Short hairpin RNA silencing of interleukin-6 in human bone marrow-derived mesenchymal stromal cells inhibits multiple myeloma cell growth

Pathology ◽  
2016 ◽  
Vol 48 ◽  
pp. S99 ◽  
Author(s):  
Hoon Koon Teoh ◽  
Pei Pei Chong ◽  
Maha Abdullah ◽  
Zamberi Sekawi ◽  
Geok Chin Tan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Growth ◽  
Stromal Cells ◽  
Interleukin 6 ◽  
Rna Silencing ◽  
Myeloma Cell ◽  
Hairpin Rna ◽  
Multiple Myeloma Cell ◽  
Short Hairpin

scholarly journals Small interfering RNA silencing of interleukin-6 in mesenchymal stromal cells inhibits multiple myeloma cell growth

2016 ◽  
Vol 40 ◽  
pp. 44-53 ◽  
Author(s):  
Hoon Koon Teoh ◽  
Pei Pei Chong ◽  
Maha Abdullah ◽  
Zamberi Sekawi ◽  
Geok Chin Tan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Interleukin 6 ◽  
Rna Silencing ◽  
Small Interfering Rna ◽  
Myeloma Cell ◽  
Multiple Myeloma Cell ◽  
Interfering Rna

scholarly journals Bone Marrow-Derived Mesenchymal Stromal Cells are Attracted by Multiple Myeloma Cell-Produced Chemokine CCL25 and Favor Myeloma Cell Growth in Vitro and In Vivo

Stem Cells ◽  
2012 ◽  
Vol 30 (2) ◽  
pp. 266-279 ◽  
Author(s):  
Song Xu ◽  
Eline Menu ◽  
Ann De Becker ◽  
Ben Van Camp ◽  
Karin Vanderkerken ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Growth ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloma Cell ◽  
Multiple Myeloma Cell

scholarly journals CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf–mediated interactions with bone marrow stromal cells

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4309-4318 ◽  
Author(s):  
Yu-Tzu Tai ◽  
Ender Soydan ◽  
Weihua Song ◽  
Mariateresa Fulciniti ◽  
Kihyun Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Molecular Mechanisms ◽  
Myeloma Cell ◽  
Marrow Stromal Cells ◽  
Growth And Survival ◽  
Multiple Myeloma Cell

Abstract CS1 is highly expressed on tumor cells from the majority of multiple myeloma (MM) patients regardless of cytogenetic abnormalities or response to current treatments. Furthermore, CS1 is detected in MM patient sera and correlates with active disease. However, its contribution to MM pathophysiology is undefined. We here show that CS1 knockdown using lentiviral short-interfering RNA decreased phosphorylation of ERK1/2, AKT, and STAT3, suggesting that CS1 induces central growth and survival signaling pathways in MM cells. Serum deprivation markedly blocked survival at earlier time points in CS1 knockdown compared with control MM cells, associated with earlier activation of caspases, poly(ADP-ribose) polymerase, and proapoptotic proteins BNIP3 and BIK. CS1 knockdown further delayed development of MM tumor and prolonged survival in mice. Conversely, CS1 overexpression promoted myeloma cell growth and survival by significantly increasing myeloma adhesion to bone marrow stromal cells (BMSCs) and enhancing myeloma colony formation in semisolid culture. Moreover, CS1 increased c-maf–targeted cyclin D2-dependent proliferation, -integrin β7/αE-mediated myeloma adhesion to BMSCs, and -vascular endothelial growth factor-induced bone marrow angiogenesis in vivo. These studies provide direct evidence of the role of CS1 in myeloma pathogenesis, define molecular mechanisms regulating its effects, and further support novel therapies targeting CS1 in MM.

scholarly journals Annexin II interactions with the annexin II receptor enhance multiple myeloma cell adhesion and growth in the bone marrow microenvironment

Blood ◽  
2012 ◽  
Vol 119 (8) ◽  
pp. 1888-1896 ◽  
Author(s):  
Sonia D'Souza ◽  
Noriyoshi Kurihara ◽  
Yusuke Shiozawa ◽  
Jeena Joseph ◽  
Russell Taichman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Stromal Cells ◽  
Critical Role ◽  
Myeloma Cell ◽  
Annexin Ii ◽  
Multiple Myeloma Cell ◽  
B Cell Malignancy ◽  
Multiple Signaling

Abstract Multiple myeloma (MM) is an incurable B-cell malignancy in which the marrow microenvironment plays a critical role in our inability to cure MM. Marrow stromal cells in the microenvironment support homing, lodging, and growth of MM cells through activation of multiple signaling pathways in both MM and stromal cells. Recently, we identified annexin II (AXII) as a previously unknown factor produced by stromal cells and osteoclasts (OCL) that is involved in OCL formation, HSC and prostate cancer (PCa) homing to the BM as well as mobilization of HSC and PCa cells. AXII expressed on stromal cells supports PCa cell lodgment via the AXII receptor (AXIIR) on PCa cells, but the role of AXII and AXIIR in MM is unknown. In this study, we show that MM cells express AXIIR, that stromal/osteoblast-derived AXII facilitates adhesion of MM cells to stromal cells via AXIIR, and OCL-derived AXII enhances MM cell growth. Finally, we demonstrate that AXII activates the ERK1/2 and AKT pathways in MM cells to enhance MM cell growth. These results demonstrate that AXII and AXIIR play important roles in MM and that targeting the AXII/AXIIR axis may be a novel therapeutic approach for MM.

Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 703-705 ◽  
Author(s):  
Teru Hideshima ◽  
Masaharu Akiyama ◽  
Toshiaki Hayashi ◽  
Paul Richardson ◽  
Robert Schlossman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Growth ◽  
P38 Mapk ◽  
Myeloma Cell ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Multiple Myeloma Cell ◽  
Mitogen Activated Protein

p38 mitogen-activated protein kinase (MAPK) is a member of the MAPK family which is activated by cytokines and growth factors, but its role in pathogenesis of multiple myeloma (MM) is unknown. In this study, we demonstrate that the specific p38 MAPK inhibitor VX-745 inhibits interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) secretion in bone marrow stromal cells (BMSCs), without affecting their viability. Tumor necrosis factor alpha (TNF-α)–induced IL-6 secretion in BMSCs is also inhibited by VX-745. Importantly, VX-745 inhibits both MM cell proliferation and IL-6 secretion in BMSCs triggered by adherence of MM cells to BMSCs, suggesting that it can inhibit paracrine MM cell growth in the BM milieu and overcome cell adhesion–related drug resistance. These studies therefore identify p38 MAPK as a novel therapeutic target to overcome drug resistance and improve patient outcome in MM.

scholarly journals A Peculiar Molecular Profile of Umbilical Cord-Mesenchymal Stromal Cells Drives Their Inhibitory Effects on Multiple Myeloma Cell Growth and Tumor Progression

2015 ◽  
Vol 24 (12) ◽  
pp. 1457-1470 ◽  
Author(s):  
Sabino Ciavarella ◽  
Anna Caselli ◽  
Antonella Valentina Tamma ◽  
Annalisa Savonarola ◽  
Giuseppe Loverro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Tumor Progression ◽  
Umbilical Cord ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloma Cell ◽  
Molecular Profile ◽  
Inhibitory Effects ◽  
Multiple Myeloma Cell

scholarly journals Annexin II Interactions with the Annexin II Receptor Enhance Multiple Myeloma Cell Adhesion and Growth in the Bone Marrow Microenvironment,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3942-3942
Author(s):  
Sonia D'Souza ◽  
Noriyoshi Kurihara ◽  
Yusuke Shiozawa ◽  
Jeena Joseph ◽  
Russell Taichman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Growth ◽  
Cell Lines ◽  
Stromal Cells ◽  
Critical Role ◽  
Myeloma Cell ◽  
Bone Marrow Microenvironment ◽  
Annexin Ii

Abstract Abstract 3942 Background: Multiple myeloma (MM) is an incurable B-cell malignancy that develops in the bone marrow. The marrow microenvironment plays a critical role in supporting homing, lodging, and growth of MM cells by activating signaling pathways in both MM and bone marrow stromal cells (BMSC). We previously showed that annexin II (AXII) is involved in prostate cancer cell lodgment to the bone marrow via the annexin II receptor (AXIIR) expressed on prostate cancer cells. We hypothesized that MM cells use a similar mechanism to lodge and grow in the bone marrow. In support of this hypothesis, we found that MM cell lines and primary MM cells from 8 MM patients express the AXIIR protein, and that MM cells adhered significantly better to BMSC from AXII+/+ mice than from AXII−/− mice. Further, knockdown of AXIIR by siRNA in MM1.S and ANBL-6 MM cells decreased AXII binding and decreased adherence of MM cells to human stromal cells and BMSC from AXII+/+ mice. Furthermore, addition of an anti-AXII antibody to MM1.S cells, did not effect MM cell growth demonstrating that AXII expressed by MM cells does not support MM cell growth. Importantly, soluble AXII was released by osteoclasts into their conditioned media which stimulated the growth of MM cells via ERK1/2 and AKT phosphorylation. In the further study, we further characterized the role of AXIIR in MM-BMSC interactions. Methods: AXIIR expression in MM cells was determined by RT-PCR, Western blotting, and immunocytochemistry. Adhesion and growth assays were performed between MM cells and BMSC or AXII to determine the contribution of the AXII/AXIIR axis in supporting adhesion and growth of MM cells. In addition, MM cells or CD138+ cells from MM patients were treated with AXII to determine AXII-dependent MM cell growth. Further, adhesion and growth assays were performed on MM cells expressing either siAXIIR or shAXIIR. Phosphorylation assays were performed to determine the pathways stimulated by AXII in MM cells. Since OCL secrete large amount of AXII, MM cell growth assays were performed with OCL-CM from AXII+/+ and AXII−/− mice in the presence of an AXII antibody. Results: We now report that in addition to MM1.S and ANBL-6 cells, other MM cell lines, including U266, H929, and OPM2 also express AXIIR, and that AXII stimulated the growth of RPMI8226, ANBL-6 and U266 in addition to MM1.S cells. Finally, an AXIIR antibody prevented adhesion of MM1.S cells to AXII, and that AXII upregulated the adhesion molecule, RhoA in MM cells. Additionally, AXII did not stimulate the proliferation of MM1.SshAXIIR cells compared to MM1.SshControl or untreated MM cells, demonstrating that AXII specifically acts through its receptor, AXIIR on MM cells to promote proliferation. More importantly, AXII stimulated the growth of CD138+ cells obtained from MM patients. Conclusions: Based on our results, we conclude that the interaction between AXII and AXIIR in the bone marrow microenvironment supports adhesion via RhoA and growth of MM cells by stimulating the Erk1/2 and Akt pathways, AXII produced by MM cells does not act in an autocrine manner on MM cell growth. Thus, AXII and AXIIR are key players in MM and targeting the AXII/AXIIR axis may be a novel therapeutic approach for MM. Disclosures: Roodman: Amgen: Consultancy; Millennium: Consultancy.

scholarly journals Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B

Blood ◽  
1996 ◽  
Vol 87 (3) ◽  
pp. 1104-1112 ◽  
Author(s):  
D Chauhan ◽  
H Uchiyama ◽  
Y Akbarali ◽  
M Urashima ◽  
K Yamamoto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Adhesion ◽  
Cell Growth ◽  
Stromal Cells ◽  
Interleukin 6 ◽  
Bone Marrow Stromal Cells ◽  
Fold Increase ◽  
Marrow Stromal Cells ◽  
Nf Kappa B

Adhesion of multiple myeloma (MM) cells to bone marrow stromal cells (BMSCs) not only localizes MM cells in the marrow microenvironment, but also triggers interleukin-6 (IL-6) secretion by BMSCs and related MM cell proliferation. In the present study, we characterized the regulation of IL-6 gene expression in BMSCs during MM cell adhesion. Adhesion of ARH-77, HS-Sultan, IM-9, and U266 MM cell lines to BMSCs and BMSC lines (LP 101 and AA 101) triggered 5-through 15-fold and 2- through 4-fold increases in IL-6 secretion, respectively. IL-6 mRNA transcripts were undetectable by Northern blotting in IM-9 MM cells or LP 101 BMSCs cultured alone; however, adherence of IM-9 cells to LP 101 cells induced a transient increase in IL-6 transcripts at 6 hours, followed by peak IL-6 secretion at 24 hours. To confirm increased IL-6 transcription and characterize its regulation, LP101 BMSCs were transiently transfected with full length and deletion fragments of the IL-6 promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene. Transient transfection of LP101 BMSCs with plasmid containing an intact NF-kappa B site showed a 6.8 +/- 0.4-fold increase in CAT activity triggered by IM-9 MM cell adhesion (n = 3, P < .05). Transfection of LP 101 cells with plasmid containing a single base pair deletion from the NF-kapp B binding motif abolished the MM adhesion- induced increase in CAT activity, whereas transfection with plasmid containing three copies of synthetic NF-kappa B sequence resulted in an 8.1 +/- 0.7-fold increase in CAT activity related to MM adhesion (n = 3, P < .05). These data suggest that the NF-kappa B site is one of the essential regulatory elements for MM cell adhesion-induced IL-6 transcription in BMSCs. Electrophoretic mobility shift assays confirmed the involvement of NF-kappa B activation in regulating MM adhesion- induced IL-6 transcription in BMSCs. Further characterization of the upstream events in the signalling cascade regulating IL-6 may not only delineate mechanisms of IL-6 regulation during paracrine MM cell growth, but also provide new therapeutic strategies based on interruption of IL-6 mediated tumor cell growth.

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