Abstract
Type VII collagen defects cause recessive dystrophic epidermolysis bullosa (RDEB), a blistering skin disorder often accompanied by epidermal cancers. To study the role of collagen VII in these cancers, we examined Ras-driven tumorigenesis in RDEB keratinocytes. Cells devoid of collagen VII did not form tumors in mice, whereas those retaining a specific collagen VII fragment (the amino-terminal noncollagenous domain NC1) were tumorigenic. Forced NC1 expression restored tumorigenicity to collagen VII-null epidermis in a non-cell-autonomous fashion. Fibronectin-like sequences within NC1 (FNC1) promoted tumor cell invasion in a laminin 5-dependent manner and were required for tumorigenesis. Tumor-stroma interactions mediated by collagen VII thus promote neoplasia, and retention of NC1 sequences in a subset of RDEB patients may contribute to their increased susceptibility to squamous cell carcinoma.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adolescent
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Adult
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Animals
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Antibodies / immunology
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Apoptosis
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Carcinoma, Squamous Cell / etiology
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Carcinoma, Squamous Cell / physiopathology*
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Cell Adhesion Molecules / immunology
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Cell Adhesion Molecules / metabolism
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Cell Proliferation
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Cell Transformation, Neoplastic
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Child
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Collagen Type VII / chemistry
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Collagen Type VII / genetics*
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Collagen Type VII / immunology
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Collagen Type VII / physiology*
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Disease Susceptibility
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Epidermolysis Bullosa Dystrophica / complications
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Epidermolysis Bullosa Dystrophica / genetics*
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Epidermolysis Bullosa Dystrophica / metabolism
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Epidermolysis Bullosa Dystrophica / pathology
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Female
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Genes, ras*
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Humans
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism
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Kalinin
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Keratinocytes / metabolism*
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Keratinocytes / pathology
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Male
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Mice
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Mice, SCID
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Middle Aged
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Mutation
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NF-KappaB Inhibitor alpha
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Neoplasm Invasiveness
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Protein Structure, Tertiary
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Skin Neoplasms / etiology
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Skin Neoplasms / pathology
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Skin Neoplasms / physiopathology*
Substances
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Antibodies
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Cell Adhesion Molecules
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Collagen Type VII
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I-kappa B Proteins
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NFKBIA protein, human
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Nfkbia protein, mouse
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NF-KappaB Inhibitor alpha