Ultraviolet exposure of melanoma cells induces fibroblast activation protein-alpha in fibroblasts: Implications for melanoma invasion
2011 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 39, no 1, 193-202 p.Article in journal (Refereed) Published
Fibroblast activation protein-alpha (FAP-alpha) 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-alpha is unknown. We examined the effect of UVR on FAP-alpha expression in melanocytes, keratinocytes and fibroblasts from the skin and in melanoma cells. UVR induces upregulation of FAP-alpha in fibroblasts, melanocytes and primary melanoma cells (PM) whereas keratinocytes and metastatic melanoma cells remained FAP-alpha negative. UVA and UVB stimulated FAP-alpha-driven migration and invasion in fibroblasts, melanocytes and PM. In co-culture systems UVR of melanocytes, PM and cells from regional metastases upregulated FAP-alpha in fibroblasts but only supernatants from non-irradiated PM were able to induce FAP-alpha in fibroblasts. Further, UV-radiated melanocytes and PM significantly increased FAP-alpha expression in fibroblasts through secretory crosstalk via Wnt5a, PDGF-BB and TGF-beta 1. Moreover, UV radiated melanocytes and PM increased collagen I invasion and migration of fibroblasts. The FAP-alpha/DPPIV inhibitor Gly-ProP(OPh)(2) significantly decreased this response implicating FAP-alpha/DPPIV as an important protein complex in cell migration and invasion. These experiments suggest a functional association between UVR and FAP-alpha expression in fibroblasts, melanocytes and melanoma cells implicating that UVR of malignant melanoma converts fibroblasts into FAP-alpha 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-beta 1 and Wnt5a and these factors should be evaluated as targets to reduce FAP-alpha activity and prevent early melanoma dissemination.
Place, publisher, year, edition, pages
Spandidos Publications , 2011. Vol. 39, no 1, 193-202 p.
FAP-alpha; UV irradiation; melanoma; fibroblast; invasion
National CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-69844DOI: 10.3892/ijo.2011.1002ISI: 000291504900022OAI: oai:DiVA.org:liu-69844DiVA: diva2:433452