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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. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-05-1634v1 103/10/3883    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Santos, S. C. R. Articles by Dias, S. Search for Related Content PubMed PubMed Citation Articles by Santos, S. C. R. Articles by Dias, S. Related Collections Hemostasis, Thrombosis, and Vascular Biology Neoplasia Apoptosis Signal Transduction Social Bookmarking                   What's this?  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 10, 2009; 38(1): 29 - 41. [Abstract] [Full Text] [PDF] C. Marty, R. Chaligne, C. Lacout, S. N. Constantinescu, W. 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