Abstract
c-FOS promotes preneoplastic epidermal lesions via recruitment of proinflammatory CD4+ T cells.
Major finding: c-FOS promotes preneoplastic epidermal lesions via recruitment of proinflammatory CD4+ T cells.
Mechanism: c-FOS induces MMP10 and S100A7A15, which stimulate infiltration of IL-22–producing T cells.
Impact: Inhibition of these c-FOS targets may suppress T-cell recruitment and human SCC progression.
Chronic inflammation has been implicated in the development of skin squamous cell carcinoma (SCC), but the signals that control this inflammatory response and the mechanisms by which inflammation regulates epidermal tumorigenesis remain unclear. In addition, upregulation of AP-1 transcription factors including c-FOS occurs in human SCC and has been suggested to contribute to SCC development in mice; however, the role of c-FOS in inflammation-associated epidermal proliferation is unknown. Briso and colleagues found that inducible, keratinocyte-specific expression of c-FOS in mice was sufficient to promote epidermal hyperplasia and the formation of preneoplastic skin lesions characterized by increased proliferation and inflammatory cell infiltration. Expression of c-FOS stimulated keratinocyte proliferation and survival via non–cell-autonomous signaling and the selective recruitment and chronic accumulation of interleukin-22–producing CD4+ T cells in the skin. This T-cell infiltration was dependent on c-FOS–mediated transcriptional induction of matrix metallopeptidase 10 (Mmp10) and S100 calcium binding protein A7/A15 (S100a7a15), which encode for secreted proteins known to regulate immune cell recruitment, in keratinocytes; inhibition of MMP activity impaired T-cell recruitment, diminished keratinocyte proliferation, and suppressed the development of preneoplastic lesions. Furthermore, c-FOS cooperated with 7,12-dimethylbenz(a)anthracene (DMBA) to accelerate the formation of papillomas and invasive SCCs, whereas treatment with the anti-inflammatory drug sulindac suppressed SCC growth, further supporting a role for c-FOS–driven T-cell infiltration in SCC pathogenesis. Importantly, elevated c-FOS expression was correlated with increased levels of MMP10 and the human ortholog S100A15 and with CD4+ T-cell infiltration in human SCC samples. These findings identify c-FOS as a critical factor linking proinflammatory responses and the formation of preneoplastic epidermal lesions and suggest that inhibition of the c-FOS targets MMP10 and S100A15 may be therapeutically beneficial in human SCC.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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