Cell; co-auth.: group Reymond

Cell. 2012 Jun 8;149(6):1207-20.

Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling.

Hu BCastillo EHarewood LOstano PReymond ADummer RRaffoul WHoetzenecker WHofbauer GF,Dotto GP.


Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland.


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.