Type VII collagen is required for Ras-driven human epidermal tumorigenesis

Science. 2005 Mar 18;307(5716):1773-6. doi: 10.1126/science.1106209.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Antibodies / immunology
  • Apoptosis
  • Carcinoma, Squamous Cell / etiology
  • Carcinoma, Squamous Cell / physiopathology*
  • Cell Adhesion Molecules / immunology
  • Cell Adhesion Molecules / metabolism
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Child
  • Collagen Type VII / chemistry
  • Collagen Type VII / genetics*
  • Collagen Type VII / immunology
  • Collagen Type VII / physiology*
  • Disease Susceptibility
  • Epidermolysis Bullosa Dystrophica / complications
  • Epidermolysis Bullosa Dystrophica / genetics*
  • Epidermolysis Bullosa Dystrophica / metabolism
  • Epidermolysis Bullosa Dystrophica / pathology
  • Female
  • Genes, ras*
  • Humans
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / metabolism
  • Kalinin
  • Keratinocytes / metabolism*
  • Keratinocytes / pathology
  • Male
  • Mice
  • Mice, SCID
  • Middle Aged
  • Mutation
  • NF-KappaB Inhibitor alpha
  • Neoplasm Invasiveness
  • Protein Structure, Tertiary
  • Skin Neoplasms / etiology
  • Skin Neoplasms / pathology
  • Skin Neoplasms / physiopathology*

Substances

  • Antibodies
  • Cell Adhesion Molecules
  • Collagen Type VII
  • I-kappa B Proteins
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • NF-KappaB Inhibitor alpha