Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-63204
Hu, B; Castillo, E; Harewood, L; Ostano, P; Reymond, A; Dummer, R; Raffoul, W; Hoetzenecker, W; Hofbauer, G F; Dotto, G P (2012). Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling. Cell, 149(6):1207-1220.
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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-Jk, 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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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic|
|Dewey Decimal Classification:||610 Medicine & health|
|Date:||8 June 2012|
|Deposited On:||20 Jun 2012 14:48|
|Last Modified:||01 Jan 2014 03:44|
|Funders:||Swiss National Science Foundation (SNSF; grant 3100A0-122281/1; CRSI33-130576/1)|
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