<0.05), indicating a role for CXCL1 in MM pathophysiology. We went on to investigate the role of CXCL1 in MBD and performed co-cultures of HMCLs and pMMCs with hMSCs or hOBs. Baseline CXCL1 expression was absent in HMCLs and low or absent in hMSCs or hOBs at baseline. RNA expression as well as protein excretion by hMSCs and hOBs were induced after co-culture with myeloma cells. For example, pMMCs from different individuals led to a mean 154-fold upregulation of CXCL1 mRNA levels in hMSCs and to a mean upregulation of CXCL1 protein in cell culture supernatants from <31.5 pg/mL at baseline to 2140 pg/mL after co-cultures. In order to investigate the potential function of elevated CXCL1 levels in the bone marrow microenvironment, the expression of CXCR2, the receptor for CXCL1, was analyzed. Pre-OCs as well as a majority of pMMCs expressed CXCR2 mRNA. CXCR2 protein expression in pMMCs was verified using immunohistochemistry on MM bone marrow biopsies. Human recombinant CXCL1 significantly increased pre-OC cell migration in a dose-dependent manner. For example, 50 ng/mL or 100 ng/mL of CXCL1 increased mean pre-OC migration along a CXCL1 gradient 2.5-fold and 5.6-fold over baseline, respectively. In addition, mean pMMC migration was increased 3.8-fold compared to baseline along a 100 ng/mL gradient of recombinant CXCL1. The osteoclastogenic capacity of the migrated pre-OCs was confirmed by TRAP expression after stimulation with RANKL and M-CSF. Conclusion We describe here a novel role for the chemokine CXCL1 in myeloma bone disease. We demonstrate that CXCL1 is induced in hMSCs and hOBs by co-culture with MM cells. CXCL1 leads to chemoattraction of both pre-OCs and pMMCs. These effects could lead to co-localization of OCs and MM cells in the bone marrow microenvironment and contribute to the tumor-promoting interaction between these cell types. Our data indicate the CXCL1-CXCR2 axis as a therapeutic target in myeloma bone disease. Disclosures: No relevant conflicts of interest to declare.

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Targeting Wnt Signaling in Myeloma In Vivo; Differential Effects on Tumor Burden and Myeloma Bone Disease.

Blood ◽

10.1182/blood.v110.11.812.812 ◽

2007 ◽

Vol 110 (11) ◽

pp. 812-812

Author(s):

Claire M. Edwards ◽

James R. Edwards ◽

Seint T. Lwin ◽

Gregory R. Mundy

Keyword(s):

Bone Marrow ◽

Wnt Signaling ◽

Bone Disease ◽

Tumor Burden ◽

Bone Microenvironment ◽

Myeloma Cells ◽

Myeloma Bone Disease ◽

Osteolytic Bone Disease

Abstract Multiple myeloma is characterized by uncontrolled proliferation of myeloma cells within the bone marrow and the development of a severe osteolytic bone disease. In addition to a well characterized increase in osteoclastic bone resorption, myeloma bone disease is associated with a reduction in bone formation. Osteoblast differentiation and bone formation are regulated in vivo by canonical Wnt signaling and activation of β-catenin. Therefore increasing Wnt signaling in the bone microenvironment in multiple myeloma may prevent the development of myeloma bone disease. In support of this, we have previously demonstrated that activation of Wnt signaling with lithium chloride (LiCl) in the 5TGM1 murine model of myeloma reduces tumor burden and osteolytic bone disease. However, we also found that LiCl treatment increased subcutaneous (s.c.) tumor growth. This suggests that the reduction in tumor burden within the bone microenvironment may be an indirect effect mediated through the effects of LiCl to prevent myeloma bone disease. The aim of the current study was to determine the effect of specific molecular blockade of Wnt signaling in myeloma cells in vivo. 5TGM1-GFP myeloma cells were transfected by electroporation with either myc-tagged dominant negative TCF4 (DNTCF4) or pcDNA. Following stable selection by culture in G418, expression of DNTCF4 was confirmed by western blot for myc. No difference was found in the growth rates of 5TGM1-pcDNA or 5TGM1-DNTCF4 in vitro. Treatment with LiCl or Wnt3A had no significant effect on cell viability in vitro, but significantly increased β-catenin activity, as measured by TOPFLASH activity in 5TGM1-pcDNA cells. This increase was not observed in 5TGM1-DNTCF4, confirming that expression of DNTCF4 blocked Wnt signaling induced by LiCl in 5TGM1 myeloma cells. C57Bl/KaLwRij mice were inoculated with 5TGM1-pcDNA or 5TGM1-DNTCF4 cells by either intravenous (i.v.) or s.c. injection. Mice were treated from time of tumor cell inoculation with 200mg/kg/day LiCl or vehicle control (d.H20) by oral gavage for 28 days. I.v. inoculation of myeloma cells resulted in a significant increase in serum IgG2bκ concentrations and the proportion of GFP-positive cells in the bone marrow. A significant reduction in trabecular bone volume was also observed. MicroCT analysis of the tibia demonstrated that LiCl significantly increased trabecular bone volume in both 5TGM1-pcDNA and 5TGM1-DNTCF4 myeloma-bearing mice. LiCl significantly decreased serum IgG2bκ concentrations in both 5TGM1-pcDNA and 5TGM1-DNTCF4 myeloma-bearing mice, with a greater effect in 5TGM1-DNTCF4 myeloma-bearing mice. FACS analysis of GFP-positive cells demonstrated that LiCl significantly reduced tumor burden in the bone marrow in both 5TGM1-pcDNA and 5TGM1-DNTCF4 myeloma-bearing mice. However, following s.c inoculation, LiCl significantly increased s.c. tumor volume of 5TGM1-pcDNA tumors, but had no effect on 5TGM1-DNTCF4 s.c. tumor volume. Taken together these results demonstrate that the effect of increasing Wnt signaling in myeloma is dependent upon the microenvironment. By specific inhibition of β-catenin activity in myeloma cells combined with systemic stimulation of the Wnt signaling pathway, our results suggest that increasing Wnt signaling in myeloma in vivo has dual effects; firstly to enhance myeloma growth directly, and secondly to enhance osteoblast differentiation and thus indirectly reduce tumor burden in bone, highlighting the importance of the bone marrow microenvironment in regulating myeloma growth and survival.

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Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo

Blood ◽

10.1182/blood-2007-03-077685 ◽

2008 ◽

Vol 111 (5) ◽

pp. 2833-2842 ◽

Cited By ~ 118

Author(s):

Claire M. Edwards ◽

James R. Edwards ◽

Seint T. Lwin ◽

Javier Esparza ◽

Babatunde O. Oyajobi ◽

...

Keyword(s):

Bone Marrow ◽

Tumor Growth ◽

Wnt Signaling ◽

Bone Disease ◽

Critical Role ◽

Tumor Burden ◽

Bone Marrow Microenvironment ◽

Myeloma Bone Disease ◽

Osteolytic Bone Disease

There is increasing evidence to suggest that the Wnt signaling pathway plays a critical role in the pathogenesis of myeloma bone disease. In the present study, we determined whether increasing Wnt signaling within the bone marrow microenvironment in myeloma counteracts development of osteolytic bone disease. C57BL/KaLwRij mice were inoculated intravenously with murine 5TGM1 myeloma cells, resulting in tumor growth in bone and development of myeloma bone disease. Lithium chloride (LiCl) treatment activated Wnt signaling in osteoblasts, inhibited myeloma bone disease, and decreased tumor burden in bone, but increased tumor growth when 5TGM1 cells were inoculated subcutaneously. Abrogation of β-catenin activity and disruption of Wnt signaling in 5TGM1 cells by stable overexpression of a dominant-negative TCF4 prevented the LiCl-induced increase in subcutaneous growth but had no effect on LiCl-induced reduction in tumor burden within bone or on osteolysis in myeloma-bearing mice. Together, these data highlight the importance of the local microenvironment in the effect of Wnt signaling on the development of myeloma bone disease and demonstrate that, despite a direct effect to increase tumor growth at extraosseous sites, increasing Wnt signaling in the bone marrow microenvironment can prevent the development of myeloma bone disease and inhibit myeloma growth within bone in vivo.

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Immunoexpression of Macrophage Inflammatory Protein-1 Alpha on Bone Marrow Trephine Biopsies Correlates with the Extent of Bone Disease in Newly Diagnosed Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v112.11.5119.5119 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5119-5119

Author(s):

Maria Roussou ◽

Anna Tasidou ◽

Efstathios Kastritis ◽

Magdalini Migkou ◽

Maria Gavriatopoulou ◽

...

Keyword(s):

Bone Marrow ◽

Bone Disease ◽

Newly Diagnosed ◽

Santa Cruz ◽

Myeloma Bone Disease ◽

Inflammatory Protein ◽

Lytic Lesions ◽

Intermediate Expression ◽

Macrophage Inflammatory Protein

Abstract Macrophage inflammatory protein-1 alpha (MIP-1alpha) is a low molecular weight chemokine that belongs to the RANTES family and is a potent osteoclast stimulator. Previous studies have shown that malignant plasma cells (PCs) from myeloma cell lines produce MIP-1alpha, while MIP-1alpha levels are elevated in the bone marrow plasma and the serum of patients with multiple myeloma (MM) and correlate with the extent of bone disease. The purpose of our study was to evaluate the role of MIP-1alpha immunoexpression on bone marrow trephine biopsies in myeloma bone disease and examine possible correlations between MIP-1alpha expression with survival and prognostic factors of MM. We evaluated formalin fixed paraffin-embedded bone marrow sections of 130 patients with newly diagnosed MM (66M/64F, median age: 68 years). Bone marrow sections were subjected to immunohistochemistry study using the anti-MIP- 1alpha monoclonal antibody (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA). The immunoreactivity of MIP-1alpha was examined on the basis of positive PCs with the following cut off values: <20% positive PCs (negative expression group, group I), 20–50% positive PCs (intermediate expression group, group II) and >50% positive PCs (high expression group, group III). Moreover MIP-1alpha was measured using ELISA methodology (R&D Systems, Minneapolis, MN, USA) in the serum of the patients. The extent of bone disease was assessed radiographically, and grading was performed as follows: group A included 43 patients (33%) who had no lytic lesions and/or osteoporosis only, group B included 24 patients (18%) who had lytic lesions in 1–3 areas, whereas group C included 63 patients (48%) with lytic lesions in >3 areas and/or a bone fracture. Thirty-seven (28%) patients had negative MIP-1alpha expression, 17 (13%) intermediate expression and 79 (59%) high expression of MIP-1alpha. MIP-1alpha expression of ≥20% PCs in the trephine biopsies significantly correlated with the extent of bone disease (Figure 1, ANOVA p<0.0001). Furthermore, 91 patients (70%) had values of serum MIP-1alpha >14 pg/ml, which was the median value observed in 20 controls of similar age and gender (p<0.001). MIP-1alpha serum levels also correlated with the extent of bone disease (ANOVA p<0.0001). In terms of overall survival, no significant association was observed in relation to MIP-1alpha expression. Increased immunoexpression of MIP-1alpha was associated with high plasma cell infiltration in the bone marrow (r=0.348, p<0.0001), low platelet count (r=0.282; p=0.0012), hypercalcemia (r=0.246; p=0.022), elevated serum creatinine (r=0.258, p=0.027), and advanced disease stage (ISS, p=0.034). Our findings underline, for the first time, the increased incidence of high immunoexpression of MIP-1alpha in the malignant PCs of myeloma patients and the correlation between the expression of MIP-1alpha by myeloma PCs in the trephine biopsies and the extent of lytic bone disease. These results confirm the significant role of MIP-1alpha in the pathogenesis of myeloma bone disease and suggest that MIP-1alpha may represent a rational therapeutic target for the management of bone destruction in myeloma. Figure Figure

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Multiple Myeloma and Bone Marrow Microenvironment Immunohistochemical Study of the Expression of 15 Proteins Related to Myeloma Bone Disease

Blood ◽

10.1182/blood.v126.23.5318.5318 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5318-5318 ◽

Cited By ~ 1

Author(s):

Patrik Flodr ◽

Pavla Latalova ◽

Petra Pusciznova ◽

Tomas Pika ◽

Jaroslav Bacovsky ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Disease ◽

Conflicts Of Interest ◽

Activin A ◽

Annexin A2 ◽

Bone Marrow Microenvironment ◽

Therapeutic Approaches ◽

Variable Expression ◽

Myeloma Bone Disease

Abstract Objective: Neoplastic milieu is an integral part of all malignant diseases including multiple myeloma and plays variable role in their development, retention/adhesivity, resistency or sensitivity to therapeutic approach, homing and also paraneoplastic manifestations. Relatively genetically stable milieu may play an important role in new specific molecular therapeutic approaches and therefore should be contextually studied with neoplastic cells as complex neoplastic tissues. The expressions of 15 proteins with close relation to the development of myeloma bone disease (MBD) were analysed in consecutive multiple myeloma specimens. Methods: Bone marrow trephine biopsy specimens (n=57) with multiple myeloma were included in our prospective study. FFPE tissues were processed in app. 5microm sections and placed on charged slides. The indirect immunohistochemical staining was applicated after antigen retrieval and commercial primary antibodies were used for the detection of observed proteins. Standard secondary antibody and ABC method were included in visualisation. We analysed the expressions of MIP1alfa, Annexin A2, TRAP, DKK-1, RANK, RANKL, OPG, Sclerostin, Activin A, NFkappaB proteins (p50, p52, p65), p62 (sequestosome 1), MMP9 and RUNX2. Results: Bone marrow multiple myeloma specimens showed variable positivity of MIP1alfa in 60% (cut-off point 20%), Annexin A2 in 42% (myeloma cells, cut-off point 30%) and in 74% (stromal cells, cut-off point 5%), TRAP in 28% (cut-off point 5%), DKK-1 in 23% (cut-off point 30%), RANK in 53% (cut-off point 30%), RANKL in 70%, OPG in 39% (cut-off point 5%), Sclerostin in 95% (cut-off point 90%), Activin A in 35% (cut-off point 30%), cytoplasmic positivity of p50 in 5% (cut-off point 10%), p52 in 86% (cut-off point 10%), p62 in 91% (cut-off point 10%), p65 in 89% (cut-off point 10%), positivity of MMP9 in 22% (cut-off point 30%) and positivity of RUNX2 in 56% (cut-off point 30%). Conclusion: Our study showed variable expression of proteins related to MBD in multiple myeloma and its bone marrow microenvironment that imply biological heterogeneity, different development and stromal plasticity in this complex hemato-oncological disease. The exact and contextual knowledge of the engaged signaling pathways may suggest more specific or tailored therapeutic approaches (e.g. anti-RANKL, anti-DKK-1, anti-Sclerostin, anti-Activin A). Supported by the grant NT 14393. Disclosures No relevant conflicts of interest to declare.

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Osteoclast Gene Expression Profiling in Multiple Myeloma

Blood ◽

10.1182/blood.v112.11.2735.2735 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2735-2735

Author(s):

Jerome Moreaux ◽

Dirk Hose ◽

Thierry Rème ◽

Philippe Moine ◽

Karène Mahtouk ◽

...

Keyword(s):

Gene Expression ◽

Multiple Myeloma ◽

Bone Marrow ◽

Bone Resorption ◽

Bone Disease ◽

Plasma Cells ◽

Osteoclastic Bone Resorption ◽

Myeloma Cells ◽

Myeloma Bone Disease ◽

Osteolytic Bone Disease

Abstract Multiple myeloma (MM) 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 (MMC) 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. In order to investigate the gene expression profile (GEP) of osteoclastic cells, we compare GEP of osteoclastic cells (7 samples) with normal B cells (7 samples), normal bone marrow plasma cells (7 samples), bone marrow stromal cells (5 samples), bone marrow CD3 cells (5 samples), CD14 cells (7 samples), CD15 cells (7 samples), CD34 cells (7 samples) and primary MMC (123 samples). Using SAM analysis, a set of 552 genes was overexpressed in osteoclasts compared to others cell subpopulations with a FDR ≤ 1% and a ratio ≥ 2. Osteoclasts specifically overexpressed genes coding for chemokines (CCL2, CCL7, CCL8, CCL13, CCL18, CXCL5 and CCL23) and MMC growth factors (IGF-1, APRIL and IL-10). Anti- IGF-1 receptor and TACI-Fc inhibit MMC growth induced by osteoclasts. Among the chemokines overexpressed by osteoclasts, the majority of them have a common receptor: CCR2 expressed by MMC. Anti-CCR2 MoAb inhibits migration of the CCR2+ HMCL in response to osteoclasts. Expression data of purified MMC were analyzed by supervised clustering of group with higher (CCR2high) versus lower (CCR2low) CCR2 expression level. Patients in the CCR2high group are characterized by a higher bone disease. A set of 176 genes was differentially expressed between CCR2high and CCR2low MMC. CCR2high displayed a gene signature linked to the dependency of MMC on the interactions with the BM osteoclastic subpopulation and the osteoclastic bone resorption. Taken together, our findings suggest addition of chemokine antagonists to current treatment regimens for MM should result in better therapeutic responses because of the loss of both the protective effect of the bone marrow environment on the MMC and the osteoclastic cells activity.

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Myeloma Bone Disease: A Comprehensive Review

International Journal of Molecular Sciences ◽

10.3390/ijms22126208 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6208

Author(s):

Shiva Kumar Reddy Mukkamalla ◽

Dhatri Malipeddi

Keyword(s):

Bone Marrow ◽

Bone Remodeling ◽

Bone Disease ◽

Plasma Cells ◽

Cord Compression ◽

Bone Marrow Microenvironment ◽

Myeloma Bone Disease ◽

Clonal Proliferation ◽

Inhibitory Factors ◽

Increased Risk

Multiple myeloma (MM) is a neoplastic clonal proliferation of plasma cells in the bone marrow microenvironment, characterized by overproduction of heavy- and light-chain monoclonal proteins (M-protein). These proteins are mainly found in the serum and/or urine. Reduction in normal gammaglobulins (immunoparesis) leads to an increased risk of infection. The primary site of origin is the bone marrow for nearly all patients affected by MM with disseminated marrow involvement in most cases. MM is known to involve bones and result in myeloma bone disease. Osteolytic lesions are seen in 80% of patients with MM which are complicated frequently by skeletal-related events (SRE) such as hypercalcemia, bone pain, pathological fractures, vertebral collapse, and spinal cord compression. These deteriorate the patient’s quality of life and affect the overall survival of the patient. The underlying pathogenesis of myeloma bone disease involves uncoupling of the bone remodeling processes. Interaction of myeloma cells with the bone marrow microenvironment promotes the release of many biochemical markers including osteoclast activating factors and osteoblast inhibitory factors. Elevated levels of osteoclast activating factors such as RANK/RANKL/OPG, MIP-1-α., TNF-α, IL-3, IL-6, and IL-11 increase bone resorption by osteoclast stimulation, differentiation, and maturation, whereas osteoblast inhibitory factors such as the Wnt/DKK1 pathway, secreted frizzle related protein–2, and runt-related transcription factor 2 inhibit osteoblast differentiation and formation leading to decreased bone formation. These biochemical factors also help in development and utilization of appropriate anti-myeloma treatments in myeloma patients. This review article summarizes the pathophysiology and the recent developments of abnormal bone remodeling in MM, while reviewing various approved and potential treatments for myeloma bone disease.

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Bone Marrow Adipocyte Shapes Metabolism and Immunity in Tumor Microenvironment to Promote Multiple Myeloma

Blood ◽

10.1182/blood-2021-150208 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 892-892

Author(s):

Lingling Shu ◽

Jinyuan Li ◽

Shuzhao Chen ◽

Han-Ying Huang ◽

Yang Li ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Fatty Acid ◽

Lipid Metabolism ◽

Lipid Binding ◽

Bone Marrow Microenvironment ◽

Acid Uptake ◽

Fatty Acid Binding ◽

Myeloma Cells

Abstract Multiple myeloma (MM) often occurs in middle-aged, elderly and obese patients with ectopic accumulation of fat cells in the bone marrow. Bone marrow adipocytes (BMAs) display unique immunomodulatory properties instead of simply providing energy substrates, which can cause distinct change of bone marrow microenvironment. Although BMA accounts for 70% of the total volume of bone marrow, the mechanism on how BMA affects tumor progression remains elusive. This study aims to explore the pathogenesis of BMA in promoting myeloma and new potential treatment strategies targeting bone marrow microenvironment. Newly diagnosed MM patients in our cancer center and their relative healthy controls are recruited. A significant increase of BMA quantity in multiple myeloma patients was observed. Moreover, analysis of transcriptome sequencing data of BMA derived from MM patients demonstrated a distinctive gene expression profiles (Fig A). It worth to note that, expression of fatty acid-binding protein 4 (FABP4, also known as A-FABP or aP2), a member of the FABP family abundantly expressed in adipocytes, functions as a lipid-binding chaperone that regulates trafficking and cellular signaling of fatty acids, and plays an important role in linking lipid metabolism with immunity and inflammation, was increased significantly in BMA of MM patients (Fig B). To further explore the role of FABP4 in pathogenesis in MM, FABP4 knockout (KO) mice and their wide-type (WT) littermates were adopted, and fed with standard chow (STC) or high-fat diet (HFD, 45 kcal % Fat, D12451). FABP4 deficiency significantly attenuated the tumor burden and MM-related osteolytic lesions in mice fed with HFD (Fig C-D). Moreover, levels of pro-inflammatory cytokines including TNFα, IL-6, RANKL and DPP4 were significantly reduced in FABP4 deficient adipocytes (Fig E). Flow cytometry analysis showed that the infiltration and pro-inflammatory polarization (M1/M2) of macrophages (MΦ) decreased significantly in FABP4 KO bone marrow (Fig F). In addition, FABP4 promoted the infiltration of Th1 and Th17 cells, while impaired the recruitment of Th2 and Treg cells (Fig G). Furthermore, administration of exogenous FABP4 recombinant protein significantly increased the fatty acid uptake and oxygen consumption of myeloma cells (Fig H). In contrast, pharmacological inhibition of FABP4 with BMS309403 alleviated the invasion and metastasis of MM in mice fed with HFD (Fig I-J). In summary, BMA increased in MM patients, reshapes the metabolism and immunity in bone marrow microenvironment through regulating FABP4 functions. FABP4 enhanced the energy and lipid metabolism of myeloma cells, and manipulated the bone marrow microenvironment to pro-tumor environment, therefore promoted the proliferation and migration of myeloma cells. This study will not only clarify the critical role of BMA in MM pathogenesis, but also provide therapeutic potential of FABP4 selective inhibitor BMS309403 for multiple myeloma treatment, especially for obese MM patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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The Role of Marrow Microenvironment in the Growth and Development of Malignant Plasma Cells in Multiple Myeloma

International Journal of Molecular Sciences ◽

10.3390/ijms22094462 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4462

Author(s):

Nikolaos Giannakoulas ◽

Ioannis Ntanasis-Stathopoulos ◽

Evangelos Terpos

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Stromal Cells ◽

Genetic Background ◽

Growth And Development ◽

Plasma Cells ◽

Critical Role ◽

Bone Marrow Microenvironment ◽

Myeloma Cells

The development and effectiveness of novel therapies in multiple myeloma have been established in large clinical trials. However, multiple myeloma remains an incurable malignancy despite significant therapeutic advances. Accumulating data have elucidated our understanding of the genetic background of the malignant plasma cells along with the role of the bone marrow microenvironment. Currently, the interaction among myeloma cells and the components of the microenvironment are considered crucial in multiple myeloma pathogenesis. Adhesion molecules, cytokines and the extracellular matrix play a critical role in the interplay among genetically transformed clonal plasma cells and stromal cells, leading to the proliferation, progression and survival of myeloma cells. In this review, we provide an overview of the multifaceted role of the bone marrow microenvironment in the growth and development of malignant plasma cells in multiple myeloma.

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