Direct and tumor microenvironment mediated influences of 5′‐deoxy‐5′‐(methylthio)adenosine on tumor progression of malignant melanoma |
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| Authors: | Axel P Stevens Barbara Spangler Susanne Wallner Marina Kreutz Katja Dettmer Peter J Oefner Anja K Bosserhoff |
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| Institution: | 1. Institute of Functional Genomics, University of Regensburg Medical School, Josef‐Engert‐Str. 9, D‐93053 Regensburg, Germany;2. Institute of Pathology, University of Regensburg Medical School, Franz‐Josef‐Strauss‐Allee 11, D‐93053 Regensburg, Germany;3. Department of Hematology and Oncology, University of Regensburg Medical School, Franz‐Josef‐Strauss‐Allee 11, D‐93053 Regensburg, Germany |
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| Abstract: | Recent studies have shown that a loss of methylthioadenosine phosphorylase (MTAP) gene expression exerts a tumor‐promoting effect, including induction of invasiveness, enhanced cell proliferation, and resistance against cytokines. To date, the molecular mechanisms underlying these effects remain unknown. Since the loss of MTAP expression resulted in induced secretion of 5′‐deoxy‐5′‐(methylthio)adenosine (MTA), we hypothesized that MTA might modulate the observed effects. We first determined MTA levels produced by tumor cells in vitro and in situ by means of stable isotope dilution liquid chromatography tandem mass spectrometry. Subsequently, we revealed induction of matrix metalloproteinase (MMP) and growth factor gene expression in melanoma cells accompanied by enhanced invasion and vasculogenic mimicry. In addition, MTA induced the secretion of basis fibroblast growth factor (bFGF) and MMP3 from fibroblasts and the upregulation of activator protein‐1 (AP‐1) activity in melanoma cells and fibroblasts. In summary, we demonstrated a tumor‐supporting role of MTA. J. Cell. Biochem. 106: 210–219, 2009. © 2008 Wiley‐Liss, Inc. |
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| Keywords: | malignant melanoma tumor microenvironment methylthioadenosine |
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