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Stromal fibroblast-specific expression of ADAM-9 modulates proliferation and apoptosis in melanoma cells in vitro and in vivo.

Authors
  • Abety, Anna N1
  • Fox, Jay W2
  • Schönefuß, Alexander1
  • Zamek, Jan1
  • Landsberg, Jenny3
  • Krieg, Thomas1
  • Blobel, Carl4
  • Mauch, Cornelia1
  • Zigrino, Paola5
  • 1 Department of Dermatology, University Hospital of Cologne, Cologne, Germany. , (Germany)
  • 2 Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
  • 3 Department of Dermatology, University of Bonn, Bonn, Germany. , (Germany)
  • 4 Hospital for Special Surgery at Weill Medical College of Cornell University, New York, New York, USA.
  • 5 Department of Dermatology, University Hospital of Cologne, Cologne, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
Journal of Investigative Dermatology
Publisher
Elsevier
Publication Date
Oct 01, 2012
Volume
132
Issue
10
Pages
2451–2458
Identifiers
DOI: 10.1038/jid.2012.153
PMID: 22622419
Source
Medline
License
Unknown

Abstract

ADAMs are members of the zinc metalloproteinase superfamily characterized by the presence of disintegrin and metalloprotease domains. In human melanoma, ADAM-9 is expressed in focalized areas of the tumor-stroma border in both melanoma and stromal cells. However, the role of ADAM-9 in melanoma progression remains elusive. To analyze the role of stromal-derived ADAM-9 for the growth and survival of melanoma cells, we have used in vitro coculture systems of melanoma cells and ADAM-9(-/-) fibroblasts. Coculture of melanoma cells in the presence of ADAM-9(-/-) fibroblasts led to increased melanoma cell proliferation and reduced apoptosis as compared with control cocultures. We identified TIMP-1 and sTNFRI as the two relevant factors expressed in increased amounts in culture supernatants from ADAM-9(-/-) fibroblasts. TIMP-1 was associated with induced melanoma cell proliferation, whereas soluble TNFR1 mediated the reduced cellular apoptosis in vitro. In vivo, injection of murine melanoma cells into the flank of ADAM-9(-/-) animals resulted in the development of significantly larger tumors than in wild-type animals as a result of increased proliferation and decreased apoptosis of melanoma cells. Taken together, stromal expression of ADAM-9 during melanoma development modulates the expression of TIMP-1 and sTNFR1, which in turn affect tumor cell proliferation and apoptosis.

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