Inactivation of Rb in stromal fibroblasts promotes epithelial cell invasion

Adam Pickard, Ann-Christin Cichon, Anna Barry, Declan Kieran, Daksha Patel, Peter Hamilton, Manuel Salto-Tellez, Jacqueline James, Dennis J McCance

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Stromal-derived growth factors are required for normal epithelial growth but are also implicated in tumour progression. We have observed inactivation of the retinoblastoma protein (Rb), through phosphorylation, in cancer-associated fibroblasts in oro-pharyngeal cancer specimens. Rb is well known for its cell-autonomous effects on cancer initiation and progression; however, cell non-autonomous functions of Rb are not well described. We have identified a cell non-autonomous role of Rb, using three-dimensional cultures, where depletion of Rb in stromal fibroblasts enhances invasive potential of transformed epithelia. In part, this is mediated by upregulation of keratinocyte growth factor (KGF), which is produced by the depleted fibroblasts. KGF drives invasion of epithelial cells through induction of MMP1 expression in an AKT- and Ets2-dependent manner. Our data identify that stromal fibroblasts can alter the invasive behaviour of the epithelium, and we show that altered expression of KGF can mediate these functions. © European Molecular Biology Organization.

Original languageEnglish
Pages (from-to)3092-3103
Number of pages12
JournalThe EMBO Journal
Volume31
Issue number14
DOIs
Publication statusPublished - 18 Jul 2012

Keywords

  • invasion
  • keratinocyte growth factor
  • MMP1
  • retinoblastoma
  • stroma

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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