title: Ultraviolet exposure of melanoma cells induces fibroblast activation protein-α in fibroblasts: Implications for melanoma invasion.
abstract: Fibroblast activation protein-α (FAP-α) promotes tumor growth and cell invasiveness through extracellular matrix degradation. How ultraviolet radiation (UVR), the major risk factor for malignant melanoma, influences the expression of FAP-α is unknown. We examined the effect of UVR on FAP-α expression in melanocytes, keratinocytes and fibroblasts from the skin and in melanoma cells. UVR induces upregulation of FAP-α in fibroblasts, melanocytes and primary melanoma cells (PM) whereas keratinocytes and metastatic melanoma cells remained FAP-α negative. UVA and UVB stimulated FAP-α-driven migration and invasion in fibroblasts, melanocytes and PM. In co-culture systems UVR of melanocytes, PM and cells from regional metastases upregulated FAP-α in fibroblasts but only supernatants from non-irradiated PM were able to induce FAP-α in fibroblasts. Further, UV-radiated melanocytes and PM significantly increased FAP-α expression in fibroblasts through secretory crosstalk via Wnt5a, PDGF-BB and TGF-β1. Moreover, UV radiated melanocytes and PM increased collagen I invasion and migration of fibroblasts. The FAP-α/DPPIV inhibitor Gly-ProP(OPh)2 significantly decreased this response implicating FAP-α/DPPIV as an important protein complex in cell migration and invasion. These experiments suggest a functional association between UVR and FAP-α expression in fibroblasts, melanocytes and melanoma cells implicating that UVR of malignant melanoma converts fibroblasts into FAP-α expressing and ECM degrading fibroblasts thus facilitating invasion and migration. The secretory crosstalk between melanoma and tumor surrounding fibroblasts is mediated via PDGF-BB, TGF-β1 and Wnt5a and these factors should be evaluated as targets to reduce FAP-α activity and prevent early melanoma dissemination.
authors.affiliation: Division of Dermatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Wäster
authors.forename: Inger
authors.initials: I
authors.lastname: Rosdahl
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Gilmore
authors.forename: Oliver
authors.initials: O
authors.lastname: Seifert
mesh_terms: D000077214:Becaplermin; D002460:Cell Line; D002465:Cell Movement / Q000528:radiation effects; D010450:Endopeptidases; D005347:Fibroblasts / Q000378:metabolism* / Q000528:radiation effects*; D018093:Gelatinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D008544:Melanocytes / Q000378:metabolism / Q000528:radiation effects; D008545:Melanoma / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D012697:Serine Endopeptidases / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000077214:Becaplermin; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D020574:Proto-Oncogene Proteins c-sis; D012697:Serine Endopeptidases; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D000099167:Fibroblast Activation Protein Alpha; C085389:WNT5A protein, human