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Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling


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.

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-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.

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-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.

Citations

51 citations in Web of Science®
64 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:8 June 2012
Deposited On:20 Jun 2012 14:48
Last Modified:05 Apr 2016 15:52
Publisher:Elsevier
ISSN:0092-8674
Funders:Swiss National Science Foundation (SNSF; grant 3100A0-122281/1; CRSI33-130576/1)
Publisher DOI:https://doi.org/10.1016/j.cell.2012.03.048
PubMed ID:22682244

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