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Blood, 1 March 2006, Vol. 107, No. 5, pp. 2013-2021. Prepublished online as a Blood First Edition Paper on November 8, 2005; DOI 10.1182/blood-2005-05-1795. This Article Full Text (PDF) All Versions of this Article: 2005-05-1795v1 107/5/2013    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 Gottfried, E. Articles by Kreutz, M. Search for Related Content PubMed PubMed Citation Articles by Gottfried, E. Articles by Kreutz, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 3, 2005 Accepted October 18, 2005 Tumor-derived lactic acid modulates dendritic cell activation and antigen expression Eva Gottfried, Leoni A Kunz-Schughart, Stephanie Ebner, Wolfgang Mueller-Klieser, Sabine Hoves, Reinhard Andreesen, Andreas Mackensen, and Marina Kreutz* Hematology and Oncology, University of Regensburg, Regensburg, Germany Institute of Pathology, University of Regensburg, Regensburg, Germany Institute of Physiology and Pathophysiology, University of Mainz, Mainz, Germany * Corresponding author; email: marina.kreutz{at}klinik.uni-regensburg.de. The tumor milieu can influence dendritic cell (DC) differentiation. We analyzed DC differentiation in a 3-dimensional tumor model and propose a new mechanism of DC modulation by the tumor environment. Monocytes were cultured in the presence of IL-4 and GM-CSF within multicellular tumor spheroids (MCTS) generated from different tumor cell lines. Monocytes invaded the MCTS and differentiated into tumor-associated dendritic cells (TADC). The antigen expression was altered on TADC independent of the culture conditions (immature/mature DC, langerhans cells) and IL-12 secretion was reduced. Supernatants of MCTS could partially transfer the suppressive effect. Conditioned media from urothelial carcinoma cell lines contained high levels of M-CSF and IL-6, both cytokines known to modulate DC differentiation. In contrast, melanoma and prostate carcinoma MCTS co-cultures produced little M-CSF and IL-6, but high levels of lactic acid. Indeed, addition of lactic acid during DC differentiation in vitro induced a phenotype comparable to TADC generated within melanoma and prostate carcinoma MCTS. Blocking of lactic acid production in melanoma MCTS co-cultures reverted the TADC phenotype back to normal. We therefore conclude that tumor-derived lactic acid is an important factor modulating the DC phenotype in the tumor environment which may critically contribute to tumor escape mechanisms. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Shime, M. Yabu, T. Akazawa, K. Kodama, M. Matsumoto, T. Seya, and N. Inoue Tumor-Secreted Lactic Acid Promotes IL-23/IL-17 Proinflammatory Pathway J. Immunol., June 1, 2008; 180(11): 7175 - 7183. [Abstract] [Full Text] [PDF] K. Fischer, P. Hoffmann, S. Voelkl, N. Meidenbauer, J. Ammer, M. Edinger, E. Gottfried, S. Schwarz, G. Rothe, S. Hoves, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells Blood, May 1, 2007; 109(9): 3812 - 3819. [Abstract] [Full Text] [PDF]

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