Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling.
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.
Department of Biochemistry, University of Lausanne, Switzerland.
Bing
B
Hu
Einar
E
Castillo
Louise
L
Harewood
Paola
P
Ostano
Alexandre
A
Reymond
Reinhard
R
Dummer
Wassim
W
Raffoul
Wolfram
W
Hoetzenecker
Günther F L
GF
Hofbauer
G Paolo
GP
Dotto
D000818:Animals; D001284:Atrophy / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003872:Dermatitis / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000473:pathology; D007642:Keratosis / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009124:Muscle Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C499035:Smpx protein, mouse