scholarly journals The type III transforming growth factor-β receptor inhibits proliferation, migration, and adhesion in human myeloma cells

2011 ◽  
Vol 22 (9) ◽  
pp. 1463-1472 ◽  
Author(s):  
Kathleen E. Lambert ◽  
Huang Huang ◽  
Karthikeyan Mythreye ◽  
Gerard C. Blobe
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Cell Growth ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Β Receptor

Transforming growth factor-β (TGF-β) plays an important role in regulating hematopoiesis, inhibiting proliferation while stimulating differentiation when appropriate. We previously demonstrated that the type III TGF-β receptor (TβRIII, or betaglycan) serves as a novel suppressor of cancer progression in epithelial tumors; however, its role in hematologic malignancies is unknown. Here we demonstrate that TβRIII protein expression is decreased or lost in the majority of human multiple myeloma specimens. Functionally, restoring TβRIII expression in myeloma cells significantly inhibited cell growth, proliferation, and motility, largely independent of its ligand presentation role. In a reciprocal fashion, shRNA-mediated silencing of endogenous TβRIII expression enhanced cell growth, proliferation, and motility. Although apoptosis was not affected, TβRIII inhibited proliferation through induction of the cyclin-dependent kinase inhibitors p21 and p27. TβRIII further regulated myeloma cell adhesion, increasing homotypic myeloma cell adhesion while decreasing myeloma heterotropic adhesion to bone marrow stromal cells. Mechanistically, live cell imaging of myeloma and stroma cell cocultures revealed that TβRIII-mediated inhibition of heterotropic adhesion was associated with decreased duration of myeloma/bone marrow stromal cell interaction. These results suggest that loss of TβRIII expression during multiple myeloma progression contributes to disease progression through its functional effects on increased cell growth, proliferation, motility, and adhesion.

scholarly journals An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti–IL-6 antibody-induced apoptosis

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1829-1837 ◽  
Author(s):  
Karène Mahtouk ◽  
Michel Jourdan ◽  
John De Vos ◽  
Catherine Hertogh ◽  
Geneviève Fiol ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Growth ◽  
Cell Lines ◽  
Stromal Cells ◽  
Egf Receptor ◽  
Myeloma Cell ◽  
Factor Activity ◽  
Myeloma Cells ◽  
Induced Apoptosis

Abstract We previously found that some myeloma cell lines express the heparin-binding epidermal growth factor–like growth factor (HB-EGF) gene. As the proteoglycan syndecan-1 is an HB-EGF coreceptor as well as a hallmark of plasma cell differentiation and a marker of myeloma cells, we studied the role of HB-EGF on myeloma cell growth. The HB-EGF gene was expressed by bone marrow mononuclear cells in 8 of 8 patients with myeloma, particularly by monocytes and stromal cells, but not by purified primary myeloma cells. Six of 9 myeloma cell lines and 9 of 9 purified primary myeloma cells expressed ErbB1 or ErbB4 genes coding for HB-EGF receptor. In the presence of a low interleukin-6 (IL-6) concentration, HB-EGF stimulated the proliferation of the 6 ErbB1+ or ErbB4+ cell lines, through the phosphatidylinositol 3-kinase/AKT (PI-3K/AKT) pathway. A pan-ErbB inhibitor blocked the myeloma cell growth factor activity and the signaling induced by HB-EGF. This inhibitor induced apoptosis of patients'myeloma cells cultured with their tumor environment. It also increased patients' myeloma cell apoptosis induced by an anti–IL-6 antibody or dexamethasone. The ErbB inhibitor had no effect on the interaction between multiple myeloma cells and stromal cells. It was not toxic for nonmyeloma cells present in patients' bone marrow cultures or for the growth of hematopoietic progenitors. Altogether, these data identify ErbB receptors as putative therapeutic targets in multiple myeloma.

scholarly journals Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 11-13 ◽  
Author(s):  
XG Zhang ◽  
B Klein ◽  
R Bataille
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Growth ◽  
Interleukin 6 ◽  
Myeloma Cell ◽  
S Phase ◽  
Myeloma Cells ◽  
Severity Of The Disease

Abstract It has recently been demonstrated that interleukin-6 (IL-6) is a potent myeloma-cell growth factor in the majority of patients with multiple myeloma (MM). Using an anti-bromodeoxyuridine monoclonal antibody (MoAb) to specifically count myeloma cells in the S-phase (ie, labeling index, LI), we demonstrate that the IL-6 responsiveness of myeloma cells in vitro is directly correlated with their LI in vivo. Myeloma cells from all 13 patients with high LIs in vivo (greater than or equal to 1%) responded in vitro to IL-6, the strongest response occurring in cells from five patients with plasma-cell leukemia. In contrast, the cells of only two of eight patients with low myeloma-cell LIs in vivo (less than 1%) responded to IL-6 in vitro. After seven days of culturing with 1,000 U/mL recombinant IL-6 (rIL-6), the median LI value in the first group of patients (in vivo LI greater than or equal to 1%) was 11%, ie 11 times higher (P less than .01) than the median LI value (1%) in the second group of patients (in vivo LI less than 1%). Thus, the in vitro IL-6 responsiveness of myeloma cells is directly related to their in vivo proliferative status, and hence to the severity of the disease.

scholarly journals Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 11-13 ◽  
Author(s):  
XG Zhang ◽  
B Klein ◽  
R Bataille
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Growth ◽  
Interleukin 6 ◽  
Myeloma Cell ◽  
S Phase ◽  
Myeloma Cells ◽  
Severity Of The Disease

It has recently been demonstrated that interleukin-6 (IL-6) is a potent myeloma-cell growth factor in the majority of patients with multiple myeloma (MM). Using an anti-bromodeoxyuridine monoclonal antibody (MoAb) to specifically count myeloma cells in the S-phase (ie, labeling index, LI), we demonstrate that the IL-6 responsiveness of myeloma cells in vitro is directly correlated with their LI in vivo. Myeloma cells from all 13 patients with high LIs in vivo (greater than or equal to 1%) responded in vitro to IL-6, the strongest response occurring in cells from five patients with plasma-cell leukemia. In contrast, the cells of only two of eight patients with low myeloma-cell LIs in vivo (less than 1%) responded to IL-6 in vitro. After seven days of culturing with 1,000 U/mL recombinant IL-6 (rIL-6), the median LI value in the first group of patients (in vivo LI greater than or equal to 1%) was 11%, ie 11 times higher (P less than .01) than the median LI value (1%) in the second group of patients (in vivo LI less than 1%). Thus, the in vitro IL-6 responsiveness of myeloma cells is directly related to their in vivo proliferative status, and hence to the severity of the disease.

scholarly journals Transforming growth factor-β receptor III downregulation in prostate cancer: is inhibin B a tumor suppressor in prostate?

2007 ◽  
Vol 39 (5) ◽  
pp. 329-332 ◽  
Author(s):  
Nima Sharifi ◽  
Robert J Lechleider ◽  
William L Farrar
Keyword(s):  
Prostate Cancer ◽  
Growth Factor ◽  
Cell Growth ◽  
Epithelial Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Invasion And Metastasis ◽  
Dual Roles ◽  
Growth Inhibitory ◽  
Β Receptor

AbstractThe transforming growth factor-β (TGF-β) pathway plays dual roles in cancer, inhibiting epithelial cell growth under normal physiologic conditions, but promoting invasion and metastasis once growth inhibitory responses are lost. Two recent papers show that TGF-β receptor III is the most common TGF-β pathway component downregulated in prostate cancer. Here, we discuss the implications of these findings and what it may mean about the biology of this disease.

Influence of Targeted Therapy in Redefining High-Risk Myeloma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-7-sci-7
Author(s):  
Lori Hazlehurst ◽  
William S. Dalton ◽  
Danielle Yarde ◽  
Yulia Nefedova ◽  
Dmitry Gabrilovich
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Clinical Trials ◽  
Cell Adhesion ◽  
Tumor Microenvironment ◽  
Residual Disease ◽  
Myeloma Cell ◽  
Myeloma Cells ◽  
Acquired Drug Resistance

Abstract Multiple myeloma is a disease that typically responds to initial treatment; however, the disease is not cured by chemotherapy, and drug resistance ultimately develops. Most studies investigating the problem of drug resistance have focused on acquired resistance or resistance that occurs after response to prior therapy as a result of residual disease. Intrinsic factors, such as reduced drug uptake, enhanced damage response (i.e., DNA repair), altered drug metabolism, or inhibition of programmed cell death pathways are known to contribute to acquired drug resistance. For example, it was recently reported that the acquired melphalan resistant phenotype in myeloma cell lines was associated with over-expression of the Fanconi anemia (FA)/BRCA pathway genes. Enhanced interstrand cross-link (ICL) repair via the FA/BRCA pathway was causally related to melphalan resistance and disruption of this pathway using knock-down techniques reversed drug resistance. Furthermore, bortezomib (Velcade) has been reported to enhance melphalan treatment, and recent pre-clinical data has shown that bortezomib reduces FA/BRCA gene expression and function. Clinical trials are necessary to determine the role of the FA/ BRCA pathway in acquired drug resistance for myeloma patients and whether targeting this pathway enables prevention of or the ability to overcome acquired melphalan resistance in myeloma patients. Conversely, factors that promote tumor cell survival and drug resistance that are external to the tumor cell itself might exist. Evidence supporting the importance of understanding the influence of the tumor microenvironment on drug sensitivity has been reported by several investigators. The tumor microenvironment for hematologic malignancies, including myeloma, is principally the bone marrow. The bone marrow contains candidate components that contribute to reduced drug activity, minimal residual disease, and emergence of drug resistant cells. Cell adhesion molecules expressed by myeloma cells, including the β integrins, bind to fibronectin and other extracellular matrix components of the bone marrow, and this interaction contributes to a reversible, de novo drug resistance phenotype called “cell adhesion mediated drug resistance” or CAMDR. Adhesion via integrins is known to activate a network of signal transduction pathways that influence cell survival, growth, and differentiation. Several targets that are influenced by integrin adhesion and may contribute to CAM-DR include the following: reduced proapoptotic Bim levels, alterations in nuclear topoisomerase II levels, increased p27 kip1 levels, and changes in FLIP1 levels. In addition, myeloma cell adhesion to bone marrow stroma (BMS) involves other adhesion molecules and signaling events that promote CAMDR. For example, Notch1 receptors expressed on multiple myeloma cells when stimulated by Jagged causes growth arrest and protection from drug-induced apoptosis. Recently, approaches to inhibit integrin and Notch signaling associated with CAM-DR have been examined pre-clinically. Clinical trials are necessary to determine if these approaches will prevent or overcome CAM-DR in patients.

scholarly journals Transforming growth factor β from multiple myeloma cells inhibits proliferation and IL-2 responsiveness in T lymphocytes

1999 ◽  
Vol 66 (6) ◽  
pp. 981-988 ◽  
Author(s):  
Gordon Cook ◽  
John D. M. Campbell ◽  
Christine E. Carr ◽  
Kelly S. Boyd ◽  
Ian M. Franklin
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
T Lymphocytes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Myeloma Cells

Syndecan-1 Is Essential for the Myeloma Cell Growth Factor Activity of EGF-Family Ligands in Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 626-626
Author(s):  
Karène Mahtouk ◽  
Friedrich W. Cremer ◽  
Thierry Rème ◽  
Michel Jourdan ◽  
Marion Baudard ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Growth Factors ◽  
Cell Growth ◽  
Egf Receptor ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Erbb Receptors ◽  
Myeloma Cells ◽  
Egf Family

Abstract Aim was to assess the role of the epidermal growth factor (EGF)/EGF receptor (ErbB1 (EGFR), ErbB2, ErbB3 and ErbB4) family in the pathogenesis of multiple myeloma (MM) investigating (i) their expression profile and (ii) their functional activity. Comparing Affymetrix DNA-microarray-expression-profiles of CD138-purified plasma-cells from 65 MM patients and 7 normal individuals to those of plasmablastic- and B-cells, we found 5/10 EGF-family genes to be overexpressed in myeloma cells (MMC). Two of them -neuregulin(NRG)-2 and NRG-3- were expressed by MMC only, while other three -NRG-1, amphiregulin (AREG) and TGF-α- were expressed by both MMC and normal bone marrow (BM) plasma cells (PCs). In addition, using real-time PCR, we found 4/10 EGF-ligands -HB-EGF, AREG, NRG-1 and epiregulin- to be expressed by cells from the BM-environment. ErbB receptors were expressed by normal and malignant plasma cells but were lacking on plasmablastic- and B-cells. ErbB1 and ErbB2 were expressed by MMC and BMPC, whereas ErbB3 and ErbB4 were expressed by MMC exclusively. The growth of myeloma cell lines was promoted by EGF-ligands able to bind heparan sulfate (HS) proteoglycans (PGs), i.e. NRG-1, amphiregulin and HB-EGF, but not by other EGF-ligands, i.e. EGF, TGF-α, epiregulin and betacellulin. Proliferation induced by HS-binding EGF-ligands was completely abrogated when the growth factors where pre-incubated with heparin. A truncated form of NRG-1 that lacks the HS-binding domain but has kept the ErbB binding domain was unable to promote MMC growth. MMC could bind large levels of HS-binding EGF-ligands through syndecan-1, which is expressed on myeloma cells at a high density contrary to other 10 HSPGs -syndecan-2-4, glypican-1-6 and CD44v3-. The binding was abrogated by either pre-treatment with heparitinase (which cleaves HS chains), or pre-incubation of the growth factors with heparin. None of the EGF-ligands could bind or induce proliferation of the XG-10 myeloma cell line which doesn’t express syndecan-1. Thus, EGF/EGF-receptor genes are expressed during plasma cell differentiation and malignant transformation: MMC express ErbB receptors and several HS-binding EGF-ligands. Cells from the BM-environment can also be a source of EGF-family members delivering a paracrine growth signal to MMC. Myeloma cell growth is stimulated by EGF-ligands that bind HS, via binding to syndecan-1, which likely concentrates high levels of HS-binding-EGF-ligands in the proximity of ErbB receptors at the cell membrane and therefore facilitates ErbB-activation. This accumulation of EGF-family members at cell membrane is required to promote their myeloma cell growth activity. We have previously shown that pan-ErbB inhibitors like CI-1033 induce strong apoptosis of primary MMC cultured with their bone-marrow environment. Together with these data, this further recommends EGF-signalling as promising target for MM therapy.

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