Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling.
Cell, 2012/6/08;149(6):1207-20.
Hu B[1], Castillo E, Harewood L, Ostano P, Reymond A, Dummer R, Raffoul W, Hoetzenecker W, Hofbauer GF, Dotto GP
Affiliations
PMID: 22682244DOI: 10.1016/j.cell.2012.03.048
Impact factor: 66.85
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.
MeSH terms
Animals; Atrophy; Carcinoma, Squamous Cell; Cells, Cultured; Dermatitis; Gene Deletion; Gene Knockdown Techniques; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein; Keratinocytes; Keratosis; Mesoderm; Mice; Muscle Proteins; Receptor, Notch1; Signal Transduction; Skin Neoplasms
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