Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling.

B Hu, E Castillo, L Harewood, P Ostano, A Reymond, R Dummer, W Raffoul, W Hoetzenecker, GF Hofbauer, GP Dotto

Research output: Contribution to journalArticle

133 Citations (Scopus)

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-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
Original languageEnglish
JournalCell
DOIs
Publication statusPublished - Jun 2012

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