[HTML][HTML] Stromal Fibroblast–Specific Expression of ADAM-9 Modulates Proliferation and Apoptosis in Melanoma Cells In Vitro and In Vivo

AN Abety, JW Fox, A Schönefuß, J Zamek… - Journal of investigative …, 2012 - Elsevier
AN Abety, JW Fox, A Schönefuß, J Zamek, J Landsberg, T Krieg, C Blobel, C Mauch…
Journal of investigative dermatology, 2012Elsevier
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 …
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.
Elsevier