Journal
CELL
Volume 149, Issue 6, Pages 1207-1220Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.03.048
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Funding
- Swiss National Science Foundation (SNSF) [3100A0-122281/1, CRSI33-130576/1]
- Oncosuisse [02361-02-2009]
- European Union [LSHB-CT-2005-019067]
- National Institutes of Health [AR39190, AR054856]
- Gottfried und Julia Bangerter Ryner Stiftung
- European Commission [037627]
- Swiss National Science Foundation (SNF) [CRSI33_130576] Funding Source: Swiss National Science Foundation (SNF)
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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-J(k), 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.
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