Cell
Volume 149, Issue 6, 8 June 2012, Pages 1207-1220
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Article
Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling

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Summary

It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-Jκ, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through upregulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix-remodeling enzymes. In human skin samples, stromal fields adjacent to multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer.

Highlights

► Mesenchymal loss of CSL/Notch results in field cancerization of the skin epithelium ► Protumorigenic consequences of CSL loss are linked to c-Jun/c-Fos upregulation ► Anti-inflammatory treatment counteracts the field cancerization phenotype ► UVA exposure alters DNA methylation to downregulate stromal Notch signaling

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