Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling
Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel les rayons ultra-violets A induisent, dans des fibroblastes dermiques, des modifications épigénétiques favorisant la formation de tumeurs cutanées
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-Jº, 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. º Mesenchymal loss of CSL/Notch results in field cancerization of the skin epithelium º Protumorigenic consequences of CSL loss are linked to c-Jun/c-Fos upregulation º Anti-inflammatory treatment counteracts the field cancerization phenotype º UVA exposure alters DNA methylation to downregulate stromal Notch signaling Mesenchymal loss of a Notch effector or downregulation of Notch signaling by UVA triggers oncogenesis in the overlying epidermis. Inflammation of the stroma precedes the spread of epithelial lesions across a patch of skin, and importantly, inhibiting this inflammatory response counteracts the spread of multifocal skin tumors.
Cell , résumé, 2011