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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4500-4507. Prepublished online as a Blood First Edition Paper on February 8, 2005; DOI 10.1182/blood-2004-08-3210. This Article Full Text (PDF) All Versions of this Article: 2004-08-3210v1 105/11/4500    most recent Alert me when this article is cited Alert me if a correction is posted 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 Shaked, Y. Articles by Ben-David, Y. Search for Related Content PubMed PubMed Citation Articles by Shaked, Y. Articles by Ben-David, Y. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 19, 2004 Accepted January 29, 2005 The splenic microenvironment is a source of pro-angiogenesis / inflammatory mediators accelerating the expansion of murine erythroleukemic cells Yuval Shaked, Dave Cervi, Manuela Neuman, Limor Chen, Giannoula Klement, Crystal R Michaud, Mehran Haeri, Brian J Pak, Robert S Kerbel, and Yaacov Ben-David* Department of Molecular and Cellular Biology, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, Canada Department of Molecular and Cellular Biology, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada Department of Molecular and Cellular Biology, Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada * Corresponding author; email: bendavid{at}srcl.sunnybrook.utoronto.ca. The stromal compartments of hematopoietic organs; e.g., spleen, are known to influence the viability and growth of diseased hematopoietic progenitors. Here we have used Friend Murine Leukemia Virus (F-MuLV)-induced erythroleukemia to investigate factors of the splenic microenvironment that may make it fertile for the expansion and survival of malignant erythroblasts. We found that splenectomized, erythroleukemic mice exhibited extended survival compared to age-matched, sham controls. In vitro, the proliferation of primary erythroleukemic cells co-cultured with leukemic-derived splenic adherent cells or their conditioned media was found to be significantly higher than that observed in co-cultures with healthy-derived adherent splenic cells. Cytokine protein arrays revealed that F-MuLV-infected splenocytes secreted elevated levels of IL-6, VEGF-A, MCP-5, sTNFR1, IL-12p70, TNF- and IL-2 over normal splenocytes. Medium supplemented with both VEGF-A and MCP-5 could sustain proliferation of primary erythroleukemic cells in vitro and significant proliferative suppression was observed upon addition of neutralizing antibodies to either of these factors. Furthermore, in vivo administration of a neutralizing antibody to VEGF-A extended survival times of erythroleukemic mice in comparison to controls. These findings suggest that VEGF-A and MCP-5 are potentially pivotal paracrine mediators occurring within the diseased splenic microenvironment capable of promoting disease acceleration and expansion of erythroleukemic blasts. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Usenko, Y.-J. Li, M. Haeri, Y. Li, L. M. Vecchiarelli-Federico, X. Zhao, J. T. Prchal, and Y. Ben-David Enrichment of Sca1+ hematopoietic progenitors in polycythemic mice inhibits leukemogenesis Blood, August 27, 2009; 114(9): 1831 - 1841. [Abstract] [Full Text] [PDF] F. Bock, J. Onderka, C. Rummelt, T. Dietrich, B. Bachmann, F. E. Kruse, U. Schlotzer-Schrehardt, and C. Cursiefen Safety Profile of Topical VEGF Neutralization at the Cornea Invest. Ophthalmol. Vis. Sci., May 1, 2009; 50(5): 2095 - 2102. [Abstract] [Full Text] [PDF] E. Weisberg, R. D. Wright, D. W. McMillin, C. Mitsiades, A. Ray, R. Barrett, S. Adamia, R. Stone, I. Galinsky, A. L. Kung, et al. Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells Mol. Cancer Ther., May 1, 2008; 7(5): 1121 - 1129. [Abstract] [Full Text] [PDF] D. Cervi, Y. Shaked, M. Haeri, T. Usenko, C. R. Lee, J. J. Haigh, A. Nagy, R. S. Kerbel, E. Yefenof, and Y. Ben-David Enhanced natural-killer cell and erythropoietic activities in VEGF-A-overexpressing mice delay F-MuLV-induced erythroleukemia Blood, March 1, 2007; 109(5): 2139 - 2146. [Abstract] [Full Text] [PDF] Y. Shaked, U. Emmenegger, S. Man, D. Cervi, F. Bertolini, Y. Ben-David, and R. S. Kerbel Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity Blood, November 1, 2005; 106(9): 3058 - 3061. [Abstract] [Full Text] [PDF]

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