UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins–TGF-β1–FAP-α

Abstract

Background: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.Methods: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.Results: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.Conclusions: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.

Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics

“…al. noted that extended in vitro culture of melanocytes caused both loss of FAP expression and acquisition of a senescent phenotype( 30 ); our lab has had similar results with primary fibroblasts, which rapidly down-regulated FAP expression in monolayer culture on plastic (unpublished data). These results could indicate that FAP is highly sensitive to substratum mechanics.…”

“…This result is consistent with past reports of FAP on macrophages in human breast cancer( 29 ). In reconstructed skin cultures consisting of layered collagen, fibroblasts, melanocytes, and keratinocytes, FAP expression could be induced in melanocytes but not in keratinocytes( 30 ).…”

“…LPS signaling through TLR4 induced TGFβ expression by primary fibroblasts, which corresponded to high FAP expression( 67 ). UV radiation induced FAP expression by up-regulating cathepsins which in turn induce TGFβ( 30 ). hTERT induced both cathepsin D and EGR-1, resulting in increased FAP( 68 ).…”

“…In support of this hypothesis, induction of FAP expression in fibroblasts did not always correlate to high levels of FAP shed into the supernatant( 25 ). Up-regulation of FAP expression in response to various stimuli can be transient, and certain culture methods caused loss of FAP expression from previously expressing cells( 26 , 30 ), indicating that FAP was undergoing turnover, though, again, the mechanisms controlling this phenomenon are unknown. Using western blotting, various groups observed protein bands which react with anti-FAP antibodies and yet have a smaller molecular mass than full length monomers; whether these are non-specific artifacts or indicate the presence of proteolytic fragments of FAP is unclear( 19 , 78 ).…”

Trajectories of Nevus Development From Age 3 to 16 Years in the Colorado Kids Sun Care Program Cohort

“…46 Exposure to UV light induces expression of growth factors that affect melanocyte proliferation. 47 These same growth factors may be expressed at higher levels in childhood and adolescence than at older ages.…”