title: Stromal fibroblast-specific expression of ADAM-9 modulates proliferation and apoptosis in melanoma cells in vitro and in vivo.
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.
authors.affiliation: Department of Dermatology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Anna N
authors.initials: AN
authors.lastname: Abety
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Fox
authors.affiliation: Department of Dermatology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schönefuß
authors.affiliation: Department of Dermatology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Zamek
authors.affiliation: Department of Dermatology, University of Bonn, Bonn, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Landsberg
authors.affiliation: Department of Dermatology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krieg
authors.affiliation: Hospital for Special Surgery at Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Blobel
authors.affiliation: Department of Dermatology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Mauch
authors.affiliation: Department of Dermatology, University Hospital of Cologne, Cologne, Germany. Electronic address: Paola.Zigrino@uni-koeln.de.
authors.forename: Paola
authors.initials: P
authors.lastname: Zigrino
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; C498316:Adam9 protein, mouse