serval:BIB_C13437B7972C
Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling.
10.1016/j.cell.2012.03.048
000305119600007
22682244
Hu
B.
author
Castillo
E.
author
Harewood
L.
author
Ostano
P.
author
Reymond
A.
author
Dummer
R.
author
Raffoul
W.
author
Hoetzenecker
W.
author
Hofbauer
G.F.
author
Dotto
G.P.
author
article
2012
Cell
1097-4172
0092-8674
journal
149
6
1207-1220
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.
Animals
Atrophy/metabolism
Atrophy/pathology
Carcinoma, Squamous Cell/metabolism
Carcinoma, Squamous Cell/pathology
Cells, Cultured
Dermatitis/metabolism
Dermatitis/pathology
Gene Deletion
Gene Knockdown Techniques
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics
Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism
Keratinocytes/pathology
Keratosis/metabolism
Keratosis/pathology
Mesoderm/metabolism
Mesoderm/pathology
Mice
Muscle Proteins/genetics
Muscle Proteins/metabolism
Receptor, Notch1/metabolism
Signal Transduction
Skin Neoplasms/metabolism
Skin Neoplasms/pathology
eng
60_published
true
peer-reviewed
University of Lausanne
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