|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2630-2636
Vascular endothelial growth factor and interleukin-6 in
paracrine tumor-stromal cell interactions in multiple myeloma
Berno Dankbar,
Teresa Padró,
Regine Leo,
Birgit Feldmann,
Martin Kropff,
Rolf M. Mesters,
Hubert Serve,
Wolfgang E. Berdel, and
Joachim Kienast
From the Department of Medicine/Hematology and Oncology, University
of Muenster, Muenster, Germany
Vascular endothelial growth factor (VEGF), a multifunctional
cytokine, potently stimulates angiogenesis including tumor
neovascularization. Although well established in solid tumors, the role
of VEGF in bone marrow neoangiogenesis and paracrine tumor-stromal cell
interactions in lymphohematopoietic malignancies has not been fully
elucidated. In multiple myeloma (MM), marrow neovascularization
parallels disease progression. This parallel prompted us
to investigate the expression and secretion of VEGF by myeloma cells
and its potential effects in myeloma-marrow stroma interactions. The
biologically active splice variants VEGF165 and VEGF121 were expressed
and secreted by myeloma cell lines and plasma cells isolated from the
marrow of patients with MM. As shown by immunocytochemistry or
RT-PCR, myeloma cells did not express or weakly expressed the VEGF receptors FLT-1 and FLK-1/KDR, indicating that autocrine stimulation is unlikely. In contrast, FLK-1/KDR was abundantly expressed by marrow stromal cells. Therefore, we studied the effects of
VEGF on marrow stroma, focusing on the secretion of interleukin-6 (IL-6), a potent growth factor for myeloma cells and an inhibitor of
plasma cell apoptosis. Exposure of stromal and microvascular endothelial cells to recombinant human (rh) VEGF165 or VEGF121 induced
a time- and dose-dependent increase in IL-6 secretion (14- to 27-fold
at 50 ng/mL after 24 hours, P < .001). Conversely, rhIL-6
stimulated VEGF expression and secretion in myeloma cell lines
(40%-60%; P < .05) and to a variable degree (up to
5.3-fold; P < .005) in plasma cells purified from the
marrow of patients with MM. This mutual stimulation suggests paracrine
interactions between myeloma and marrow stromal cells triggered by VEGF
and IL-6.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
Y. Fukaya, H. Shimada, L.-C. Wang, E. Zandi, and Y. A. DeClerck
Identification of Galectin-3-binding Protein as a Factor Secreted by Tumor Cells That Stimulates Interleukin-6 Expression in the Bone Marrow Stroma
J. Biol. Chem.,
July 4, 2008;
283(27):
18573 - 18581.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. B. Meads, L. A. Hazlehurst, and W. S. Dalton
The Bone Marrow Microenvironment as a Tumor Sanctuary and Contributor to Drug Resistance
Clin. Cancer Res.,
May 1, 2008;
14(9):
2519 - 2526.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. H. Wang, X. Y. Yang, X. Zhang, and W. L. Farrar
Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPAR{gamma} cross talk with NF-{kappa}B and C/EBP
Blood,
December 15, 2007;
110(13):
4373 - 4384.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Colla, S. Tagliaferri, F. Morandi, P. Lunghi, G. Donofrio, D. Martorana, C. Mancini, M. Lazzaretti, L. Mazzera, L. Ravanetti, et al.
The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 {alpha} (HIF-1{alpha}) activity: involvement in myeloma-induced angiogenesis
Blood,
December 15, 2007;
110(13):
4464 - 4475.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Scavelli, G. Di Pietro, T. Cirulli, M. Coluccia, A. Boccarelli, T. Giannini, G. Mangialardi, R. Bertieri, A. M. L. Coluccia, D. Ribatti, et al.
Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma
Mol. Cancer Ther.,
December 1, 2007;
6(12):
3256 - 3262.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Rega, C. Kaun, S. Demyanets, S. Pfaffenberger, K. Rychli, P.J. Hohensinner, S.P. Kastl, W.S. Speidl, T.W. Weiss, J.M. Breuss, et al.
Vascular Endothelial Growth Factor Is Induced by the Inflammatory Cytokines Interleukin-6 and Oncostatin M in Human Adipose Tissue In Vitro and in Murine Adipose Tissue In Vivo
Arterioscler. Thromb. Vasc. Biol.,
July 1, 2007;
27(7):
1587 - 1595.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Yoshio-Hoshino, Y. Adachi, C. Aoki, A. Pereboev, D. T. Curiel, and N. Nishimoto
Establishment of a New Interleukin-6 (IL-6) Receptor Inhibitor Applicable to the Gene Therapy for IL-6-Dependent Tumor
Cancer Res.,
February 1, 2007;
67(3):
871 - 875.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. G. Richardson, T. Hideshima, and K. C. Anderson
Plasma cell dyscrasias
ASH Self-Assessment Program,
January 1, 2007;
2007(1):
298 - 327.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Matuszewski, T. Persigehl, A. Wall, N. Meier, R. Bieker, H. Kooijman, B. Tombach, R. Mesters, W. E. Berdel, W. Heindel, et al.
Assessment of Bone Marrow Angiogenesis in Patients with Acute Myeloid Leukemia by Using Contrast-enhanced MR Imaging with Clinically Approved Iron Oxides: Initial Experience
Radiology,
December 1, 2006;
242(1):
217 - 224.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hideshima, P. Neri, P. Tassone, H. Yasui, K. Ishitsuka, N. Raje, D. Chauhan, K. Podar, C. Mitsiades, L. Dang, et al.
MLN120B, a Novel I{kappa}B Kinase {beta} Inhibitor, Blocks Multiple Myeloma Cell Growth In vitro and In vivo.
Clin. Cancer Res.,
October 1, 2006;
12(19):
5887 - 5894.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Levine, A. Tulpule, D. I. Quinn, G. Gorospe III, D. L. Smith, L. Hornor, W. D. Boswell, B. M. Espina, S. G. Groshen, R. Masood, et al.
Phase I Study of Antisense Oligonucleotide Against Vascular Endothelial Growth Factor: Decrease in Plasma Vascular Endothelial Growth Factor With Potential Clinical Efficacy
J. Clin. Oncol.,
April 10, 2006;
24(11):
1712 - 1719.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. G. Gunn, A. Conley, L. Deininger, S. D. Olson, D. J. Prockop, and C. A. Gregory
A Crosstalk Between Myeloma Cells and Marrow Stromal Cells Stimulates Production of DKK1 and Interleukin-6: A Potential Role in the Development of Lytic Bone Disease and Tumor Progression in Multiple Myeloma
Stem Cells,
April 1, 2006;
24(4):
986 - 991.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Bisping, M. Kropff, D. Wenning, B. Dreyer, S. Bessonov, F. Hilberg, G. J. Roth, G. Munzert, M. Stefanic, M. Stelljes, et al.
Targeting receptor kinases by a novel indolinone derivative in multiple myeloma: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups
Blood,
March 1, 2006;
107(5):
2079 - 2089.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. K. Hong, P. Kumar, L. Wang, B. Damania, M. L. Gulley, H.-J. Delecluse, P. J. Polverini, and S. C. Kenney
Epstein-Barr Virus Lytic Infection Is Required for Efficient Production of the Angiogenesis Factor Vascular Endothelial Growth Factor in Lymphoblastoid Cell Lines
J. Virol.,
November 15, 2005;
79(22):
13984 - 13992.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Terpos and M.-A. Dimopoulos
Myeloma bone disease: pathophysiology and management
Ann. Onc.,
August 1, 2005;
16(8):
1223 - 1231.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Zhu, E. Gerbino, D. M. Beaupre, P. A. Mackley, C. Muro-Cacho, C. Beam, A. D. Hamilton, M. G. Lichtenheld, W. G. Kerr, W. Dalton, et al.
Farnesyltransferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells
Blood,
June 15, 2005;
105(12):
4759 - 4766.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-L. Su, K.-P. Lai, C.-A. Chen, C.-Y. Yang, P.-S. Chen, C.-C. Chang, C.-H. Chou, C.-L. Hu, M.-L. Kuo, C.-Y. Hsieh, et al.
A Novel Peptide Specifically Binding to Interleukin-6 Receptor (gp80) Inhibits Angiogenesis and Tumor Growth
Cancer Res.,
June 1, 2005;
65(11):
4827 - 4835.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Vincent, D. K. Jin, M. A. Karajannis, K. Shido, A. T. Hooper, W. K. Rashbaum, B. Pytowski, Y. Wu, D. J. Hicklin, Z. Zhu, et al.
Fetal Stromal-Dependent Paracrine and Intracrine Vascular Endothelial Growth Factor-A/Vascular Endothelial Growth Factor Receptor-1 Signaling Promotes Proliferation and Motility of Human Primary Myeloma Cells
Cancer Res.,
April 15, 2005;
65(8):
3185 - 3192.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Zhang, V. Vakil, M. Braunstein, E. L. P. Smith, J. Maroney, L. Chen, K. Dai, J. R. Berenson, M. M. Hussain, U. Klueppelberg, et al.
Circulating endothelial progenitor cells in multiple myeloma: implications and significance
Blood,
April 15, 2005;
105(8):
3286 - 3294.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Sanda, S. Iida, H. Ogura, K. Asamitsu, T. Murata, K. B. Bacon, R. Ueda, and T. Okamoto
Growth Inhibition of Multiple Myeloma Cells by a Novel I{kappa}B Kinase Inhibitor
Clin. Cancer Res.,
March 1, 2005;
11(5):
1974 - 1982.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Podar and K. C. Anderson
The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications
Blood,
February 15, 2005;
105(4):
1383 - 1395.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hayashi, T. Hideshima, A. N. Nguyen, O. Munoz, K. Podar, M. Hamasaki, K. Ishitsuka, H. Yasui, P. Richardson, S. Chakravarty, et al.
Transforming Growth Factor {beta} Receptor I Kinase Inhibitor Down-Regulates Cytokine Secretion and Multiple Myeloma Cell Growth in the Bone Marrow Microenvironment
Clin. Cancer Res.,
November 15, 2004;
10(22):
7540 - 7546.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Le Gouill, K. Podar, M. Amiot, T. Hideshima, D. Chauhan, K. Ishitsuka, S. Kumar, N. Raje, P. G. Richardson, J.-L. Harousseau, et al.
VEGF induces Mcl-1 up-regulation and protects multiple myeloma cells against apoptosis
Blood,
November 1, 2004;
104(9):
2886 - 2892.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Podar, R. Shringarpure, Y.-T. Tai, M. Simoncini, M. Sattler, K. Ishitsuka, P. G. Richardson, T. Hideshima, D. Chauhan, and K. C. Anderson
Caveolin-1 Is Required for Vascular Endothelial Growth Factor-Triggered Multiple Myeloma Cell Migration and Is Targeted by Bortezomib
Cancer Res.,
October 15, 2004;
64(20):
7500 - 7506.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kumar, T. E. Witzig, M. Timm, J. Haug, L. Wellik, T. K. Kimlinger, P. R. Greipp, and S. V. Rajkumar
Bone marrow angiogenic ability and expression of angiogenic cytokines in myeloma: evidence favoring loss of marrow angiogenesis inhibitory activity with disease progression
Blood,
August 15, 2004;
104(4):
1159 - 1165.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Mills, B. Parker, V. Jones, K. A. Adler, C. J. Perez, S. Johnson, M. Cohen-Zion, M. Marler, G. R. Sadler, J. E. Dimsdale, et al.
The Effects of Standard Anthracycline-Based Chemotherapy on Soluble ICAM-1 and Vascular Endothelial Growth Factor Levels in Breast Cancer
Clin. Cancer Res.,
August 1, 2004;
10(15):
4998 - 5003.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson
Advances in biology of multiple myeloma: clinical applications
Blood,
August 1, 2004;
104(3):
607 - 618.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. X. Chen
Expanding the Clinical Development of Bevacizumab
Oncologist,
June 1, 2004;
9(suppl_1):
27 - 35.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Podar, L. P. Catley, Y.-T. Tai, R. Shringarpure, P. Carvalho, T. Hayashi, R. Burger, R. L. Schlossman, P. G. Richardson, L. N. Pandite, et al.
GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment
Blood,
May 1, 2004;
103(9):
3474 - 3479.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Asosingh, H. De Raeve, E. Menu, I. Van Riet, E. Van Marck, B. Van Camp, and K. Vanderkerken
Angiogenic switch during 5T2MM murine myeloma tumorigenesis: role of CD45 heterogeneity
Blood,
April 15, 2004;
103(8):
3131 - 3137.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ikezoe, T. Saito, K. Bandobashi, Y. Yang, H. P. Koeffler, and H. Taguchi
HIV-1 protease inhibitor induces growth arrest and apoptosis of human multiple myeloma cells via inactivation of signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2
Mol. Cancer Ther.,
April 1, 2004;
3(4):
473 - 479.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Zangari, E. Anaissie, A. Stopeck, A. Morimoto, N. Tan, J. Lancet, M. Cooper, A. Hannah, G. Garcia-Manero, S. Faderl, et al.
Phase II Study of SU5416, a Small Molecule Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitor, in Patients with Refractory Multiple Myeloma
Clin. Cancer Res.,
January 1, 2004;
10(1):
88 - 95.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Walter-Yohrling, X. Cao, M. Callahan, W. Weber, S. Morgenbesser, S. L. Madden, C. Wang, and B. A. Teicher
Identification of Genes Expressed in Malignant Cells That Promote Invasion
Cancer Res.,
December 15, 2003;
63(24):
8939 - 8947.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hideshima, D. Chauhan, T. Hayashi, K. Podar, M. Akiyama, C. Mitsiades, N. MItsiades, B. Gong, L. Bonham, P. de Vries, et al.
Antitumor Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitors, a Novel Class of Agents, in Multiple Myeloma
Cancer Res.,
December 1, 2003;
63(23):
8428 - 8436.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hayashi, T. Hideshima, M. Akiyama, N. Raje, P. Richardson, D. Chauhan, and K. C. Anderson
Ex vivo induction of multiple myeloma-specific cytotoxic T lymphocytes
Blood,
August 15, 2003;
102(4):
1435 - 1442.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Giuliani, S. Colla, M. Lazzaretti, R. Sala, G. Roti, C. Mancini, S. Bonomini, P. Lunghi, M. Hojden, G. Genestreti, et al.
Proangiogenic properties of human myeloma cells: production of angiopoietin-1 and its potential relationship to myeloma-induced angiogenesis
Blood,
July 15, 2003;
102(2):
638 - 645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. London, A. L. Hannah, R. Zadovoskaya, M. B. Chien, C. Kollias-Baker, M. Rosenberg, S. Downing, G. Post, J. Boucher, N. Shenoy, et al.
Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Malignancies
Clin. Cancer Res.,
July 1, 2003;
9(7):
2755 - 2768.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Lentzsch, M. Gries, M. Janz, R. Bargou, B. Dorken, and M. Y. Mapara
Macrophage inflammatory protein 1-alpha (MIP-1alpha ) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells
Blood,
May 1, 2003;
101(9):
3568 - 3573.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Bisping, R. Leo, D. Wenning, B. Dankbar, T. Padro, M. Kropff, C. Scheffold, M. Kroger, R. M. Mesters, W. E. Berdel, et al.
Paracrine interactions of basic fibroblast growth factor and interleukin-6 in multiple myeloma
Blood,
April 1, 2003;
101(7):
2775 - 2783.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kumar, R. Fonseca, A. Dispenzieri, M. Q. Lacy, J. A. Lust, L. Wellik, T. E. Witzig, M. A. Gertz, R. A. Kyle, P. R. Greipp, et al.
Prognostic value of angiogenesis in solitary bone plasmacytoma
Blood,
March 1, 2003;
101(5):
1715 - 1717.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
