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

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Serval ID
serval:BIB_C13437B7972C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling.
Journal
Cell
Author(s)
Hu B., Castillo E., Harewood L., Ostano P., Reymond A., Dummer R., Raffoul W., Hoetzenecker W., Hofbauer G.F., Dotto G.P.
ISSN
1097-4172 (Electronic)
ISSN-L
0092-8674
Publication state
Published
Issued date
2012
Peer-reviewed
Oui
Volume
149
Number
6
Pages
1207-1220
Language
english
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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
05/07/2012 18:04
Last modification date
20/08/2019 15:35
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