|
|
Blood, 15 May 2004, Vol. 103, No. 10, pp. 3883-3889.
Prepublished online as a Blood First Edition Paper on January 15, 2004; DOI 10.1182/blood-2003-05-1634.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways
Susana Constantino Rosa Santos, and
Sérgio Dias
From the Angiogenesis Laboratory, CIPM/Instituto Português de Oncologia Francisco Gentil (IPOFG), Lisboa, and the Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Besides being expressed on endothelial cells, vascular endothelial growth factor receptors (VEGFRs) are also functional on subsets of leukemias, resulting in autocrine loops that sustain leukemia migration and proliferation. While recent evidence suggests that VEGF supports hematopoietic stem cell survival via an internal loop, the molecular mechanisms whereby autocrine stimulation of VEGFR-2 (KDR) promotes leukemia growth are not well understood. Here we show on acute myeloid primary leukemias and cell lines that VEGF/KDR autocrine loops operate both internally and externally. First, we demonstrate that KDR is constitutively phosphorylated and located at the nucleus of VEGF-producing leukemias. Treatment with anti-VEGF antibody, which acts externally, blocked KDR nuclear translocation and inhibited nuclear factor  B (NF-B; p65 and c-rel) activation. In contrast, a KDR-specific intracellular inhibitor failed to block KDR nuclear translocation, but inhibited the constitutive activation of mitogen activated protein kinase (MAPK)/Erk and the phosphatidylinositol 3-kinase/AKT pathways. Notably, treatment with the anti-VEGF antibody alone had little effect on cell survival, while the internal inhibitor induced leukemia apoptosis, and the 2 drugs produced synergistic effects, together and with chemotherapy, reducing cell survival to a larger extent than either agent alone. Our results demonstrate that internal and external VEGF/KDR autocrine loops regulate leukemia survival via different mechanisms, and suggest that blocking both may have therapeutic potential.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
F. T. H. Wu, M. O. Stefanini, F. Mac Gabhann, C. D. Kontos, B. H. Annex, and A. S. Popel
Computational kinetic model of VEGF trapping by soluble VEGF receptor-1: effects of transendothelial and lymphatic macromolecular transport
Physiol Genomics,
June 1, 2009;
38(1):
29 - 41.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Marty, R. Chaligne, C. Lacout, S. N. Constantinescu, W. Vainchenker, and J.-L. Villeval
Ligand-independent Thrombopoietin Mutant Receptor Requires Cell Surface Localization for Endogenous Activity
J. Biol. Chem.,
May 1, 2009;
284(18):
11781 - 11791.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Thill, N. V. Strunnikova, M. J. Berna, N. Gordiyenko, K. Schmid, S. W. Cousins, D. J. S. Thompson, and K. G. Csaky
Late Outgrowth Endothelial Progenitor Cells in Patients with Age-Related Macular Degeneration
Invest. Ophthalmol. Vis. Sci.,
June 1, 2008;
49(6):
2696 - 2708.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. N. Re and J. L. Cook
The Basis of an Intracrine Pharmacology
J. Clin. Pharmacol.,
March 1, 2008;
48(3):
344 - 350.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. J.M. de Jonge, A. C. Weidenaar, A. ter Elst, H. M. Boezen, F. J.G. Scherpen, J. C.A. Bouma-ter Steege, G. J.L. Kaspers, B. F. Goemans, U. Creutzig, M. Zimmermann, et al.
Endogenous Vascular Endothelial Growth Factor-C Expression Is Associated with Decreased Drug Responsiveness in Childhood Acute Myeloid Leukemia
Clin. Cancer Res.,
February 1, 2008;
14(3):
924 - 930.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. F. Yang, R. T.P. Poon, Y. Liu, C. K. Lau, D. W. Ho, K. H. Tam, C. T. Lam, and S. T. Fan
High doses of tyrosine kinase inhibitor PTK787 enhance the efficacy of ischemic hypoxia for the treatment of hepatocellular carcinoma: dual effects on cancer cell and angiogenesis.
Mol. Cancer Ther.,
September 1, 2006;
5(9):
2261 - 2270.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Wada, J. J. Haigh, M. Ema, S. Hitoshi, R. Chaddah, J. Rossant, A. Nagy, and D. van der Kooy
Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival.
J. Neurosci.,
June 21, 2006;
26(25):
6803 - 6812.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Xu, J. E. Thompson, and M. Carroll
mTOR regulates cell survival after etoposide treatment in primary AML cells
Blood,
December 15, 2005;
106(13):
4261 - 4268.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Das, H. Yeger, R. Tsuchida, R. Torkin, M. F.W. Gee, P. S. Thorner, M. Shibuya, D. Malkin, and S. Baruchel
A Hypoxia-Driven Vascular Endothelial Growth Factor/Flt1 Autocrine Loop Interacts with Hypoxia-Inducible Factor-1{alpha} through Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathway in Neuroblastoma
Cancer Res.,
August 15, 2005;
65(16):
7267 - 7275.
[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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
