Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling
Copyright policy )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.
- University of Zurich Switzerland
- Harvard University United States
- University Hospital of Zurich Switzerland
- University of Tübingen Germany
- University Hospital of Lausanne Switzerland
Keratinocytes, Skin Neoplasms, 610, Muscle Proteins, 610 Medicine & health, Dermatitis, Mesoderm, Mice, 1300 General Biochemistry, Genetics and Molecular Biology, Animals, Humans, Receptor, Notch1, Cells, Cultured, Biochemistry, Genetics and Molecular Biology(all), 10177 Dermatology Clinic, Keratosis, 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, name=SDG 3 - Good Health and Well-being, Gene Knockdown Techniques, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Carcinoma, Squamous Cell, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, Atrophy, Gene Deletion, Signal Transduction
Keratinocytes, Skin Neoplasms, 610, Muscle Proteins, 610 Medicine & health, Dermatitis, Mesoderm, Mice, 1300 General Biochemistry, Genetics and Molecular Biology, Animals, Humans, Receptor, Notch1, Cells, Cultured, Biochemistry, Genetics and Molecular Biology(all), 10177 Dermatology Clinic, Keratosis, 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, name=SDG 3 - Good Health and Well-being, Gene Knockdown Techniques, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Carcinoma, Squamous Cell, /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being, Atrophy, Gene Deletion, Signal Transduction
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