Overexpression of heme oxygenase-1 in bone marrow stromal cells promotes multiple myeloma resistance through the JAK2/STAT3 pathway

Life Sciences ◽  
2020 ◽  
Vol 257 ◽  
pp. 118088
Author(s):  
Jun Huang ◽  
Lai-quan Huang ◽  
He-sheng He ◽  
Jiawei Yan ◽  
Chen Huang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Heme Oxygenase ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Heme Oxygenase 1 ◽  
Stat3 Pathway

Combined Disruption of Both the MEK/ERK and the IL-6R/STAT3 Pathways Is Required To Induce Apoptosis of Multiple Myeloma Cells in the Presence of Bone Marrow Stromal Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4839-4839
Author(s):  
Manik Chatterjee ◽  
Thorsten Stuehmer ◽  
Pia Herrmann ◽  
Kurt Bommert ◽  
Bernd Dorken ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Mapk Pathway ◽  
Underlying Mechanism ◽  
Marrow Stromal Cells ◽  
Erk Pathway ◽  
Stat3 Pathway ◽  
Survival Effect

Abstract The IL-6R/STAT3 pathway has been reported to critically contribute to the pathogenesis of multiple myeloma (MM) and to protect MM cells from apoptosis. However, recently we could demonstrate that MM cells become independent of the IL-6R/STAT3 pathway if they are cocultured with bone marrow stromal cells (BMSCs), suggesting that the BM microenvironment stimulates IL-6-independent pathways that exert a pro-survival effect. It was therfore the aim of this study to analyze the underlying mechanism of this phenomenon. Pathway analysis revealed that BMSCs stimulate STAT3 via the IL-6R, and MAPK in parts via IL-6R-independent mechanisms. Abolition of MEK1, 2 activity with PD98059, or of ERK1,2 through siRNA constructs, was insufficient to induce apoptosis. However, the combined disruption of the IL-6R/STAT3 and MEK1,2/ERK1,2 pathways led to strong induction of apoptosis even in the presence of BMSCs. Thus, disruption of the MEK/ERK pathway restores IL-6/STAT3 dependence of MM cells in the presence of BMSCs indicating that BMSC-mediated induction of the MEK/MAPK pathway is the mechanism by which BMSCs render MM cells IL-6/STAT3 idependent. Consequently, in the presence of cells from the BM microenvironment the combined targeting of different (and independently activated) pathways is required to efficiently induce apoptosis of MM cells. This effect was observed with MM cell lines and with primary MM cells and might have direct implications for the development of future therapeutic strategies for MM.

In the presence of bone marrow stromal cells human multiple myeloma cells become independent of the IL-6/gp130/STAT3 pathway

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3311-3318 ◽  
Author(s):  
Manik Chatterjee ◽  
Dirk Hönemann ◽  
Suzanne Lentzsch ◽  
Kurt Bommert ◽  
Christine Sers ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Myeloma Cells ◽  
Farnesyl Transferase ◽  
Stat3 Pathway ◽  
Induced Apoptosis

AbstractThe interleukin 6/glycoprotein 130/signal transducer and activator of transcription 3 (IL-6/gp130/STAT3) pathway has been reported to play an important role in the pathogenesis of multiple myeloma (MM) and for survival of MM cells. However, most data concerning the role of IL-6 and IL-6–triggered signaling pathways were obtained from experiments performed with MM cell lines and without considering the bone marrow microenvironment. Thus, the precise role of IL-6 and its intracellular signaling pathways for survival of human MM cells is still unclear. Here we show that treatment of human MM cells (IL-6–dependent MM cell line INA-6 and primary MM cells) with the IL-6 receptor antagonist Sant7 or with an anti-gp130 monoclonal antibody (mAb) induced apoptosis if the cells were cultured in the absence of bone marrow stromal cells (BMSCs). In contrast, apoptosis could not be observed if the MM cells were cocultured with BMSCs. The analysis of intracellular pathways revealed that Sant7 and anti-gp130 mAb were effectively inhibiting the phosphorylation of gp130 and STAT3 in the absence and presence of BMSCs, whereas ERK1 and ERK2 (ERK1,2) phosphorylation was only slightly affected. In contrast, treatment with the farnesyl transferase inhibitor, FPT III, induced apoptosis in MM cells in the absence or presence of BMSCs and led to a complete inhibition of the Ras/mitogen-activated protein kinase pathway. These observations indicate that the IL-6/gp130/STAT3 pathway is not essential for survival of human myeloma cells if they are grown in the presence of cells from the bone marrow microenvironment. Furthermore, we provide evidence that farnesyl transferase inhibitors might be useful for the development of novel therapeutic strategies for the treatment of MM.

CD56 Expression Is the Potent Prognostic Marker of the Thalidomide Efficacy in the Patients with Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5142-5142
Author(s):  
Akio Mori ◽  
Yutaka Tsutsumi ◽  
Satoshi Hashino ◽  
Hiroe Kanamori ◽  
Makoto Ibata ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Adhesion ◽  
Adhesion Molecules ◽  
Prognostic Marker ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Myeloma Cells ◽  
Cd56 Expression

Abstract Thalidomide (Thal) alone or in combination with steroids achieves responses even in the setting of refractory multiple myeloma (MM), however, responses are still limited. The precise mechanism of Thal action is unknown, further, no distinct marker, which could prognosticate the efficacy of Thal, is known. Therefore, we evaluated the correlation between the efficacy of Thal and the potent prognostic factors in patients with refractory MM. Ten patients with refractory MM received Thal at doses of 50 or 100 mg per day and steroids, either dexamethasone (Dex) or prednisolone (PSL). Dex was administrated 20 mg per day, 4 days every 28 days, and PSL was administrated 10 mg per day. The median age was 71.5 years (range, 62–79 years) and 20 % were man, and all patients were diagnosed as clinical stage IIIA based on the Durie and Salmon classification. The therapeutic response was assessed according to the modified criteria of Southwest Oncology Group (SWOG). Among 10 patients, 7 patients were the responders; 2 had complete remission, 3 had partial remission, and 2 had minimal remission. There were no differences in the pretreatment characteristics of responders and nonresponders (age, sex, type and concentration of serum and/or urine monoclonal component, international prognostic index, presence of bone lesion, and chromosomal abnormalities). However, flow cytometric evaluation of the myeloma cells revealed that CD56, which is one of the adhesion molecules N-CAM, expressed more than 45 % in all responders, while those expressed less than 5 % in all nonresponders (84 ± 19 (±SD) % v/s 4 ± 2 %, P=0.017). Furthermore, CD56 expression of the myeloma cells was reduced from 84% to 70 ± 32 % after Thal therapy in all evaluated responders (P =0.048). These results suggest that CD56 expression of the myeloma cells could be the potent prognostic marker of the Thal efficacy. Moreover, it was reported that Thal reduced the expression of cell adhesion molecules, such as LFA-1 and ICAM-1, and abrogated the binding of MM cells to bone marrow stromal cells, that triggered the secretion of interleukin-6 and vascular endothelial growth factor. Taken together, it was suggested that Thal reduced the expression of CD56 and altered the MM cell adhesion to bone marrow stromal cells, and that could be one of the pathogenesis of anti-MM activity of Thal.

Nifuroxazide Inhibits STAT3 Function and Shows Potent Anti-Tumor Activity Against Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3450-3450
Author(s):  
Erik A. Nelson ◽  
Teru Hideshima ◽  
Laurie Gashin ◽  
Sarah R. Walker ◽  
Rebecca A. Lynch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Transcriptional Activity ◽  
Marrow Stromal Cells ◽  
Normal Peripheral Blood ◽  
Myeloma Cells ◽  
Stat3 Signaling ◽  
Nf Kappab

Abstract Activation of the transcription factor STAT3 is essential for the pathogenesis of many cancers, including multiple myeloma. While normal cells can tolerate a reduction in STAT3 function, tumors often require constitutive STAT3 signaling for survival. Thus, identifying drugs that inhibit STAT3 activity may provide new therapeutic agents useful for cancer treatment. We have developed a high throughput cell-based screen to identify drugs that inhibit STAT3-dependent transcriptional activity. To assure the specificity of these drugs for STAT3 function, we performed a counter screen assessing NF-kappaB-dependent transcriptional activity. To bypass the difficulties inherent in the development of novel small molecules for clinical use, we analyzed a library of 1120 drugs that are either FDA approved, or are otherwise known to be safe in humans. From this screen, we identified nifuroxazide, a drug used to treat dehydration associated with diarrheal illness, as a potent inhibitor of STAT3 transcriptional activity. By contrast, nifuroxazide has no effect on NF-kappaB-dependent transcription. Myeloma cells containing constitutive STAT3 activation show decreased STAT3 tyrosine phosphorylation when incubated with 10 uM nifuroxazide. In addition, expression of STAT3 target genes necessary for myeloma survival, including bcl-x, mcl-1, and cyclin D1, is markedly reduced by 10 uM nifuroxazide. To determine whether these effects of nifuroxazide on STAT3 signaling alter cell viability, we utilized U266 myeloma cells, which depend on STAT3 activation for survival. U266 viability is inhibited by nifuroxazide at an EC50 of approximately 3 uM. Notably, RPMI 8226 myeloma cells, which do not contain activated STAT3, are not affected by comparable concentrations of nifuroxazide. In addition, this dose has no effect on normal peripheral blood mononuclear cells. Given that myeloma cells receive survival signals from bone marrow stromal cells, we determined if nifuroxazide affects myeloma survival in stromal cell co-cultures. Nifuroxazide is effective at reducing U266 viability in the presence of bone marrow stromal cells at an EC50 of approximately 3 uM. Thus, screening for compounds that inhibit STAT3 transcriptional activity is useful in identifying potential drugs for myeloma therapy. Through this approach, we have identified a novel STAT3 inhibitory function for nifuroxazide. Nifuroxazide inhibits STAT3 mediated survival of myeloma cells and may be useful, either alone or in combination with other drugs, for the treatment of patients with multiple myeloma.

p38MAPK Inhibitor LSN2322600 Modulates the Bone Marrow Microenvironment and Inhibits Osteoclastogenesis in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5042-5042
Author(s):  
Kenji Ishitsuka ◽  
Teru Hideshima ◽  
Paola Neri ◽  
Sonia Vallet ◽  
Norihiko Shiraishi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Mononuclear Cells ◽  
Severe Combined Immunodeficiency ◽  
Marrow Stromal Cells ◽  
Skeletal Complications

Abstract The interaction between multiple myeloma (MM) cells and the bone marrow (BM) microenvironment plays a crucial role not only in proliferation and survival of MM cells, but also in osteoclastogenesis. In this study, we examined diverse potential of novel p38MAPK inhibitor LSN2322600 (LSN) for MM therapy in vitro and in vivo. The cytotoxic activity of LSN against MM cell lines was modest; however, LSN significantly enhances the cytotoxicity of Bortezomib by down-regulating Bortezomib-induced heat shock protein (HSP) 27 phosphorylation. We next examined the effects of LSN on cytokine secretion in MM cells, bone marrow stromal cells and osteoclast precursor cells. LSN inhibited IL-6 secretion from long-term cultured-bone marrow stromal cells (LT-BMSCs) and bone marrow mononuclear cells (BMMNCs) from MM patients in remission. LSN also inhibited MIP-1 α secretion by fresh tumor cells, BMMNCs and CD14 positive cells. Since these cytokines mediate osteoclastogenesis, we further examined whether LSN could inhibit osteoclastogenesis. Importantly, LSN inhibited in vitro osteoclastogenesis induced by macrophage-colony stimulating factor (M-CSF) and soluble receptor activator of nuclear factor- κ B ligand (sRANKL), as well as osteoclastogenesis in the severe combined immunodeficiency (SCID)-Hu mouse model of human MM. These results suggest that LSN represents a promising novel targeted strategy to reduce skeletal complications as well as to sensitize or overcome resistance to Bortezomib.

MicroRNA Changes Occur in Multiple Myeloma Cells in the Context of Bone Marrow Milieu.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1785-1785 ◽  
Author(s):  
Roccaro M. Roccaro ◽  
Antonio Sacco ◽  
Abdel Kareem Azab ◽  
Feda Azab ◽  
Hai Ngo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Expression Patterns ◽  
Mirna Gene ◽  
Marrow Stromal Cells ◽  
Stem Loop ◽  
Mirna Profiling ◽  
Qrt Pcr

Abstract Abstract 1785 Poster Board I-811 Background We and Others have previously demonstrated that primary multiple myeloma (MM) cells are characterized by a specific microRNA (miRNA) signature compared to the related normal plasmacell counterpart; and that miRNAs play a crucial role in regulating MM pathogenesis. Nevertheless, miRNA changes that occur in MM cells in the context of the bone marrow microenvironment have not been previously examined. Therefore, characterization of miRNA profiling of MM cells in conjunction with bone marrow stromal cells (BMSCs) is important to better understand the underlying molecular changes that lead to initiation and progression of this disease. Methods We performed miRNA-expression-profiling of MM cell lines (MM.1S; RPMI8226) that were co-cultured with primary BMSCs obtained from 5 MM patients, using liquid phase Luminex microbead miRNA profiling (Luminex, Austin, TX). The expression patterns of unfiltered data were performed using unsupervised hierarchical clustering of samples, based on centroid linkage and 1-correlation distance metric, using dChip (www.dchip.org). To further define those miRNAs differentially expressed between groups (patients vs normal), the data were filtered on significance of differences using ANOVA test, (P < 0.05). Microbead-miRNA profiling data were validated data by stem-loop qRT-PCR. To identify specific predicted miRNA-targeted mRNAs, TargetScan, PicTar, and miRanda algorithms were used. Results miRNA profiling of MM cells cultured with primary BMSCs (MM+BMSC system) differs from MM cells which were not grown in contact with primary BMSCs (MM cells alone). Specifically, we observed increased expression of miRNA-450, -432*, -299-5p, -409-3p, -29b, -542-5p, -184, -517*, -218, 128b, -142-5p and -211 (P<0.05) in MM cells obtained from the MM+BMSC system, compared to MM cells alone. Stem-loop qRT-PCR was performed on matched samples and showed expression patterns similar to those observed in miRNA analysis. Using algorithms commonly used to predict human miRNA gene targets (miRanda; TargetScan; PicTar), predicted targets of the increased miRNAs included negative regulators of NFkB, PI3K/Akt/mTOR, and MAPK/ERK signaling pathways, such as PTEN, KSR2, TWEAK, and DUSP; as well as tumor suppressors (MCC, TSSC1, TUSC1, FBW7, RHOBTB), pro-apoptotic factors and cyclin-dependent kinases inhibitors. These data demonstrate that bone marrow stromal cells exert a modulatory effect on miRNA profiling in MM cells, which results in promoting MM cell growth and reducing MM cell survival. Disclosures Ghobrial: Millennium : Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

The Relationship of Myeloma Cells, Stromal Cells and Monocytes Under Bone Marrow Microenvironment

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4987-4987
Author(s):  
Hiroshi Ikeda ◽  
Yuka Aoki ◽  
Nasanori Nojima ◽  
Hiroshi Yasui ◽  
Toshiaki Hayashi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Proliferation ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Marrow Stromal Cells ◽  
Myeloma Cells ◽  
Growth And Survival

Abstract Abstract 4987 The Bone marrow (BM) microenvironment plays crucial role in pathogenesis of Multiple myeloma(MM). Myeloma cells contacts with bone marrow stromal cells (BMSCs), which secrete factors/cytokines, promoting tumor cell growth and survival. Paracrine secretion of cytokines(i. e., interleukin-6 (IL-6) insulin-like growth factor-1, inflammatory protein-1a) in BM stromal cells promotes multiple myeloma cell proliferation and protects against drug-induced cytotoxicity. These cytokines provide stimulatory signals for multiple myeloma growth and survival. Bone involvement is a common feature in MM patient, solid and hematologic cancers. MM localizes to the bone in nearly all patients ranges between 40% and 75%. Disease-related skeletal complications result in significant morbidity due to pain, pathologic fractures and spinal cord compression. The bone microenvironment creates a supportive niche for tumor growth. Osteoclasts and bone marrow stromal cells, along with extracellular matrix and cytokines stimulate tumor cell proliferation and confer chemoresistance. Therefore, the reciprocal interactions between tumor cells, osteoclasts, osteoblasts, and bone marrow stromal cells present an important. In current study, monocyte can directly promote mesenchymal stem cells osteogenic differentiation through cell contact interactions, thus resulting in the production of osteogenic factors by the monocytes. This mechanism is mediated by the activation of STAT3 signaling pathway in the mesechymal stem cells that leads to the upregulation of Osteoblasts-associated genes such as Runx2 and alkaline phosphatase (ALP), and the down-regulation of inhibitors such as DKK1 to drive the differentiation of mesechymal stem cells into osteoblasts. In this study, we examined the role of monocyte, component of BM cells, as a potential niche component that supports myeloma cells. We investigated the proliferation of MM cell lines cultured alone or co-cultured with BM stromal cells, monocytes, or a combination of BM stromal cells and monocytes. Consistently, we observed increased proliferation of MM cell lines in the presence of either BM stromal cells or monocytes compared to cell line-only control. Furthermore, the co-culture of BM stromal cells plus monocytes induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, BMSCs and monocytes decreased the rate of apoptosis of myeloma cells. Our results therefore suggest that highlights the role of monocyte as an important component of the BM microenvironment. Disclosures: No relevant conflicts of interest to declare.

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