Ultraviolet radiation (UVR) is the major risk factor for development of malignant melanoma.,Fibroblast activation protein (FAP)-α is a serine protease expressed on the surface of activated fibroblasts, promoting tumour invasion through extracellular matrix (ECM) degradation.,The signalling mechanism behind the upregulation of FAP-α is not yet completely revealed.,Expression of FAP-α was analysed after UVR exposure in in vitro co-culture systems, gene expression arrays and artificial skin constructs.,Cell migration and invasion was studied in relation to cathepsin activity and secretion of transforming growth factor (TGF)-β1.,Fibroblast activation protein-α expression was induced by UVR in melanocytes of human skin.,The FAP-α expression was regulated by UVR-induced release of TGF-β1 and cathepsin inhibitors prevented such secretion.,In melanoma cell culture models and in a xenograft tumour model of zebrafish embryos, FAP-α mediated ECM degradation and facilitated tumour cell dissemination.,Our results provide evidence for a sequential reaction axis from UVR via cathepsins, TGF-β1 and FAP-α expression, promoting cancer cell dissemination and melanoma metastatic spread.
Nodular melanoma is one of the most life threatening tumors with still poor therapeutic outcome.,Similarly to other tumors, permissive microenvironment is essential for melanoma progression.,Features of this microenvironment are arising from molecular crosstalk between the melanoma cells (MC) and the surrounding cell populations in the context of skin tissue.,Here, we study the effect of melanoma cells on human primary keratinocytes (HPK).,Presence of MC is as an important modulator of the tumor microenvironment and we compare it to the effect of nonmalignant lowly differentiated cells also originating from neural crest (NCSC).,Comparative morphometrical and immunohistochemical analysis of epidermis surrounding nodular melanoma (n = 100) was performed.,Data were compared to results of transcriptome profiling of in vitro models, in which HPK were co-cultured with MC, normal human melanocytes, and NCSC, respectively.,Differentially expressed candidate genes were verified by RT-qPCR.,Biological activity of candidate proteins was assessed on cultured HPK.,Epidermis surrounding nodular melanoma exhibits hyperplastic features in 90% of cases.,This hyperplastic region exhibits aberrant suprabasal expression of keratin 14 accompanied by loss of keratin 10.,We observe that MC and NCSC are able to increase expression of keratins 8, 14, 19, and vimentin in the co-cultured HPK.,This in vitro finding partially correlates with pseudoepitheliomatous hyperplasia observed in melanoma biopsies.,We provide evidence of FGF-2, CXCL-1, IL-8, and VEGF-A participation in the activity of melanoma cells on keratinocytes.,We conclude that the MC are able to influence locally the differentiation pattern of keratinocytes in vivo as well as in vitro.,This interaction further highlights the role of intercellular interactions in melanoma.,The reciprocal role of activated keratinocytes on biology of melanoma cells shall be verified in the future.,The online version of this article (doi:10.1186/1476-4598-14-1) contains supplementary material, which is available to authorized users.