Abstract

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-Jk, 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.